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Background Sasanlimab is a monoclonal antibody that binds to the programmed cell death receptor 1 (PD-1). Anti-PD-1 monoclonal antibodies have improved patient clinical outcomes; however, not all treated patients derive clinical benefit. Further insights on potential biomarkers beyond PD-L1 expression levels would help to identify the patients most likely to respond to treatment. Objective This study evaluated tumor biopsies from patients treated with intravenous or subcutaneous sasanlimab to identify biomarkers of response and characterize pharmacodynamic activity. Methods Anti-PD-1/PD-ligand 1 (PD-L1)-naive patients with advanced solid tumors received sasanlimab intravenously at 1, 3, or 10 mg/kg every 3 weeks (n = 23) or subcutaneously at 300 mg every 4 weeks (n = 15). Best tumor percentage change from baseline was determined by RECIST. Whole-exome DNA and RNA sequencing were performed in tumor samples collected from treated patients at protocol-defined timepoints. PD-L1 and CD8 protein expression were evaluated in tumor biopsies by immunohistochemistry. Associations with response were assessed by linear regression analysis. Results Baseline tumor mutational burden (TMB), as well as PD-L1 and CD8 expression, were significantly associated with response to sasanlimab across the multiple dose levels, routes of administration, and range of tumor types evaluated. TMB is an independent biomarker from the various tumor inflammatory genes and signatures evaluated. Gene set enrichment analysis showed that higher baseline expression levels of genes related to the interferon-γ and PD-1 signaling pathways and the cell cycle were significantly associated with response to sasanlimab across tumor types. No differences were observed between routes of administration with regard to response to sasanlimab for the biomarkers of interest (TMB, PD-L1, CD8, and interferon-γ signature). Evaluation of pharmacodynamic changes showed increased tumor expression of genes enriched in adaptive immune response pathways. Conclusions Our findings indicate an active, immunomodulatory mechanism for the anti-PD-1 antibody sasanlimab across different tumor types and routes of administration. Trial Registration ClinicalTrials.gov identifier NCT02573259; registered October 2015. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00833-2.

Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody–drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective response rate by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1) was 39% [95% confidence interval (CI), 26.0–52.4], and median progression-free survival was 8.2 (95% CI, 4.4–8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade ≥3 treatment-emergent adverse events were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI–resistant cancers independent of resistance mechanisms, providing an approach to treat a broad range of drug-resistant cancers. Significance: In metastatic EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy, treatment approaches include genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism. See related commentary by Lim et al., p. 16. This article is highlighted in the In This Issue feature, p. 1

Introduction This open-label, phase 1–2 study evaluated the safety and efficacy of rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate targeting DLL3, plus immune checkpoint inhibitors nivolumab plus or minus ipilimumab in previously treated extensive-stage SCLC (ES SCLC). Methods Patients with histologically or cytologically confirmed, previously treated (two or more lines of therapy) ES SCLC were enrolled into two cohorts. Cohort 1 received 0.3 mg/kg Rova-T (once every 6 wk for two cycles) plus 360 mg nivolumab (two 3-wk cycles beginning on week 4). Cohort 2 received the same dosage of Rova-T as cohort 1 plus 1 mg/kg nivolumab (four 3-wk cycles) and 1 mg/kg ipilimumab (beginning week 4). Both cohorts received 480 mg nivolumab every 4 weeks starting at week 10. Key objectives were to evaluate safety and tolerability and efficacy (per Response Evaluation Criteria in Solid Tumors version 1.1). The response-related results are based on centrally read data. Results A total of 42 patients received therapy: cohort 1, n = 30; cohort 2, n = 12. Overall, 43% received two or more previous lines of therapy. All patients experienced one or more treatment-emergent adverse event (TEAE); 41 patients reported AEs considered related to the study drug by the investigator. The most frequent TEAE was pleural effusion (n = 20, 48%); most common grade greater than or equal to 3 was anemia (n = 9, 21%). Three grade 5 TEAEs considered related to the study drug were reported (cohort 1): pneumonitis (n = 2), acute kidney injury (n = 1). The objective response rate was 30% (12 of 40): cohort 1, 27.6% (8 of 29); cohort 2, 36.4% (4 of 11); all partial responses. Conclusions Despite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab plus or minus ipilimumab was not well tolerated at the dose levels and administration schedules evaluated.

Purpose: Although PD-(L)1 inhibitors have shown efficacy in advanced/metastatic non–small cell lung cancer (NSCLC), many patients do not respond to this treatment and more effective combinations with acceptable toxicities are needed. To assess the potential benefit of combining localized innate immune stimulation with checkpoint blockade, the TLR9 agonist DV281 was combined with nivolumab in a phase Ib study. Patients and Methods: Patients after one or two prior lines of systemic therapy were enrolled in a dose-escalation study with a 3+3 design. DV281 was administered via inhalation in five dose cohorts at 1 to 25 mg; nivolumab 240 mg was administered intravenously every 2 weeks. Safety, tolerability, pharmacodynamics, and response to treatment were assessed. Results: Twenty-six patients with advanced NSCLC enrolled. Baseline programmed death ligand 1 (PD-L1) expression was present in 16 patients (61.5%); 21 (80.7%) had received previous anti–PD-1/PD-L1. Thirteen patients (50%) had stable disease, nine (34.6%) had progressive disease, and four (15.4%) were not evaluable. Median duration of disease control was 124 days. Adverse events were seen in 16 patients (61.5%), mostly grade 1/2 chills, fatigue, flu-like symptoms, diarrhea, and rash; there was only one grade 3 adverse event (dyspnea). Pharmacodynamic assessment, measured by IFN- inducible gene expression, showed target engagement in all dose cohorts. Systemic pharmacodynamic responses plateaued in the 2 highest dose cohorts. Conclusions: DV281 with nivolumab was well tolerated with target engagement observed at every dose. Pharmacodynamic advantages at doses above 10 mg were unclear. The long duration of disease control in 50% of patients suggests clinically relevant activity in this population of heavily pretreated patients.

Purpose: PROCLAIM-CX-2029 is a phase I first-in-human study of CX-2029, a Probody–drug conjugate targeting CD71 (transferrin receptor 1) in adults with advanced solid tumors. Although the transferrin receptor is highly expressed across multiple tumor types, it has not been considered a target for antibody–drug conjugates (ADCs) due to its broad expression on normal cells. CX-2029 is a masked form of a proprietary anti-CD71 antibody conjugated to monomethyl auristatin E, designed to be unmasked in the tumor microenvironment by tumor-associated proteases, therefore limiting off-tumor toxicity and creating a therapeutic window for this previously undruggable target. Patients and Methods: This was a dose-escalation, multicenter trial to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of CX-2029. The primary endpoint was to determine the maximum tolerated dose (MTD) and cycle 1 dose-limiting toxicity (DLT). CX-2029 was administered i.v. every 3 weeks. Results: Forty-five patients were enrolled in eight dose levels. No DLTs were reported in the dose escalation through 4 mg/kg. At 5 mg/kg, there were two DLTs (febrile neutropenia and pancytopenia). Following expansion of the 4 mg/kg dose to six patients, two additional DLTs were observed (infusion-related reaction and neutropenia/anemia). Both the 4 and 5 mg/kg doses were declared above the maximum tolerated dose. The recommended phase II dose is 3 mg/kg. The most common dose-dependent hematologic toxicities were anemia and neutropenia. Confirmed partial responses were observed in three patients, all with squamous histologies. Conclusions: The Probody therapeutic platform enables targeting CD71, a previously undruggable ADC target, at tolerable doses associated with clinical activity. See related commentary by Oberoi and Garralda, p. 4459

Neoantigens are critical targets of antitumor T-cell responses. The ATLAS bioassay was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in Escherichia coli, pulsing autologous dendritic cells in an ordered array, and testing the patient's T cells for recognition in an overnight assay. Profiling of T cells from patients with lung cancer revealed both stimulatory and inhibitory responses to individual neoantigens. In the murine B16F10 melanoma model, therapeutic immunization with ATLAS-identified stimulatory neoantigens protected animals, whereas immunization with peptides associated with inhibitory ATLAS responses resulted in accelerated tumor growth and abolished efficacy of an otherwise protective vaccine. A planned interim analysis of a clinical study testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified stimulatory neoantigens showed that it is well tolerated. In an adjuvant setting, immunized patients generated both CD4+ and CD8+ T-cell responses, with immune responses to 99% of the vaccinated peptide antigens. Significance: Predicting neoantigens in silico has progressed, but empirical testing shows that T-cell responses are more nuanced than straightforward MHC antigen recognition. The ATLAS bioassay screens tumor mutations to uncover preexisting, patient-relevant neoantigen T-cell responses and reveals a new class of putatively deleterious responses that could affect cancer immunotherapy design. This article is highlighted in the In This Issue feature, p. 521

Purpose: The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%–2% of non–small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating RET gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood. Patients and Methods: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have MET amplification associated with resistance to selpercatinib. We validated MET activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP). Results: MET amplification was identified in posttreatment biopsies in 4 patients with RET fusion–positive NSCLC treated with selpercatinib. In at least one case, MET amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in RET fusion–positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months. Conclusions: Through the use of SPPs, we were able to offer combination therapy targeting MET-amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.

517 Background: ADP-A2M4CD8 is a specific peptide enhanced affinity receptor mixed CD4+ and CD8+ T-cell therapy targeting the cancer testis antigen MAGE-A4 and modified with addition of a CD8α co-receptor designed to provide additional functionality to CD4+ T-cells. ADP-A2M4CD8 has demonstrated an acceptable benefit to risk profile in the Phase 1 SURPASS trial (NCT04044859) in HLA A*02–eligible patients with unresectable or metastatic tumors positive for MAGE-A4.1 Here we report updated clinical outcomes in patients with urothelial cancer (UC). Methods: SURPASS is a first-in-human trial consisting of a modified 3+3 dose-escalation design and an expansion cohort. Autologous T-cells are obtained by leukapheresis, transduced with a self-inactivating lentiviral vector expressing the MAGE-A4-specific T-cell receptor and the CD8α co-receptor, and infused back to the patients as ADP-A2M4CD8 following lymphodepleting chemotherapy. Primary and secondary objectives are safety and anti-tumor activity, respectively. Results: At ESMO 2022, we reported promising results from SURPASS in several tumour types.2 In the 43 evaluable patients, the overall response rate was 28%, including 1 complete response and 11 partial responses (PR), and an additional 2 unconfirmed PRs awaiting confirmatory scans (as of August 1, 2022). Data from the 7 evaluable patients in the UC subset (updated September 6, 2022) showed that 3 (43%) had a best overall response of PR, and 1 (14%) had an unconfirmed PR. Disease control rate was 100% (3 PR + 1 unconfirmed PR + 3 stable disease). Adverse events have been consistent with those typically observed with lymphodepletion chemotherapy or cellular therapy. This trial is ongoing; data from additional patients with UC treated by January 2023 and updated translational data will be presented. Conclusions: ADP-A2M4CD8 continues to show an acceptable benefit to risk profile in multiple MAGE-A4+ unresectable or metastatic tumors, and preliminary encouraging evidence of efficacy in UC. An additional treatment cohort has been included in the updated trial protocol to evaluate ADP-A2M4CD8 combined with nivolumab. 1. Hong DS, et al. E-poster 540P: ESMO 2021; Virtual. 2. Hong DS, et al. Ann Oncol 33(suppl_7); S331-S355, Abstract 735MO. ESMO 2022. Clinical trial information: NCT04044859 .

349 Background: ADP-A2M4CD8 is a specific peptide enhanced affinity receptor mixed CD4+ and CD8+ T-cell therapy targeting the cancer testis antigen MAGE-A4 and modified with addition of a CD8α co-receptor designed to provide additional functionality to CD4+ T-cells. ADP-A2M4CD8 has demonstrated a favorable benefit to risk profile in the Phase 1 SURPASS trial (NCT04044859) in HLA A*02–eligible patients (pts) with unresectable or metastatic tumors positive for MAGE-A4 (Hong DS, et al. E-poster 540P: ESMO 2021; Virtual). Here we report updated clinical outcomes in pts with esophageal, esophagogastric junction (EGJ), or gastric cancer. Methods: SURPASS is a first-in-human trial consisting of a modified 3+3 dose-escalation design and an expansion cohort. Autologous T-cells are obtained by leukapheresis, transduced with a self-inactivating lentiviral vector expressing the MAGE-A4-specific T-cell receptor and the CD8α co-receptor, and infused back to the pts as ADP-A2M4CD8 following lymphodepleting chemotherapy. Primary and secondary objectives are safety and anti-tumor activity, respectively. Results: As September 6, 2022, 13 pts (11 male, 2 female) with esophageal (3), EGJ (8), and gastric cancer (2) received ADP-A2M4CD8 (range: 1.02–9.9x109 transduced T-cells). All pts had adenocarcinoma, median age was 55 years (range: 31–71), median MAGE-A4 expression H-score was 245 (range: 160–300), and pts received median of 2 lines of prior therapy (range 1–5). Adverse events (AEs) were consistent with those typically associated with lymphodepleting chemotherapy, cellular therapy, and/or disease. One pt had a Grade 5 (fatal) AE of pancytopenia. Overall response rate per RECIST v1.1 by investigator review was 15% (2 partial response [PR]). Disease control rate was 77% (2 PR+8 stable disease). This trial is ongoing, and additional data will be presented. Conclusions: Results indicate an acceptable benefit to risk profile and encouraging anti-tumor activity of ADP-A2M4CD8. An additional treatment cohort has been included in the updated SURPASS trial protocol to evaluate ADP-A2M4CD8 combined with nivolumab. A Phase 2, open-label trial in advanced esophageal and EGJ cancers has been initiated (SURPASS-2; NCT04752358). Clinical trial information: NCT04044859 .

Introduction Although chemoradiotherapy (CRT) is the standard of care for patients with unresectable stage III non–small-cell lung cancer (LA-NSCLC), most patients relapse. Tecemotide is a MUC1 antigen-specific cancer immunotherapy vaccine. Bevacizumab improves survival in advanced nonsquamous (NS)-NSCLC and has a role in immune modulation. This phase II trial tested the combination of tecemotide and bevacizumab following CRT in patients with LA-NSCLC. Patients and Methods Subjects with stage III NS-NSCLC suitable for CRT received carboplatin/paclitaxel weekly + 66 Gy followed by 2 cycles of consolidation carboplatin/paclitaxel ≤ 4 weeks of completion of CRT (Step 1). Patients with partial response/stable disease after consolidation therapy were registered onto step 2, which was 6 weekly tecemotide injections followed by every 6 weekly injections and bevacizumab every 3 weeks for up to 34 doses. The primary endpoint was to determine the safety of this regimen. Results Seventy patients were enrolled; 68 patients (median age, 63 years; 56% male; 57% stage IIIA) initiated therapy, but only 39 patients completed CRT and consolidation therapy per protocol, primarily owing to disease progression or toxicity. Thirty-three patients (median age, 61 years; 58% male; 61% stage IIIA) were registered to step 2 (tecemotide + bevacizumab). The median number of step 2 cycles received was 11 (range, 2-25). Step 2 worst toxicity included grade 3, N = 9; grade 4, N = 1; and grade 5, N = 1. Grade 5 toxicity in step 2 was esophageal perforation attributed to bevacizumab. Among the treated and eligible patients (n = 32) who were treated on step 2, the median overall survival was 42.7 months (95% confidence interval, 21.7-63.3 months), and the median progression-free survival was 14.9 months (95% confidence interval, 11.0-20.9 months) from step 1 registration. Conclusions This cooperative group trial met its endpoint, demonstrating tolerability of bevacizumab + tecemotide after CRT and consolidation. In this selected group of patients, the median progression-free survival and overall survival are encouraging. Given that consolidation immunotherapy is now a standard of care following CRT in patients with LA-NSCLC, these results support a role for continued investigation of antiangiogenic and immunotherapy combinations in LA-NSCLC.

Objectives This phase 1 study investigated safety/tolerability, pharmacokinetics, and preliminary efficacy of SC-002, a delta-like ligand 3-directed antibody-drug conjugate, in advanced small cell lung cancer and large cell neuroendocrine carcinoma. Materials and methods Eligible patients received SC-002 at 1 of 7 dose levels during the dose-escalation portion of the study. Results Thirty-five enrolled patients received ≥1 dose of SC-002. Twenty-three (66%) patients experienced serious adverse events (AEs), 37% considered related to SC-002. Grade 3/4 AEs occurred in 21 (60%) and 2 (6%) patients; the most common were effusion and hypoalbuminemia. One grade 5 AE occurred in 1 patient. Five (14%) patients achieved a partial response and no patients achieved a complete response. Conclusion SC-002 treatment was associated with systemic toxicity and limited efficacy.

Objectives Efficacy and safety of necitumumab when combined with pembrolizumab was assessed in patients with Stage IV non-small cell lung cancer (NSCLC) of squamous and nonsquamous histology, who had progressed after treatment with a platinum-based doublet. Materials and methods This single-arm, multicenter, phase Ib study had a dose-finding phase, in which escalating doses of necitumumab (600 mg and 800 mg IV) were administered on Day 1 and 8 every 3 weeks (Q3W) in combination with pembrolizumab (200 mg IV) on Day 1 Q3W, and expansion cohorts. Patients were treated until progressive disease (PD), toxicity requiring cessation, protocol noncompliance, or withdrawal of consent. Efficacy was evaluated by overall response rate (ORR). Results In 64 treated patients (32 patients [50 %] were programmed death-ligand 1 [PD-L1] negative), confirmed ORR was 23.4 % (95 % confidence interval [CI] 13.8 %–35.7 %). Two patients (3.1 %) had complete response (CR), 13 patients (20.3 %) had partial response (PR), 26 patients (40.6 %) had stable disease, 17 patients (26.6 %) had PD, and 6 patients (9.4 %) were not evaluable. Regardless of histology or PD-L1 status, median PFS (mPFS) was 4.1 months (95 % CI 2.4–6.9 months) and OS at 6 months was 74.7 % (61.5%–83.9%). Confirmed disease control rate was 64.1 % (95 % CI 51.5–75.7). Patients with programmed death-ligand 1 (PD-L1) ≥1% had numerically improved ORR and median progression-free survival when compared with patients with PD-L1 negative cancer. No dose-limiting toxicities were recorded and the combination of necitumumab 800 mg with pembrolizumab 200 mg was considered tolerable. Conclusion Results suggest modest benefits of second-line necitumumab and pembrolizumab combination therapy in patients with Stage IV NSCLC. Safety profiles were consistent with class effects typical of epidermal growth factor receptor inhibitors and immunotherapies with no additive toxicities.

Purpose: This first-in-human study assessed the safety, tolerability, dose-limiting toxicities (DLT), antitumor activity, and pharmacokinetics of cemiplimab, a monoclonal anti-programmed cell death-1 (PD-1), as monotherapy and in combination with hypofractionated radiotherapy (hfRT) and/or cyclophosphamide (CPA) in patients with advanced solid tumors. Patients and Methods: Patients were enrolled in 1 of 10 dose escalation cohorts and received cemiplimab 1, 3, or 10 mg/kg every 2 weeks intravenously for up to 48 weeks. Depending on the cohort, patients received hfRT and/or low-dose (200 mg/m2) CPA. Safety was evaluated. Antitumor activity was assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Results: Sixty patients were enrolled. The median duration of follow-up was 19.3 weeks (range, 2.3–84.3). There were no DLTs. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (45.0%), nausea (36.7%), and vomiting (25.0%). The most common immune-related adverse events (irAEs) of any grade were arthralgia (10.0%), hypothyroidism (8.3%), and maculopapular rash (8.3%). Cemiplimab pharmacokinetic parameters increased in a close to dose-proportional manner and were similar regardless of combination therapy regimen. Two patients (one with cutaneous squamous cell carcinoma and one with cervical cancer) experienced a complete response; 7 had a partial response. Observed duration of response was ≥12 months in 6 patients. Conclusions: The safety profile of cemiplimab was comparable with other anti–PD-1 agents. Addition of hfRT and/or CPA did not appear to increase grade ≥3 irAEs, suggesting that cemiplimab can be safely administered with hfRT and/or CPA. Cemiplimab exhibited encouraging antitumor activity with 2 complete responses and 7 partial responses observed; responses were also durable.

BackgroundBDB001 is an intravenously administered TLR 7/8 dual agonist immune modulator capable of reprogramming dendritic cells to produce antitumor activities. BDB001 monotherapy has demonstrated favorable tolerability and robust systemic immune activation leading to durable clinical responses in a Phase I trial. Here, we report on the safety and efficacy of BDB001 in combination with atezolizumab in a Phase I dose escalation/expansion trial in advanced solid tumors (NCT04196530).MethodsBDB001-102 is a Phase 1, open label, dose escalation/expansion trial of BDB001 (IV, Q1W) in combination with an anti-PD-L1 antibody, atezolizumab (IV, Q3W), in patients with advanced solid tumors. The primary endpoint was safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics and pharmacodynamic profiling of immune activation.ResultsForty-one subjects with 17 different tumor types were enrolled across 4 dose levels. Fifty-nine percent were female, median age was 67 years (range, 32–80), median number of prior therapies was 3 (range, 0–8), and 63% of tumors had progressed on prior anti-PD-(L)1 therapy. Overall, BDB001 in combination with atezolizumab was well tolerated and 13 (31.7%) subjects did not experience any treatment related adverse events (TRAEs). No dose-limiting toxicities were observed. Common TRAEs were transient Grade 1 or 2 fatigue (31.7%), fever (26.8%) and chills/rigor (26.8%). Only 3 (7.3%) subjects experienced Grade 3 TRAEs of fatigue and nausea. There were no Grade 4 or 5 TRAEs and no new safety concerns. Pharmacodynamic evaluation of plasma cytokine levels showed robust increases in interferon gamma and interferon inducible protein-10 (IP-10) at BDB001 Dose Level 4. IP-10 induction was associated with clinical responses. Preliminary efficacy evaluation of the 19 subjects at Dose Level 4 showed durable and deep clinical responses in 3 (16%) subjects, 2 with urothelial carcinoma and 1 with anti-PD-1 mAb refractory NSCLC. All responders remain on treatment, with a duration of response ranging from 7.1+ to 34.1+ weeks. Ten (53%) subjects had stable disease (DCR 68%), 3 of whom had a reduction in tumor burden and were on treatment for over 18 weeks (up to 56 weeks).ConclusionsIntravenous BDB001 in combination with atezolizumab is well tolerated. Deep and durable clinical responses were observed in PD-1 refractory and naive patients, supported by robust systemic immune activation. BDB001 in combination with atezolizumab is a promising therapeutic option for patients with advanced solid tumors. A phase 2 trial (NCT03915678) of BDB001 in combination with atezolizumab and radiotherapy is currently enrolling patients.Ethics ApprovalThis study was approved by the institutional review boards at the five participating institutions. All subjects signed informed consent before enrolling in the clinical trial.

BackgroundInnate immune activation is a desirable goal in anticancer therapy. Stimulator of Interferon Genes (STING) agonists represent one approach to this goal; to date most studies have utilized intra-tumoral administration. SNX281 is a novel small molecule agonist of human and mammalian STING with favorable pharmacokinetic properties thatto enable systemic intravenous administration. The molecule dimerizes in the binding site of STING to induce activation. In preclinical studies using THP-1 cells or human PBMCs, SNX281 caused both pathway activation and the induction of signature cytokines, IFN-b, TNF-a and IL-6 in a STING dependent manner. Intravenously delivered SNX281 caused complete and durable tumor regression in mice bearing CT26 colon carcinomas with induction of immune memory. Mice that were cured of their primary CT26 tumors were completely resistant to re-challenge. Increased T cell responses were observed against the endogenous CT26 rejection antigen AH1. Maximal tumor control depended on CD8+ T cells, confirming the involvement of an adaptive immune component in SNX281 mediated anti-tumor activity, although some tumor control was observed even in the absence of T cells. In addition, combining STING-dependent T cell priming induced by SNX281 with anti-PD-1 resulted in robust antitumor activity and significant survival benefit in multiple tumor models (CT26, MC38 and B16- F10) that are resistant to checkpoint therapy alone.MethodsThis is a multicenter, open-label, phase I dose-escalation followed by dose expansion study of SNX281 as monotherapy and in combination with pembrolizumab. SNX281 is administered as a 30-minute intravenous infusion QW for 3 weeks followed by Q3W for six cycles. Eligible patients for the dose escalation phase will have, among other criteria, histologically confirmed advanced solid tumors or lymphomas which have failed prior therapy and/or are not eligible for therapies, as well as adequate organ function, life expectancy of at least 12 weeks, and measurable disease. Monotherapy dose escalation accrued initially with single patient cohorts advancing to a 3+3 design. The dose expansion phases of each treatment arm will begin following the determination of an MTD or alternative dose of SNX281 in each respective treatment arm. The single-agent treatment arm of SNX281 is planned to evaluate at least 2 expansion cohorts in ovarian cancer and colorectal carcinoma while the combination treatment arm of SNX281 and pembrolizumab is planned to enroll subjects with advanced cancer who have relapsed on or have become refractory to prior immune checkpoint therapy given in an indicated setting. Clinical Trial Information: NCT04609579Trial RegistrationNCT04609579Ethics ApprovalIRB approval from IntegReview IORG0000689.

BackgroundGEN-009 adjuvanted personalized cancer vaccine contains up to 20 neoantigens selected by ATLAS™, an ex vivo bioassay screening autologous T-cells for immune responses against both neoantigens and Inhibigens™. Inhibigen-specific T-cells suppress immunity, have been shown to accelerate tumor progression in mice, and are excluded from GEN-009. In cohort A, all patients immunized in the adjuvant setting with GEN-009 monotherapy developed immune responses. Ninety-nine percent of selected peptides were immunogenic: ex vivo CD4+ and CD8+ fluorospot responses specific for 51% and 41% of immunized peptides, respectively.1 Six of 8 patients continue without progression with a median follow up >2 years.MethodsGEN-009 was administered to patients with advanced cancer who received standard-of-care (SOC) PD-1 inhibitor as monotherapy or in combination therapy during vaccine manufacturing. Five vaccine doses were administered over 24 weeks in combination with single agent anti-PD-1. Patients who progressed prior to vaccination received salvage therapy followed by GEN-009 in combination. Peripheral T-cell responses were measured by ex vivo and in vitro stimulated fluorospot assays. Circulating tumor (ct) DNA levels were evaluated in a subset of patients pre- and post-GEN-009 administration.Results15 patients received GEN-009 in combination with PD-1 inhibitor; 1 patient received GEN-009 monotherapy. Median number of neoantigens per vaccine was 14 (range 5–18). GEN-009-related adverse events were limited to vaccine injection site reactions, mild myalgias or fatigue. Sequential vaccination with GEN-009 had an additive effect on the magnitude of ex vivo T-cell responses, that persisted in some patients for 12+ months post first vaccine dose. An association between proportion of peptides eliciting significant cytokine responses and RECIST response is apparent. Epitope spread was detected in CD8+ T-cells from CPI-sensitive patients, but not refractory patients. Four patients who responded to PD-1 inhibition followed by disease stabilization then demonstrated further tumor reduction after GEN-009 vaccination. Seven of 9 CPI responsive patients are progression-free 7 to 18 months after first vaccine dose. Three of 7 CPI-refractory patients have experienced unexpected prolonged stable disease, with 2 PR and 1 SD after vaccination lasting up to 10 months. Plasma ctDNA kinetics mirrored RECIST responses in each tested patient; in some responders, all evidence of ctDNA disappeared, including non-targeted antigens.ConclusionsVaccination with GEN-009 alone or in combination with anti-PD-1 was well tolerated. Preliminary data demonstrate induction of robust, durable neoantigen-specific immune responses and epitope spreading in the presence of PD-1 CPI. Broad immunity against tumor specific targets and encouraging patient outcomes support further study.Trial Registration clinicaltrials.gov identifier: NCT03633110ReferencesLam H, et al. An empirical antigen selection method identifies neoantigens that either elicit broad anti-tumor response or drive tumor growth. Cancer Discovery 2021 March;11(3):696–713.Ethics ApprovalThis study was approved by Western Institutional Review Board, approval number 1-1078861-1

Background: This study assessed the checkpoint kinase 1 inhibitor prexasertib in patients with extensive-stage small-cell lung cancer (ED-SCLC). Patients and Methods: This was a parallel-cohort phase II study of 105 mg/m2 prexasertib once every 14 days for patients who progressed after no more than two prior therapies and had platinum-sensitive (Cohort 1) or platinum-resistant/platinum-refractory (Cohort 2) disease. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Exploratory endpoints included biomarker identification and assessment of an alternative regimen (Cohort 3: 40 mg/m2 days 1-3, 14-day cycle). Results: In Cohort 1 (n = 58), ORR was 5.2%; DCR, 31%; median PFS, 1.41 months (95% confidence interval [CI], 1.31-1.64); and median OS, 5.42 months (95% CI, 3.75-8.51). In Cohort 2 (n = 60), ORR was 0%; DCR, 20%; median PFS, 1.36 months (95% CI, 1.25-1.45); and median OS, 3.15 months (95% CI, 2.27-5.52). The most frequent all-grade, related, treatment-emergent adverse events were decreased neutrophil count (Cohort 1, 69.6%; Cohort 2, 73.3%), decreased platelet count (Cohort 1, 51.8%; Cohort 2, 50.0%), decreased white blood cell count (Cohort 1, 28.6%; Cohort 2, 40.0%), and anemia (Cohort 1, 39.3%; Cohort 2, 28.3%). Eleven patients (19.6%) in Cohort 1 and one patient (1.7%) in Cohort 2 experienced grade ?3 febrile neutropenia. Prexasertib pharmacokinetics were consistent with prior studies. Cohort 3 outcomes were similar to those of Cohorts 1 and 2. No actionable biomarkers were identified. Conclusion: Prexasertib did not demonstrate activity to warrant future development as monotherapy in ED-SCLC. © 2021 The Authors Boehringer Ingelheim; Amgen; Bristol-Myers Squibb; Eli Lilly and Company; Pfizer; Astellas Pharma US; AstraZeneca; Merck; Novartis; Roche; AbbVie; University of Michigan; Takeda Pharmaceuticals U.S.A.; Merck Sharp and Dohme; PTC Therapeutics; TG Therapeutics; NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research; Bayer Fund; National Institute for Health Research; European Commission; Daiichi-Sankyo; Oryzon Genomics; Otsuka Pharmaceutical; UCLH Biomedical Research Centre We thank the patients who participated in this trial and the study coordinators, nurses, nurse practitioners, clinical research assistants, and doctors who assisted with the research. The authors also thank Erin Wagner from BioStat Solutions, Inc., for statistical support and Lisa Golden, Rod Decker, and Elizabeth Spoljoric for their input and contributions to the study. MDF is supported by the University College London/University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre and runs early phase studies in the NIHR UCLH Clinical Research Facility supported by the University College London Experimental Cancer Medicine Centre. Eli Lilly and Company contracted with Syneos Health for writing support provided by Andrea D. Humphries, PhD, and editing support provided by Noelle Gasco. L.A. Byers reports receiving research funding and fees as an advisor or consultant from AstraZeneca, GenMab, and Sierra Oncology; research funding from Tolero Pharmaceuticals; and fees as an advisor or consultant from Bristol Myers Squibb, Althia, Merck, Pfizer, PharmaMar, AbbVie, Jazz Pharmaceuticals, Genentech, and Debiopharm Group. A. Navarro reports receiving fees as an advisor or consultant from Pfizer and Boehringer Ingelheim; fees from Roche and AstraZeneca speakers’ bureaus; fees for expert testimony from Oryzon Genomics and MedSIR; and fees or reimbursement for travel, accommodations, or other expenses from Roche, Pfizer, and Boehringer Ingelheim. M. Johnson reports grant funding to her institution from Eli Lilly and Company, Abbvie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, EMD Serono, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Hengrui Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Merck, Mirati Therapeutics, Neovia Onclogy, Novartis, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Regeneron Pharmaceuticals, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, TMUNITY Therapeutics, University of Michigan, and WindMIL; receiving fees for consulting services from Eli Lilly and Company, Abbvie, Amgen, AstraZeneca, Atreca, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Daiichi Sankyo, EMD Serono, Genentech/Roche, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Incyte, Janssen, Loxo Oncology, Merck, Mirati Therapeutics, Novartis, Pfizer, Ribon Therapeutics, Sanofi, WindMIL, Achilles Therapeutics, Bristol Myers Squibb, Eisai, G1 Therapeutics, and Association of Community Cancer Centers; and receiving fees for consulting services performed by her spouse from Astellas and Otsuka Pharmaceuticals. K.H. Dragnev reports funding to the institution for the conduct of the trial from Eli Lilly and Company and support to the institution for conduct of company-sponsored trials from Merck, Roche/Genentech, G1 Therapeutics, Io Therapeutics, and Novartis. S. McNeely reports receiving personal fees and non-financial support from Eli Lilly and Company. A.B. Lin and spouse are both employees and shareholders of Eli Lilly and Company. M. Forster reports receiving educational grants from Merck Sharp & Dohme for the EACH study and the POPPY study, from Boehringer Ingelheim for the DARWIN1 study, and from AstraZeneca for the ORCA2 study, as well as fees for advisory and consultancy work from Achilles, AstraZeneca, Bristol Myers Squibb, Merck, Nanobiotix, Novartis, Pfizer, Pharmamar, Roche, Takeda, Bayer, and Guardant Advisory. The remaining authors have stated that they have no conflicts of interest.

BackgroundOncolytic viruses (OVs) show significant potential for treating tumors alongside immunotherapies.1 VV1 is an OV derived from the innocuous vesicular stomatitis virus (VSV). VV1 has been engineered to expresses human interferon (IFN) β and thyroidal sodium iodide symporter (NIS).2 VV1-infected cells produce IFNβ, which protects non-cancer cells from VV1 and allows VV1 to spread more efficiently in cancerous tissue.3 4 NIS expression on cells imports 99mTc pertechnetate, which facilitates in vivo imaging of virus infection.2 This three-part, phase 1–2 study was designed to determine the safety and tolerability of VV1 in patients with advanced unresectable and metastatic solid tumors. Here we report on the second part of this study: selection of recommended phase 2 regimen (RP2D), comprising further assessment of both duration and dose.MethodsPatients (n=29) were enrolled to receive a single IV infusion of VVI monotherapy. 23 patients received IV VV1 1.7 x1010 TCID50 over 15, 30, 60 or 180 min. Six patients received 1.0 x1011 TCID50 over 30 min with aggressive premedication and fluid support overnight. Patients were monitored for dose limiting toxicities over 21 days with efficacy assessments after 6 weeks and then every 3 months for survival. The primary objective was to establish the safety and tolerability of IV VV1. Secondary objectives included preliminary efficacy, pharmacokinetics and pharmacodynamics.ResultsIn this study VV1, demonstrated an acceptable safety profile. No deaths or Grade 4 infusion-related reactions (IRR) were reported. VV1 shedding by buccal swabs was negative at all study visits. Peak IFNβ serum levels and preliminary efficacy signals (2 PRs) were associated with 30 min infusion duration and higher dose, with RECIST data pending for 1 x 1011(table 1).Abstract 505 Table 1ConclusionsIn this study, the absence of viral shedding demonstrates that VV1 is safe for patient and caregiver with little/no environmental impact. There was no difference in safety between the lower and the higher dose infusions. In this patient population acceptable tolerability was observed at the higher dose with 30 min duration, thus the RP2D is 1x 1011 over 30 mins.Trial RegistrationNCT02923466ReferencesHemminki O, Dos Santos JM, Hemminki A. Oncolytic viruses for cancer immunotherapy. J Hematol Oncol 2020;13(1):84.Naik S, Nace R, Federspiel MJ, Barber GN, Peng KW, Russell SJ. Curative one-shot systemic virotherapy in murine myeloma. Leukemia 2012;26(8):1870–1878.Barber GN. Vesicular stomatitis virus as an oncolytic vector. Viral Immunol 2004;17(4):516–527.Lichty BD, Power AT, Stojdl DF, Bell JC. Vesicular stomatitis virus: re-inventing the bullet. Trends Mol Med 2004;10(5):210–216.Ethics ApprovalEthics approval was granted by WCG IRB. IRB tracking number: 20163005. Voluntary written informed consent was obtained from every patient prior to participation.

BackgroundT-cell redirecting bispecific antibodies (bsAbs) are therapeutics that recognize two distinct antigens: a tumor-associated antigen on tumor cells to promote recruitment of T-cells to the tumor, and a receptor on T-cells to potentiate anti-tumor activity. REGN7075 is a human immunoglobulin G4-based costimulatory bsAb designed to bridge epidermal growth factor receptor (EGFR) positive tumor cells with CD28 positive T-cells and to provide amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor, through the activation of CD28 co-stimulation. In genetically humanized immunocompetent mouse models, REGN7075 in combination with anti–PD-1 (antibody directed against programmed cell death-1 receptor) improved anti-tumor activity compared with either single agent alone.1MethodsThis is an open label, Phase I/II, first-in-human study evaluating the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of REGN7075 (EGFRxCD28) alone and in combination with cemiplimab in patients with advanced solid tumors (NCT04626635). Patients must have a protocol-defined advanced solid tumor, be ≥18 years of age (≥20 years in Japan), have an Eastern Cooperative Oncology Group performance status of 0 or 1, and be naïve to anti–PD-1/anti–PD-ligand(L)1.This study includes dose escalation (a 4+3 design modified from 3+3; Part 1) and expansion phases (Part 2). In Part 1, patients will receive a lead-in of REGN7075 monotherapy for 3 weeks followed by combination therapy with cemiplimab 350 mg every 3 weeks. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or other stopping criterion is met. Once a recommended Phase 2 dose is determined in Part 1, four tumor-specific expansion cohorts will be opened: non-small cell lung cancer (PD-L1 ≥50%), triple-negative breast cancer, colorectal cancer (microsatellite stable), and cutaneous squamous cell carcinoma. Primary endpoints are safety and tolerability of REGN7075 alone or in combination with cemiplimab for Part 1, and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 for Part 2. This study is currently open to enrollment.Trial RegistrationClinicalTrials.gov identifier NCT04626635.ReferencesWaite JC, Wang B, Haber L, et al. Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy. Sci Transl Med 2020;12:2325.Ethics ApprovalThis study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The study protocol and all amendments were approved by the institutional review board/ethics committee at each participating study site.ConsentAll patients provided written informed consent.

BackgroundTo address the heterogeneity of response to therapies, the oncology field is moving toward precision medicine (PM), with therapy tailored to a patient‘s disease. Biomarker assessment is now critical when screening for enrollment into clinical studies, such as for T-cell receptor therapies and combination studies, and determining status of a single analyte does not always correlate to clinical benefit.1 This shift may increase enrollment screen-failure rates due to restrictive eligibility criteria (e.g., biomarker prevalence). For oncology patients, the need for timely treatment does not allow for a sequential, complex, and time-consuming screening process for each individual clinical trial. The design and data from studies such as Lung MAP have emphasized a need to change clinical trial screening. As we begin to target less common genomic and immunotherapy subtypes, comprehensive molecular characterization may lead to rapid delivery of therapies to patients while maximizing the quality of data.2The Molecular Disease Characterization Initiative (MDCI; GlaxoSmithKline Study 213299 [NCT04772053]) screens for multiple studies at once by collecting a baseline assessment of disease prior to treatment with different therapeutic modalities, and evaluating the patient‘s tumor and blood genetics. The MDCI creates a platform to accelerate the availability of new therapeutic options for patients through matched investigative and PM clinical trials, while building a scientific database to facilitate the investigation of biological mechanisms underpinning clinical outcomes.MethodsThis multicenter study enrolls patients (N= 400) with advanced/metastatic malignancies, initially non-small cell lung cancer, to collect biospecimens for broad molecular profiling and examining the expression of specific antigens (e.g. NY-ESO-1, LAGE-1a), immune markers (e.g. ICOS, PD-L1), tumor-infiltrating immune cells, differentially expressed genes, and human leukocyte antigen (HLA). In this single-arm, non-interventional, molecular analysis study there is no administration of investigational product. MDCI interrogates patient tumor specimens using CLIA-validated immunohistochemistry assays coupled with next-generation sequencing of DNA and RNA. Blood is also collected for assessment (e.g. HLA typing, ctDNA). Based on this molecular profiling and previous medical history, potential clinical trial options are returned to both physicians and patients with the aim to reduce time-to-treatment (figure 1). Participants may be subsequently matched to ongoing clinical trials of novel immunotherapeutics or adoptive cell therapy. Patients who do not match to a clinical trial but continue with standard of care may choose longitudinal follow-up and re-analyses of disease at progression.AcknowledgementsStudy 213299 (NCT04772053) is funded by GlaxoSmithKline.ReferencesBlons H, Garinet S, Laurent-Puig P, Oudart JB. Molecular markers and prediction of response to immunotherapy in non-small cell lung cancer, an update. J Thorac Dis 2019;11(Suppl 1):S25–S36.Lam, Vincent K, Papadimitrakopoulou V. Master protocols in lung cancer: experience from lung master protocol. Curr Opin Oncol 2018;30:p92–97.Ethics ApprovalThe study was approved by Advarra Central IRB, approval date 4 January 2021.Abstract 390 Figure 1MDCI study design schema. *MDCI will be an optional protocol under select GSK oncology protocols. †Gather Share Know is an optional patient-facing portal where patients can view subsets of their results. ‡Subset of data to be shared on Gather Share Know. §Patient‘s molecular profile and medical history will be compared against the eligibility criteria of select GSK oncology protocols to identify potential trial options. MDCI, Molecular Disease Characterization Initiative.

BackgroundPD1-Fc-OX40L, is a hexameric, bi-functional fusion protein with an extracellular domain (ECD) of PD-1 (70 pM affinity to PD-L1) linked to the ECD of OX40L (324 pM affinity to OX40) through an Fc linker. The therapeutic activity of mPD1-Fc-OX40L in murine tumors was superior to PD1 blocking, OX40 agonist or combination antibody therapy.1MethodsThe first-in-human, Phase 1 dose escalation study is evaluating SL-279252 as monotherapy in patients (pts) with advanced solid tumors or lymphomas. Objectives include evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose (RP2D), pharmacokinetic (PK) parameters, pharmacodynamic (PD) effects, and anti-tumor activity per iRECIST.ResultsAs of 11 June 2021, 43 pts were enrolled and dosed intravenously with SL-279252 (median age 64 years; 56% male; median [range] of 3 [0–5] prior systemic therapies for metastatic disease): 30 pts were treated on schedule 1 (day 1, 8, 15, 29, then every 2 weeks ) from dose level 0.0001–6 mg/kg, and 13 pts treated on schedule 2 (weekly) from dose level 0.3–3 mg/kg. 58% of pts were PD-1/L1 inhibitor experienced, and most tumors lacked PD-L1 expression. Common (>15%) treatment emergent adverse events (AEs) of any grade (G) were constipation in 11 (26%) pts, back pain 8 (19%) pts, anemia 7 (16%) pts and decreased appetite 7 (16%) pts. Infusion-related reactions (G1/2) were noted in 3 (7%) pts. G3 treatment-related AEs (TRAEs) were neutropenia (2%) and hypercalcemia (2%); no G4/5 TRAEs or DLTs occurred. SL-279252 Cmax and AUC increased linearly up to 3mg/kg, and greater than proportional increase in AUC was observed at 6 mg/kg. The preliminary T½ was ~23 hours. Dose-dependent receptor occupancy on CD4+OX40+ T cells persisted for >7 days and these cells rapidly marginated from the peripheral blood post infusion. Increases in the number of proliferating central and/or effector memory T cells were seen in some pts at doses of ≥1mg/kg. Analysis of paired tumor biopsies is ongoing. Best response was 1 durable confirmed iPR (ocular melanoma, 4 prior systemic regimens) in a pt who remained on treatment for >1 yr, and iSD in 12 pts (1 unconfirmed iPR). iSD for > 24 wks occurred in 6/12 pts.ConclusionsSL-279252 is well-tolerated in pts with refractory solid tumors with no maximum tolerated dose (MTD) reached. OX40-dependent PD effects and durable anti-tumor activity was observed. Trends for PK/PD effects at ≥1 mg/kg suggests dose exploration in PD-L1 expressing cancers is warranted beyond 6 mg/kg.AcknowledgementsThanks are extended to study participants; Takeda Pharmaceutical Company, Boston, MA, United States; Cathrine Leonowens, PhD, Nuventra Pharma Sciences, Durham, NC, United States and Cadence Communications and Research, Thousand Oaks, CA, United States. This study is funded by Shattuck Labs, Inc. Austin, TX and Durham, NC, United States.Trial RegistrationNCT03894618ReferencesFromm G, de Silva S, Johannes K, Patel A, Hornblower JC, Schreiber TH. Agonist redirected checkpoint, PD1-Fc-OX40L, for cancer immunotherapy. J Immunother Cancer 2018;6: 1–16.Ethics ApprovalThis study is being conducted in full conformity with the Declaration of Helsinki and was approved by all IRBs/ethics committees from each clinical site participating in the study. Specific approval numbers can be provided upon request.

397600 Background: While PD-1 inhibitors demonstrated survival benefit compared to chemotherapy in patients (pts) with PD-L1-high, NSCLC, less than half of pts respond to monotherapy. Novel therapeutics or combinations are necessary to improve outcomes. Domvanalimab (D) is an Fc-silent humanized IgG1 monoclonal antibody (mAb) that blocks T cell Immunoglobulin and ITIM domain (TIGIT), thereby reducing immunosuppression of T/NK cells and promoting antitumor activity. Etrumadenant (E) is a selective dual antagonist of both A2a and A2b receptors (R) expressed on immune cells thereby reducing immunosuppressive extracellular adenosine. ARC-7 evaluates whether inhibition of TIGIT and adenosine pathways augments activity of zimberelimab (Z) (anti-PD-1 mAb) in pts with PD-L1-high NSCLC. Methods: ARC-7 (NCT04262856) is a randomized, open-label phase 2 clinical trial which enrolled treatment-naïve pts with Stage IV, squamous or non-squamous NSCLC with locally assessed high PD-L1 expression (TPS ≥ 50%), no EGFR or ALK alterations, and ECOG PS ≤1. Pts were randomized (1:1:1) to: Arm 1 (Z): Z 360 mg intravenously (IV) every 3 weeks (Q3W); Arm 2 (DZ): D 15 mg/kg IV Q3W + Z; Arm 3 (EDZ): E 150 mg orally once daily + DZ. Pts in Arm 1 with confirmed progression had the option to cross over to EDZ. Co-primary endpoints were overall response rate (ORR) and progression-free survival (PFS) per RECIST v1.1. Results: As of 31 August 2022, 149 pts received at least one dose of study treatment. Efficacy for this interim analysis included 133 pts randomized at least 13 weeks prior to data cut-off (ITT-13), allowing for ≥ 2 post-baseline scans. With median follow-up of 11.8 months (mo), D-containing arms, demonstrated improved ORR and PFS compared to Z. In the safety population, grade ≥3 treatment-emergent adverse events occurred in 58% (Z), 47% (DZ), and 52% (EDZ). All cases of rash were grade 1-2, manageable with topical corticosteroids, and more common in EDZ (Table). Conclusions: In the first published, randomized dataset evaluating an Fc-silent TIGIT mAb, both D containing arms demonstrated clinically meaningful improvement in ORR and PFS compared to Z. Treatment with Z, DZ and EDZ was well tolerated, and the safety profiles of D-containing arms were similar to Z. Ongoing phase 3 trials are evaluating DZ compared to standard of care in metastatic NSCLC. Clinical trial information: NCT04262856. [Table: see text]

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS(G12C)). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRAS(G12C)-mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRAS(G12C) inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non–small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRAS(G12C) allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRAS(G12C) inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRAS(G12C) inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.)

Acquired resistance (AR) to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] blockade is frequent in non-small-cell lung cancer (NSCLC), occurring in a majority of initial responders. Patients with AR may have unique properties of persistent antitumor immunity that could be re-harnessed by investigational immunotherapies. The absence of a consistent clinical definition of AR to PD-(L)1 blockade and lack of uniform criteria for ensuing enrollment in clinical trials remains a major barrier to progress; such clinical definitions have advanced biologic and therapeutic discovery. We examine the considerations and potential controversies in developing a patient-level definition of AR in NSCLC treated with PD-(L)1 blockade. Taking into account the specifics of NSCLC biology and corresponding treatment strategies, we propose a practical, clinical definition of AR to PD-(L)1 blockade for use in clinical reports and prospective clinical trials. Patients should meet the following criteria: received treatment that includes PD-(L)1 blockade; experienced objective response on PD-(L)1 blockade (inclusion of a subset of stable disease will require future investigation); have progressive disease occurring within 6 months of last anti-PD-(L)1 antibody treatment or rechallenge with anti-PD-(L)1 antibody in patients not exposed to anti-PD-(L)1 in 6 months.

In 2018 research in the field of advanced NSCLCs led to an expanded reach and impact of immune checkpoint inhibitors (ICIs) as part of a frontline treatment strategy, regardless of histologic subtype, with ICI use extended to include stage III disease, shifting the prognosis of all these patients. This new standard first-line approach opens a gap in standard second-line treatment, and older combinations may again become standard of care after progression during treatment with an ICI. The characterization of predictive biomarkers, patient selection, the definition of strategies with ICI combinations upon progression during treatment with ICIs, as well as prospective evaluation of the efficacy of ICIs in subpopulations (such as patients with poor performance status or brain metastases) represent upcoming challenges in advanced thoracic malignancies. In oncogene-addicted NSCLC three major steps were taken during 2018: next-generation tyrosine kinase inhibitors have overtaken more established agents as the new standard of care in EGFR and ALK receptor tyrosine kinase gene (ALK)-positive tumors. Mechanisms of acquired resistance have been reported among patients treated with next-generation EGFR tyrosine kinase inhibitors, reflecting the diversity of the landscape. One major step forward was the approval of personalized treatment in very uncommon genomic alterations, mainly fusions. This raises a new question about the challenge of implementation of next-generation sequencing in daily clinical practice to detect new and uncommon genomic alterations and to capture the heterogeneity of the mechanisms of acquired resistance during treatment, as well as the need to extend research into new therapeutic strategies to overcome them.

9002 Background: KRAS is a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRASG12C mutation occurs in ̃14% of NSCLC. Adagrasib, an investigational agent, is a KRASG12C inhibitor that irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib is optimized for favorable pharmacokinetic (PK) properties, including long half-life (̃24 h), dose-dependent PK, and central nervous system penetration; it has demonstrated objective response and favorable tolerability in the Phase 1/1b setting. Methods: KRYSTAL-1 (NCT03785249) is a multicohort Phase 1/2 study evaluating adagrasib as monotherapy or in combination regimens in patients with advanced solid tumors harboring a KRASG12C mutation. Here we report the first disclosure from all patients enrolled in Cohort A, a Phase 2 cohort with registrational intent, evaluating adagrasib given 600 mg orally BID in patients with NSCLC previously treated with platinum-based chemotherapy and anti-PD-1/L1 therapy. Study objectives include evaluating efficacy (objective response rate [ORR], duration of response [DOR], progression-free survival [PFS], overall survival [OS]), safety, PK, and exploratory correlative analyses. Objective tumor response was assessed per RECIST v1.1 by blinded independent central review (BICR). Results: As of the 15 October 2021 data cutoff, 116 patients with NSCLC harboring a KRASG12C mutation were enrolled and treated, with a median follow-up of 12.5 months. Baseline characteristics include median age 64 years, 65% female, and 15.5%/83.6% with ECOG PS 0/1; 98.3% of patients received adagrasib following prior treatment with immunotherapy and chemotherapy, with a median of 2 prior systemic therapies. The ORR (by BICR) was 42.9% (48/112) and the disease control rate was 79.5% (89/112); 31 patients remain on treatment. Median DOR was 8.5 months (95% CI 6.2–13.8), median PFS was 6.5 months (95% CI 4.7–8.4), median OS was 12.6 months (95% CI 9.2–NE). Treatment-related AEs (TRAEs) of any grade occurred in 97.4% of patients, grade ≥3 TRAEs in 45.7%, 2 grade 5 TRAEs, and 8 (6.9%) TRAEs led to discontinuation. The most commonly reported (≥25%) TRAEs (any grade) were diarrhea (62.9%), nausea (62.1%), vomiting (47.4%), fatigue (40.5%), ALT/AST increased (27.6%/25%), blood creatinine increased (25.9%); the most commonly reported (≥5%) TRAEs (grade 3/4) were lipase increased (6%) and anemia (5.2%). Additional subgroup analyses will be presented, including selected demographics, molecular markers and sites of metastases. Conclusions: Adagrasib is well tolerated and demonstrates promising efficacy in pretreated patients with NSCLC harboring a KRASG12C mutation. A Phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRASG12C-mutant NSCLC is ongoing (NCT04685135). Clinical trial information: NCT03785249.

1530 Background: In a prior analysis, we identified 525 pts with newly diagnosed NSCLC 4 harboring AOD in the ICD. Of these, 141 were treated prior to the reporting of AOD with chemotherapy (C), immune checkpoint inhibitor (ICI), or both. This report details the clinical outcomes of these 141 compared to the 384 treated after AOD reported. Methods: Real world data (RWD) were obtained from a curated ICD for pts with NSCLC 4 diagnosed 1/1/2018-12/31/2020 with cutoff of data 3/31/2021. Pts with EGFR, ALK, ROS1, BRAF, MET, RET, HER2, and NTRK were included if their treatment record were captured. Also included were demographics, ECOG score, date of first report of AOD and dates of initiations of first and any second line of therapy and date of apparent death (AD). Outcome measures were time to next treatment or apparent death (TTNT) and apparent survival (AS) (ICD model does not allow date of death per HIPAA de-identified Expert Determination). Descriptive statistics were used with Kaplan-Meier (K-M) estimates and Hazard Ratios (HR) by Cox regression. 3 cohorts were defined: Group (Gr) A with 384 pts treated after AOD reported and used as the comparator; the 141 pts treated before AOD with C, ICI or both were divided into Gr B (n = 51) who subsequently switched to TKI within 35 days and Gr C (n = 90) who did not switch. Results: As shown in data table, AS was significantly worse in Gr B and Gr C, TTNT was significantly worse in Gr C and with worsening trend in Gr B. Two potential confounders were identified: higher ECOG scores might indicate more urgency to assign treatment, but pts with ECOG ≥ 2 were similar in all 3 groups; also, difference in proportion of EGFRm by Group (Gr A 62%, Gr B 57%, and Gr C 29%), but separating cohorts by EGFR mutation status did not alter results. Conclusions: While subject to the limitations of a retrospective observational RWD study, this study strongly suggests outcomes are significantly compromised in pts harboring AOD but who are treated initially with C, ICI or both, even in pts quickly switched to TKI. Since a prospective clinical trial is not ethically feasible, these findings may stimulate review of current guidelines, fuel optimization of universal testing in NSCLC 4, and encourage utilization of liquid or ultra-fast NGS with their rapid turnaround times in order to improve survival in this setting. [Table: see text]

TPS2701 Background: Mutations in KRAS and NRAS occur in one quarter of human solid tumors. The G12D allele is the most commonly occurring variant in pancreatic, colorectal, non-small cell lung, ovarian, biliary and gallbladder cancers. ELI-002 2P is an immunotherapeutic comprised of a lymph-node targeted amphiphile (AMP)-modified G12D and G12R mutant KRAS peptides together with an AMP-modified CpG oligonucleotide adjuvant. In preclinical models, ELI-002 demonstrated increased cytotoxic KRAS-specific T cells compared to non-lymph node targeted controls using the same peptide and adjuvant. Clinical evaluation of adoptively transferred KRAS-specific T cells demonstrated objective antitumor activity (Tran 2016). Circulating tumor (ctDNA) methodology permits identification of patients with minimal residual disease (MRD) following locoregional treatment. In MRD setting, immunotherapy is anticipated to succeed as the ratio of effector T cells to target tumor cells is maximized prior to bulk visible disease. The AMPLIFY-201 study (NCT04853017) is evaluating ELI-002 in patients with KRAS mutated solid tumors with MRD. Methods: AMPLIFY-201 is an open-label, dose-escalation and expansion phase I, first in human, trial evaluating ELI-002 2P in patients with KRAS mutated tumors with MRD following standard of care therapy. The initial phase I cohort enrolls patients with colorectal and pancreatic cancer to receive multiple doses of AMP-peptides 70mcg each (1.4 mg total) admixed with AMP-CpG 0.1 mg, administered once every two weeks. Subsequent phase I cohorts will enroll patients with RAS-mutated pancreatic, colorectal, non-small cell lung, ovarian, bile duct or gallbladder cancer, who will receive a fixed dose of AMP-peptides 70 mcg each, together with escalating doses of AMP-CpG. Safety and efficacy will be summarized with descriptive statistics. The maximum tolerated dose (if any) and the recommended phase II dose (RP2D) will be determined with the dose-response activity of ELI-002 2P in eliciting functional KRAS-specific T cells. Preliminary antitumor activity will be characterized using changes from baseline in ctDNA, serum biomarkers appropriate for tumor type, and progression free survival time. Eligibility includes patients who have received standard of care locoregional treatment according to NCCN guidelines and whom have MRD persistence or relapse (ctDNA positive). Patients with colon and pancreas cancer with Stage IV oligometastatic disease (< 3 lesions in one organ) rendered surgically free of disease and with MRD, are also eligible. The dose escalation portion of the study is currently enrolling. Clinical trial information: NCT04853017.

2514 Background: Checkpoint inhibitors (CPIs) are usually ineffective in patients (pts) with immune-cold microsatellite stable colorectal cancer (MSS-CRC) or pancreatic cancer (PDAC) and in those who progressed on previously treated with antibodies against PD1 or PD-L1. Here, we report the combination of NT-I7 plus pembrolizumab (pembro) on CPI-naïve MSS-CRC and PDAC cohorts, and patients (pts) with CPI-treated triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC) cohorts of this ongoing phase 2a trial. Methods: Pts with CPI-naïve relapsed/refractory (R/R) MSS-CRC and PDAC, and CPI-treated R/R TNBC, NSCLC, and SCLC, were enrolled. NT-I7 (efineptakin alfa) 1200 µg/kg intramuscularly every 6 weeks and 200 mg pembro intravenously every 3 weeks were administered until disease progression/unacceptable toxicity. The primary endpoint of the Phase 2a is the objective response rate (ORR), assessed by RECIST v1.1 and iRECIST. The secondary endpoints are duration of response (DoR), disease control rate, progression-free survival, and overall survival. Results: As of 14 Jan 2022, 92 pts with metastatic or locally advanced cancer who had received a median of 3 prior treatments were enrolled in the study; 32 in PDAC, 28 in MSS-CRC, 22 in NSCLC, 6 in TNBC, and 4 in SCLC. The median age was 62 years [29-81], ECOG PS 0 in 23 (25%), 1 in 68 (74%) and 2 in 1 (1%). Among 71 evaluable pts, the median follow up (months) was 7.7, 5.3, 5.0, 3.7, and 2.4 in TNBC, MSS-CRC, NSCLC, PDAC and SCLC, respectively. The ORR was 50% (1/2) in SCLC, 12% (3/25) in MSS CRC, 8% (2/26) in PDAC 6% (1/16) in NSCLC and 0% (0/2) in TNBC per iRECIST; and 50% (1/2) in SCLC, 4% (1/25) in MSS CRC, and 4% (1/26) in PDAC per RECIST 1.1. All 7 responders are ongoing. The two PDAC pts had DoR over 1.35 months (mos) and 6.64 mos with the best tumor reduction 100% and 72% respectively. The one SCLC pt had DoR over 1.5 mos with the tumor reduction 67%. The one NSCLC pt had DoR over 2.73 mos with the tumor reduction 60%, and the three MSS-CRC pts had DoR 6.34, 2.96, and 0.03 mos with the tumor reduction 60%, 56%, and 43% respectively. A sustained and significant (approximate 3X from baseline) increase of peripheral lymphocytes in all arms was observed as shown in our previous report. Among 92 treated pts, NT-I7-related adverse events (AEs) occurred in 67 (72.8%) pts, including 52 (56.5%) Grade (G)1-2, 13 (14.1%) G3, and 2 (2.2%) G4. There were no NT-I7 related G5 AEs. Additional updated efficacy, safety and biomarker data will be presented. Conclusions: The combination of NT-I7 and pembro demonstrated antitumor activity and manageable toxicity profile in heavily pretreated pts with CPI-naïve MSS-CRC and PDAC and CPI-treated TNBC, NSCLC, and SCLC, suggesting that the addition of NT-I7 to CPI can overcome the primary resistance to CPI in the former group and acquired resistance in the latter. Clinical trial information: NCT04332653.

2533 Background: Most solid tumors are resistant to immunotherapy. In pre-clinical studies, CAR-M infiltrate tumors, phagocytose tumor cells, activate the tumor micro environment (TME), recruit T cells, and present tumor antigens to T cells leading to robust anti-tumor immunity. CT-0508 is a first in class CAR-M, comprised of autologous monocyte derived macrophages expressing an anti-HER2 CAR. Here we present preliminary clinical results from the CT-0508 Phase 1 FIH study. Methods: This multi-center, open-label study is evaluating CT-0508’s safety, tolerability, and manufacturing feasibility in 18 participants (pts) with advanced solid tumors overexpressing HER2 who have progressed on prior therapies. Monocytes are isolated from mobilized apheresis products, differentiated into macrophages and engineered with an anti-HER2 CAR. Group 1 pts (n = 9) receive a fractionated dose (D1, D3, D5) and Group 2 pts (n = 9) receive the full dose on D1. CT-0508 is administered without preparative chemotherapy (bridging is permitted). Serial blood samples, 1 pre and 2 post-treatment biopsies are collected to investigate safety, pharmacokinetics and mechanism of action. Results: Seven pts (4F/3M), median age 64 (49-73), have been treated [breast (2), esophageal (2), cholangiocarcinoma, ovarian and parotid gland cancers]. A median of 3 (2-10) prior lines of therapy have been administered, most pts (85.7%) received prior anti HER2 therapy. CT-0508 was successfully manufactured with high viability, purity and CAR expression, and was well tolerated with no dose limiting toxicities or AEs leading to discontinuation or dose modification. Two related SAEs were reported in the same pt (Grade 1 CRS, hospitalized for monitoring and Grade 2 infusion reaction, resolved within 1h). Three other pts had Grade 1-2 CRS; resolved within 4d with no use of tocilizumab needed. There were no major organ toxicities and no on-target off-tumor toxicities. Post-infusion cytokines were transiently elevated in most pts and were self-limiting. Among the 4 pts who reached week 8, the best overall response was stable disease (n = 3) and 1 pt progressed, with a median follow up of 8w. CT-0508 rapidly egressed from peripheral blood. CT-0508 CAR mRNA was detected in all tumor biopsies of the first 2 pts. CT-0508 activated the TME, with increased myeloid cell activation, T cell infiltration, activation and proliferation. TCR sequencing demonstrated peripherally expanding T cells enriched for tumor infiltrating lymphocyte clones, suggesting expansion of tumor reactive T cells. Correlative data from additional pts will be presented. Conclusions: In 7 pts, CT-0508 was safe and feasible to manufacture. Early correlative data demonstrate trafficking, TME modulation, and potential induction of anti-tumor T cell immunity. The study is actively enrolling. Clinical trial information: NCT04660929.

8566 Background: HPN328 is a delta like canonical Notch ligand 3 (DLL3)-targeting T-cell engager (TCE) derived from the TriTAC platform, designed to minimize off-target toxicities. HPN328 contains 3 binding domains, engineered to redirect T cells to kill DLL3-expressing cancer cells: anti-DLL3 for target engagement, anti-CD3 for T-cell engagement, and anti-albumin for half-life extension. Methods: This ongoing Ph1/2a study is evaluating HPN328 in patients (pts) with metastatic small cell lung cancer (SCLC) and other neuroendocrine (NE) cancers associated with DLL3 expression. Eligible pts must have disease that is relapsed/refractory to standard systemic therapy. Primary endpoints are safety, tolerability, and determination of MTD/RP2D. Secondary objectives are pharmacokinetics (PK), pharmacodynamics, immunogenicity, and preliminary anti-tumor activity (RECIST 1.1). HPN328 is administered IV, once weekly. AEs are graded by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS). Results: As of Feb 3rd, 2022, 16 pts were enrolled in 8 dose-escalation cohorts at doses from 0.015mg to 12.0mg (SCLC n = 10 (62.5%); NE prostate cancer (NEPC) n = 2 (12.5%); other NE neoplasms (NEN) n = 4 (25%)). Median pt age was 61 (43-73) yrs. Pts received a median of 3 (1-5) prior treatments; 75% received a PD-1 blocker. At baseline, 6 pts (37.5%) had treated brain metastases and 8 (50%) had liver metastases. Median treatment duration was 10.6 (3.3-31.3 plus) weeks. Treatment is ongoing in 7 pts (44%; median 16.5 weeks). CRS was reported in 5 pts (31%); events were grade 1 or 2, occurred within 24 hrs of the 1st or 2nd dose and did not recur with rechallenge. No ≥ Grade-3 CRS occurred. No dose-limiting toxicities were observed, and no AEs led to discontinuation. HPN328 exhibited linear PK, with dose-proportional increases in exposure and a median half-life of 71 hrs. Small, transient increases in select cytokines and chemokines were observed up to 24 hrs post dose. T-cell activation and margination were observed, consistent with target engagement. DLL3 expression was confirmed on IHC analysis of most baseline biopsies. 15 pts were efficacy evaluable. 6 of 15 (40%) had decrease in sum of target lesion diameters (4 SCLC, 1 NEPC, 1 NEN). 3 of 9 (33%) SCLC pts across all doses had > 30% decrease (weeks on treatment: 17.2, 16.9 [ongoing], and 25.1 [ongoing, confirmed PR]). At doses ≥1.215mg, 2 of 4 (50%) SCLC pts had > 30% decrease and 1 had > 20% decrease. 4 pts (25%) had stable disease: 2 SCLC, 1 NEPC, 1 NEN (Thymic atypical carcinoid). Conclusions: HPN328 is a novel half-life extended DLL3-targeting TCE that is well tolerated and clinically active. AEs have been transient, manageable, and consistent with class. No ≥ Grade-3 CRS occurred. Tumor shrinkage has been observed, including 1 confirmed PR. Dose escalation is ongoing; updated data will be presented. Clinical trial information: NCT04471727.

TPS8600 Background: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor characterized by early metastasis and a high recurrence rate with currently available treatment options. Although SCLC is generally sensitive to initial chemotherapy, responses are not durable and most patients eventually relapse. Prognosis is poorer in the relapsed/refractory (R/R) setting and currently available treatment options, including checkpoint inhibitors, are associated with a median overall survival of 2-9 months (Chauhan 2020; Trigo 2020; Chung 2020). Approximately 15% of patients have a TP53 wild-type ( TP53WT) gene. In patients with extensive-stage SCLC, TP53WT is paradoxically associated with an inferior response to chemotherapy (Dowlati 2016). Thus, the presence of TP53WT may help identify a small subset of patients with an even greater unmet need. Murine double minute 2 (MDM2) is the key negative regulator of the tumor suppressor protein, p53, which can induce apoptosis of malignant cells by shifting the balance between prosurvival and proapoptotic BCL-2 family members. In SCLC cell lines, MDM2 inhibition restored p53 function leading to downregulation of prosurvival Bcl-2 and Mcl-1 proteins, and upregulation of the proapoptotic Bim protein, thereby inducing cancer cell death (Yu 2019). Navtemadlin (KRT-232) is a potent, selective, orally available MDM2 inhibitor that restores p53 function to drive apoptosis of TP53WT malignancies. Treatment with navtemadlin may be an effective strategy for patients with TP53WT SCLC. Methods: The open-label, multicenter Phase 2 KRT-232-112 study (NCT05027867) is evaluating navtemadlin in TP53WT patients with R/R SCLC. Eligibility criteria include age ≥18 years, ECOG performance status ≤2, presence of measurable disease and demonstrated radiographic progression after ≥1 prior platinum-containing therapy with no curative therapy available. Patients must have received a checkpoint inhibitor if available and not contraindicated. Patients with symptomatic or uncontrolled central nervous system metastases or those with prior MDM2 inhibitor treatment will be excluded. In part 1 of the study, approximately 20 patients will be randomly assigned to receive oral navtemadlin once daily in 21-day cycles at 240 mg 7 days (D) on/14D off (Arm A) or 180 mg 7D on/14D off (Arm B) until disease progression or unacceptable toxicity. In part 2, an additional 18 patients will be enrolled in each arm selected for expansion. The primary endpoint is objective response rate per RECIST v1.1. Secondary endpoints include duration of response, progression-free survival, overall survival, disease control rate, and safety. This trial is ongoing and will enroll patients at approximately 40 global sites. Clinical trial information: NCT05027867.

3003 Background: The p53 tumor suppressor protein is a transcription factor that acts to maintain genome stability in response to cellular stress. Spontaneous mutation of the TP53 gene leading to inactivation of the p53 protein is the most common mutational event across all human cancers. PC14586 is a novel, small molecule structural corrector that binds selectively to p53 Y220C mutant protein and restores the p53 wildtype conformation and transcriptional activity, resulting in potent preclinical antitumor activity. This Phase 1 multicenter dose escalation study assesses PC14586 safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy in patients (pts) with advanced solid tumors that harbor the TP53 Y220C mutation. Methods: Eligible adult pts with locally advanced or metastastic TP53 Y220C mutant solid tumors received increasing doses of oral PC14586 using the modified Toxicity Probability Interval design to estimate toxicity and to determine maximum tolerated dose and recommended phase 2 dose. Plasma PK was characterized using standard methods. Preliminary efficacy was assessed by RECIST v1.1. Reporting of interim results was approved by the study’s Safety Review Committee. Results: As of 08 Feb 2022, 29 pts (62% female, median age 62 years) with a variety of TP53 Y220C mutant solid tumor types (median number of prior lines of therapy 3; range 1 to 8) were treated in 7 dose cohorts of PC14586: 150 mg QD (3 pts), 300 mg QD (3 pts), 600 mg QD (4 pts), 1150 mg QD (5 pts), 2000 mg QD (7 pts), 2500 mg QD (4 pts) and 1500 mg BID (3 pts). PC14586 was generally well-tolerated; treatment-related AEs were observed in 79% of pts that were all Grade 1/2 in severity except 2 Grade 3 AEs (alanine aminotransferase increased and neutrophil count decreased). The most common AEs (≥15% of pts) were nausea (34%), vomiting (24%), fatigue (21%), and aspartate aminotransferase increased (17%). There were no dose limiting toxicities and enrollment continues. PK analysis showed dose proportional increases in Cmax and AUC. Amongst 21 efficacy evaluable pts, PRs were observed in 5 pts: 1 small cell lung and 1 breast with confirmed PR (cPR), both ongoing; 1 colorectal with unconfirmed PR (uPR), and 2 prostate with uPR and ongoing. In the 3 highest dose cohorts (total daily dose 2000 to 3000 mg), there were 3 PRs (2 uPR, 1cPR) and 7 SD out of 10 efficacy evaluable pts (all ongoing). Observations of decreasing p53 Y220C circulating tumor DNA and decreasing numbers of circulating tumor cells in pts further support on-target anti-tumor activity of PC14586. Conclusions: Enrollment to a Phase 1 study is feasible in a TP53 mutation selective population. PC14586 is safe and tolerated up to 3000 mg daily. Preliminary efficacy was achieved in heavily pretreated pts. Additional safety, PK, PD and efficacy data will be reported at the annual meeting. Clinical trial information: NCT04585750.

TPS3165 Background: Murine double minute 2 (MDM2) is a potent negative regulator of the tumor suppressor p53. MDM2 induces degradation of p53 and promotes tumorigenesis in solid tumors, and preclinical models have shown that inhibition of MDM2 can restore p53 tumor suppressor activity in TP53-wild type (WT), MDM2-amplified tumors. We performed a mutual exclusivity analysis of patients with solid tumors (n = 42,125; AACR Project GENIE) and found that the frequency of co-occurring TP53 mutations decreased with increasing MDM2 copy number. An MDM2 copy number of 12 was chosen as the threshold. An estimated 1.1% of solid tumors meet this molecular criteria, excluding glioblastomas, dedifferentiated liposarcomas, and intimal sarcomas where this signature is enriched. Milademetan (RAIN-32), an oral, selective MDM2 inhibitor, inhibits growth of TP53-WT/ MDM2-amplified cell lines and patient-derived xenograft models from varying tumor types. Furthermore, tumor regression was observed in 3/3 non-liposarcoma patients with MDM2 copy number > 12 in a phase 1 trial of milademetan. MANTRA-2 (RAIN-3202) is a phase 2, multicenter, single-arm, open-label, basket trial designed to evaluate the efficacy or clinical benefit of milademetan in TP53-WT solid tumors with MDM2 amplification (copy number ≥ 12). Methods: Eligible patients must be ≥ 18 years of age with histologically and/or cytologically confirmed locally advanced, incurable or metastatic solid tumors refractory to standard therapy. Local testing demonstrating TP53 WT and MDM2 amplification is required, defined as a MDM2 copy number ≥ 12 or 6-fold increase. Patients with well-differentiated/de-differentiated liposarcomas, intimal sarcomas, or primary central nervous system tumors are excluded. Prior treatment with an MDM2 inhibitor is not permitted. Patients receive milademetan 260 mg orally once daily on Days 1–3 and 15–17 of a 28-day cycle. Tumor response is evaluated by RECIST v1.1 at Weeks 8, 16, 24, and 32, and then every 12 weeks. Primary endpoint: objective response rate. Secondary endpoints include: duration of response; progression-free survival; growth modulation index; disease control rate; overall survival; safety; health-related quality of life scores. Exploratory endpoints include: biomarkers in blood and/or tumor tissue; pharmacodynamics; pharmacokinetics. Enrollment of 65 patients is planned to ensure that 57 patients have centrally confirmed TP53 WT and MDM2 copy number ≥ 12. The trial opened in November 2021 and is actively enrolling patients. Clinical trial information: NCT05012397.

2503 Background: Modakafusp alfa (TAK-573) is a first-in-class immune-targeting attenuated cytokine designed to deliver attenuated interferon alpha-2b (IFNα2b) moieties to CD38-expressing cells. It consists of two attenuated IFNα2b molecules genetically fused to the Fc portion of a humanized, anti-CD38, IgG4 monoclonal antibody. Specificity for CD38 and reduced IFN receptor binding affinity of the attenuated IFNα2b molecules significantly reduces the potential for off-target binding and toxicity. Modakafusp alfa has demonstrated immune cell activation and antitumor activities in preclinical mouse models, including tumor models that do not express CD38, and has shown strong clinical responses and immune activation in pts with refractory/relapsed multiple myeloma. The dose-escalation phase of this phase 1b/2 study (NCT04157517) investigated safety, pharmacokinetics, immunogenicity, pharmacodynamics (PD), and preliminary efficacy of modakafusp alfa in metastatic solid tumors. Methods: Adult pts with advanced/metastatic solid tumors received modakafusp alfa IV on day 1 of a 21-day cycle (Q3W). Dose escalation started at 0.1 mg/kg and proceeded based on cycle 1 safety data via a Bayesian model with overdose control principles. Results: Twenty-one pts were dosed in the escalation phase at 0.1 (n = 3), 0.2 (n = 3), 0.4 (n = 3), 0.75 (n = 3), 1.0 (n = 3), and 1.5 mg/kg (n = 6) Q3W; median age 63 y (range 42–80); male 57.1%; GI malignancies 71.4%; median prior lines of therapy 3 (range 2–7). Two pts had dose-limiting toxicities in cycle 1 at 1.5 mg/kg; 1 pt with baseline bone infiltration had grade 4 thrombocytopenia and 1 pt had grade 3 confusion. As of Nov 2021, across all doses, pts received a median of 2 treatment cycles (range 1–11). Modakafusp alfa treatment-related adverse events (TRAEs) reported in 81% of pts included infusion-related reactions (52.4%), chills (47.6%), and nausea (33.3%). Grade ≥3 TRAEs reported in 42.9% of pts included neutropenia (14.3%) and hypertension (9.5%). There was a greater than dose proportional exposure increase in the dose range 0.1–1.5 mg/kg, with no exposure accumulation after Q3W dosing. Incidence rate of post-treatment anti-drug antibody (ADA) was 100%. PD data suggested saturation of peak IFN pathway modulation at ≥0.2 mg/kg in the peripheral blood with duration of modulation increasing with dose. Among the 14 response-evaluable pts, 7 had best response of stable disease, including 1 with cutaneous melanoma who had 21% target lesion reduction. Conclusions: Modakafusp alfa had a manageable safety profile in the dose range 0.1–1.5 mg/kg in pts with solid tumors. Proof of mechanism was validated. The recommended phase 2 dose was determined as 1.0 mg/kg Q3W based on assessment of holistic data and will be tested in combination with a checkpoint inhibitor in selected tumor types. Characterization of ADA and its impact is ongoing. Clinical trial information: NCT04157517.

TPS2696 Background: Prostaglandin E2 (PGE2) is a bioactive lipid that promotes cancer through diverse mechanisms including stimulating tumor proliferation, enhancing angiogenesis and suppressing immune function in the tumor microenvironment. PGE2 produced by tumor cells through upregulation of cyclooxygenase-2 (COX-2) is also a key mediator of adaptive resistance to immune checkpoint inhibitor therapy. While PGE2 signaling is important in cancer, how best to inhibit PGE2 for cancer treatment is under investigation. Inhibition of COX enzymes (e.g., with NSAIDS) has shown promise in large observational studies, but inconsistent results in prospective studies. Importantly, COX inhibition alters multiple prostanoids beyond PGE2, resulting in toxicity that limits therapeutic dosing for cancer. PGE2 signals through four receptors, EP1-4, that are variably expressed and have distinct activities. The tumor promoting and immunosuppressive activities of PGE2 predominantly arise from signaling through the EP2 and EP4 receptors, while signaling through the EP1 and EP3 receptors generally is pro-inflammatory. TPST-1495 is designed to be an oral, highly specific, antagonist of the EP2 and EP4 receptors, sparing the EP1 and EP3 receptors and the COX enzymes. Preclinical studies suggest that blocking EP2 and EP4 with TPST-1495 inhibits tumor proliferation and stimulates anti-cancer immunity better than inhibiting all 4 receptors together, the EP2 or EP4 receptors singly, or the upstream COX-2 enzyme. Methods: TPST-1495-001 is a first-in-human Phase 1 study (NCT04344795). In the Dose and Schedule Optimization Stage, the primary objectives are to characterize the safety and tolerability (including dose limiting toxicities) and determine the recommended phase 2 dose (RP2D) of TPST-1495 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors. Additional objectives include characterization of PK, PD, and evaluation of potential biomarkers, including through paired (pre- and on-treatment) tumor biopsies. Monotherapy dose-finding employs a modified 3+3 design evaluating BID and QD TPST-1495 schedules along with continuous or intermittent (Days 1-5 every 7 days) dosing. For the pembrolizumab combination, the starting dose and schedule of TPST-1495 are determined by safety, PK and PD of monotherapy. Indication-specific Expansion Stage cohorts will evaluate TPST-1495 at the selected RP2D and schedule for both monotherapy and combination in endometrial cancer, squamous cell carcinoma of the head and neck, and microsatellite stable colorectal cancer (combination only), as well as in a biomarker-specific cohort enrolling patients with pathogenic tumor PIK3CA gene mutation. Dose and Schedule Optimization enrollment (monotherapy and combination) is ongoing at abstract submission while Expansion Stages are planned after identification of the RP2Ds. Clinical trial information: NCT04344795.

TPS8595 Background: RET fusions are found in 1-2% of lung adenocarcinomas and 10-20% of papillary thyroid carcinomas. Activating RET mutations occur in 50-60% of medullary thyroid cancers (MTCs). Selpercatinib was the first selective RET inhibitor approved by the FDA and is indicated for patients (pts) with RET fusion-positive NSCLC and thyroid cancer, and RET mutant MTC. Despite marked and durable activity, acquired resistance can eventually develop through a variety of mechanisms. These include acquisition of RET G810X mutations at the solvent front of the ATP pocket. LOXO-260 is a highly potent and selective inhibitor of RET designed to have activity against both solvent front and gatekeeper mutations, expressed alone or together, while maintaining potency against RET fusions or mutations (Kolakowski GR. et al. 2021 Cancer Research 81 (13 Suppl) 1464). Methods: LOXO-NGR-21001 is a global, open-label, first-in-human phase 1 study of LOXO-260 in pts with RET fusion-positive advanced solid tumors and RET mutant MTC who received a prior selective RET inhibitor. Phase 1a dose escalation will utilize a modified i3+3 design, allowing for pt backfill to previously cleared dose levels. Phase 1b dose expansion will evaluate LOXO-260 in specific expansion cohorts: RET fusion-positive NSCLC or thyroid cancers and RET mutant MTC. The primary objectives in dose escalation are to determine the MTD/RP2D and safety of LOXO-260. Key secondary objectives include characterization of PK and preliminary antitumor activity of LOXO-260 per RECIST v1.1. The primary objective of dose expansion is to assess the antitumor activity of LOXO-260 based on investigator-assessed overall response rate (ORR). Key secondary objectives are to characterize the PK and antitumor activity of LOXO-260 based on progression-free survival (PFS), time to response (TTR), and duration of response (DOR). Eligible pts must have received a prior selective RET inhibitor, have a documented RET fusion or RET mutation and a diagnosis of locally advanced, unresectable and/or metastatic cancer per disease-specific criteria, and must have progressed or be intolerant to standard therapies or must have refused such a therapy. Pts must be ≥18 years old and have an ECOG PS of 0-2. Key exclusion criteria include presence of serious cardiac conditions, interstitial lung disease, symptomatic CNS metastases, or carcinomatous meningitis. Clinical trial information: NCT05241834.

TPS2677 Background: Adoptive T cell therapies have led to remarkable advances among patients with hematologic malignancies, but have had less success in those with solid tumors. Macrophages are actively recruited and abundantly present in the solid tumor microenvironment (sTME). Tumor associated macrophages are predominantly immunosuppressive and support tumor growth (M2), while a subset of proinflammatory macrophages enhance anti-tumor immunogenicity (M1). M1 macrophage function can be augmented by CAR expression to selectively recognize and phagocytose antigen overexpressing cancer cells. Moreover, CAR macrophages can reprogram the sTME and present neoantigens to T cells, leading to epitope spreading and anti-tumor immune memory. Human Epidermal Growth Factor Receptor 2 (HER2) overexpression promotes tumorigenesis in many solid tumors (Table). CT-0508 is a cell product comprised of autologous monocyte-derived proinflammatory macrophages expressing an anti-HER2 CAR. Pre-clinical studies have shown that CT-0508 induced targeted cancer cell phagocytosis while sparing normal cells, decreased tumor burden, prolonged survival, and were safe and effective in a semi-immunocompetent mouse model of human HER2 overexpressing ovarian cancer. Methods: This Phase 1, FIH study is evaluating safety, tolerability, cell manufacturing feasibility, trafficking, and preliminary evidence of efficacy of investigational product CT-0508 in 18 participants (pt) with locally advanced (unresectable) or metastatic solid tumors overexpressing HER2. Pt previously treated with available therapies, including anti-HER2 therapies, as indicated, and subsequent progression are permitted. Filgrastim is used to mobilize autologous hematopoietic progenitor cells for monocyte collection by apheresis. CT-0508 is manufactured, prepared, and cryopreserved from mobilized peripheral blood monocytes. Group 1 pt (n=9) receive CT-0508 infusion split over D1, 3, and 5. A Safety Review Committee will review dose limiting toxicities. Group 2 pt (n=9) will receive the full CT-0508 infusion on D1. Pre- and post-treatment biopsies and blood samples will be collected to investigate correlates of safety (immunogenicity), trafficking (RNA scope), CT-0508 persistence in blood and in the tumor, target antigen engagement, TME modulation (single cell RNA sequencing), immune response (TCR sequencing) and others. Radiographic imaging is also being conducted to assess preliminary tumor activity. Clinical trial information: NCT04660929. [Table: see text]

9017 Background: Patients (pts) with advanced NSCLC without EGFR-activating mutations ( EGFRm) have limited treatment options after failure of molecularly targeted therapies or platinum-based chemotherapy (PBC) with or without immunotherapy (IO). HER3-DXd is an antibody drug conjugate consisting of a fully human monoclonal antibody to HER3 attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. We previously published efficacy and safety data from a study of HER3-DXd in EGFRm NSCLC after failure of EGFR tyrosine kinase inhibitor (TKI) therapy. Here we present results in pts without EGFRm who progressed after PBC ± IO treatment. Methods: This ongoing phase 1 dose expansion study included a cohort of pts with advanced NSCLC without EGFRm who received prior PBC ± IO (NCT03260491). Pts with stable brain metastases were eligible, as were pts with non- EGFR oncogenic alterations and prior targeted therapy. The primary endpoint was confirmed ORR by blinded independent central review (BICR) per RECIST v1.1; secondary endpoints included DOR, PFS, and safety. Results: At the Mar 26, 2021, data cutoff, 47 pts had been treated with HER3-DXd 5.6 mg/kg IV every 3 wk; 17 pts had an identified driver genomic alteration (4 KRAS and 1 NRAS mutations, 4 EGFR Ex20ins, 3 ROS1 and 2 ALK fusions, and 3 other). Median age was 62 y (range, 29-79 y); 53% of pts were female; 17% had squamous NSCLC. Median follow-up was 9.5 mo (range, 3.7-19.1 mo). Median number of prior anticancer regimens in the advanced setting was 3 (range, 0-8). Median treatment duration on study was 4.1 mo (range, 0.7-13.6 mo); treatment was ongoing in 11 pts (23%) at data cutoff. Confirmed ORR by BICR was 28% (13/47 pts; 95% CI, 16%-43%; 13 PRs, 22 SD). Median DOR was 5.7 mo (95% CI, 3.7-10.7 mo) and median PFS was 5.4 mo (95% CI, 3.9-12.7 mo). Among pts with identified driver genomic alterations, 35% (6/17) had a confirmed response by BICR, including 3 of 5 pts with KRAS/NRAS mutations and 2 of 2 with ALK fusions. Among pts without identified driver genomic alterations, 23% (7/30) had a confirmed response by BICR. The most common grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia (26%), thrombocytopenia (15%), and fatigue (15%). Drug-related interstitial lung disease by central adjudication occurred in 4 pts (9%; 0 grade ≥3). Four pts (9%) had TEAEs associated with treatment discontinuation. No drug-related deaths occurred. Conclusions: These data show promising clinical activity in pts with NSCLC without EGFRm, including pts with other identified driver genomic alterations. Updated results from this study will be presented. The overall safety profile was similar to that previously reported in pts with EGFRm NSCLC. A phase 2 study of HER3-DXd in pts with EGFRm NSCLC after failure of EGFR TKI and PBC is ongoing (NCT04619004). Clinical trial information: NCT03260491.

e13598 Background: Current clinical trial selection for patients with independent screening for each trial, results in high screen failure and limited options for ineligible patients. MDCI’s concept for patient screening centers around broad molecular analysis and one screening protocol for multiple trials to increase patient inclusion and shorten recruitment time for oncology clinical trials.. Methods: MDCI was designed in collaboration with patients, physicians and study sites. Feedback from the Oncology Patient Council (OPC) was solicited beginning at study conception with input on study design, the informed consent form and the Gather Share Know participant portal. Patients provided specific detailed feedback and user acceptance throughout development to ensure a truly patient-focused approach. To track implementation of feedback, the MDCI team developed a document, which was shared with OPC, recording all feedback received and all actions taken by the study team. Feedback from study sites led to additional flexibility for visits (ie, combining study visits 1 and 2; allowing for telehealth visits for visit 3) and collection of data on medical history and prior therapies to streamline the screening process. Physician input included the acceptance of next generation sequencing (NGS) to determine the best therapy for each patient. Results: The MDCI protocol combines analysis of patient medical history, blood, and tumor assays, including HLA expression, protein analyses and NGS. A trial-matching approach, developed in collaboration with IQVIA, identifies potential clinical trials based on screening results. The Gather Share Know Hub, an optional patient-facing portal, allows patients to view the screening results identified as important for patients and information about ongoing clinical trial options. Patients also have access to a patient-friendly informational video, disease-specific education, credible resources and information on “what to expect” at study visits. Physicians receive clinical reports and molecular profiles from multiple screening tests (available through the Physician Portal), enabling them to make informed, data-driven decisions on the best clinical trial option for each patient. Conclusions: Utilizing a collaborative approach, MDCI was developed as a novel tumor-profiling protocol. MDCI is designed to rapidly prescreen patients for multiple studies at once by evaluating each patient’s tumor and blood genetics as well as their medical and cancer history using a prescreening algorithm. MDCI introduces an individualized approach to patient care with the aim of accelerating the availability of new therapeutic options. Continued feedback is solicited from patients on study design and the Gather Share Know hub through timed questionnaires to further enhance the patient experience. This study (NCT04772053) is funded by GlaxoSmithKline (GSK). Clinical trial information: NCT04772053.

9035 Background: In the Phase 3 POSEIDON study in 1L mNSCLC, adding T to D+CT resulted in statistically significant improvements in PFS and OS vs CT. No new safety signals were identified and treatment discontinuations due to treatment-related AEs (TRAEs) were similar for the T+D+CT and D+CT arms (15.5% and 14.1%). Here we present details of AEs and their management. Methods: 1013 pts with EGFR/ ALK wild-type mNSCLC were randomized 1:1:1 to 1L T+D+CT, D+CT or CT. Safety was assessed in all treated pts. Results: 330, 334 and 333 pts received T+D+CT, D+CT and CT; 78%, 82% and 74% received at least 4 cycles of platinum-based CT. The most common grade 3/4 TRAEs were hematologic (anemia in 17%, 15% and 20% of pts in the T+D+CT, D+CT and CT arms and neutropenia in 16%, 13% and 12%) and most were managed using standard approaches per local practice; 22%, 18% and 16% of pts received colony stimulating factors and 22%, 21% and 26% received blood transfusions. All grade immune-mediated AEs (imAEs) occurred in 34%, 19% and 5% of pts in the T+D+CT, D+CT and CT arms; a higher incidence of diarrhea/colitis, dermatitis/rash and endocrinopathies was seen with the addition of T to D+CT (Table). Grade 3/4 imAEs occurred in 10%, 7% and 2% of pts in the T+D+CT, D+CT and CT arms, and serious imAEs in 10%, 6% and 1%; imAEs led to discontinuation of any study treatment in 6%, 4% and 0.6%, and led to death in 0.6%, 0.3% and 0%. Most imAEs were low grade and manageable with systemic corticosteroids (received by 26%, 13% and 4% of pts in the T+D+CT, D+CT and CT arms) or endocrine therapy (12%, 8% and 1%). Median time from first dose to onset of imAEs (TTO) was generally > 60 days and the majority of non-endocrine imAEs resolved (Table). Conclusions: In POSEIDON, the safety profile of all regimens was manageable per standard guidelines and in line with the known profiles of D, T+D and CT; the most common grade 3/4 TRAEs were those typically associated with CT. As expected, more imAEs occurred with T+D+CT than D+CT, but the incidence of grade 3 or 4 imAEs, imAE-related deaths and treatment discontinuations due to imAEs was generally similar in the IO arms. T+D did not compromise the ability to administer planned CT. Clinical trial information: NCT03164616. [Table: see text]

9118 Background: Capmatinib is a selective MET inhibitor approved for patients (pts) with metastatic NSCLC harboring MET exon 14 skipping mutation. Pembrolizumab (pembro) is a programmed death protein-1 (PD-1) inhibitor approved as monotherapy for pts with advanced NSCLC expressing PD-ligand 1 (PD-L1). Preclinical studies have shown that capmatinib enhances T cell mediated antitumor response in mice treated with PD-1 inhibitors. Combining capmatinib with pembro may be beneficial in pts with advanced NSCLC expressing high tumor PD-L1. Methods: Herein we evaluated the efficacy and safety of capmatinib plus pembro (combo) versus pembro alone in tx-naïve pts with advanced MET-unselected NSCLC expressing PD-L1 with tumor proportion score (TPS) ≥50%, and no ALK or EGFR tumor aberrations. Pts received pembro 200 mg IV q3w in the pembro alone arm or with capmatinib 400 mg orally BID in the combo arm. The primary endpoint was investigator-assessed progression-free survival (PFS) using RECIST v1.1. Secondary endpoints included overall response rate (ORR), disease control rate (DCR), pharmacokinetics and safety. Results: As of the data cut off (DCO) of 28 Feb 2021, 76 pts were randomized 2:1 to the combo arm (n = 51) or pembro alone arm (n = 25). Baseline demographics and disease status were mostly comparable across study arms. At this interim analysis, PFS data were not mature. Median PFS (95% CI) was 6.3 (3.2, not evaluable [NE]) months in the combo arm and 4.3 (2.3, NE) months in the pembro alone arm. The ORR (95% CI) was 15.7% (7.0%, 28.6%) and 28.0% (12.1%, 49.4%) in the combo and pembro alone arms, respectively. The DCR (95% CI) was comparable across study arms; combo: 56.9% (42.2%, 70.7%) and pembro alone: 56.0% (34.9%, 75.6%). In the combo arm, capmatinib exposure (Cmax: 3580 ng/mL [n = 7] and AUCtau: 19700 hr*ng/mL [n = 2]) was consistent with data from previous studies. Tx-related grade (GR) ≥3 adverse events (AEs) were more common in the combo (37.3%) vs pembro alone arm (16%). Tx-related AEs occurring in ≥10% of pts are shown in the Table. Tx discontinuation and dose adjustment/interruptions were more common in the combo (27.5% and 52.9%) vs pembro alone arm (16% and 16%). Capmatinib was stopped prematurely in the combo arm, and at DCO, 32 (62.7%) pts in the combo arm and 18 (72%) pts in the pembro alone arm were receiving pembro monotherapy. Conclusions: Combination tx with capmatinib and pembro was not well tolerated and did not improve antitumor activity in tx-naïve pts with advanced NSCLC with PD-L1 TPS ≥50%. Clinical trial information: NCT04139317. [Table: see text]

TPS3166 Background: The forkhead box family transcription factor FOXP3 is essential for T regulatory cells (Tregs) development and immune suppressive function. Tregs are an integral component of the adaptive immune system and contribute to maintaining tolerance to self-antigens and preventing autoimmune diseases. In the context of cancer, however, Tregs contribute to tumor progression by suppressing antitumor immunity. To date inhibition of Treg-mediated immunosuppression tested in the clinic has lacked specificity. Targeting FOXP3 provides a selective approach to impair the immunosuppressive function of Tregs but targeting transcription factors has been a challenge using conventional drug modalities. AZD8701 employs next-generation antisense oligonucleotide (ASO) technology (Ionis Pharmaceuticals) to bind mRNA with high affinity and selectively reduce human Foxp3 mRNA expression levels. Foxp3-specific ASOs promote potent dose-dependent reductions in Foxp3 mRNA and protein in vitro. In preclinical models, AZD8701 induced Foxp3 knockdown results in Tregs with a reduced immunosuppressive capacity, loss of immunosuppressive markers, and increased markers of activation on CD8+ T-cells. AZD8701 reduces tumor growth as monotherapy in preclinical models and increased tumor inhibition is obtained by combining AZD8701 with a PD-L1 inhibitor. Methods: This is a Phase I multicenter study of AZD8701 alone or in combination with durvalumab in participants with selected advanced solid tumors. Eligible patients must have ECOG performance status 0 or 1, measurable target lesion per RECIST v1.1 and be diagnosed with selected tumor types as described below. Monotherapy and combination dose escalation phase is open for participants with head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), non-small-cell lung cancer (NSCLC), clear cell renal cell carcinoma (ccRCC), gastroesophageal cancer, melanoma, cervical cancer, small-cell lung cancer (SCLC), and/or solid tumors that have demonstrated a response to prior programmed death-ligand-1 (PD-[L]1) treatment (as defined by duration of response > 18 weeks). Participants with NSCLC, HNSCC, TNBC, and ccRCC will be included in the pharmacodynamic cohort at the selected monotherapy dose and/or disease expansion cohorts. The primary objectives are to assess safety and tolerability and to determine the preliminary antitumor activity of AZD8701 (objective response rate) when administered as monotherapy or in combination with durvalumab. Secondary endpoints include, disease control rate, duration of response, progression free survival and overall survival, pharmacokinetics and pharmacodynamics (including changes in Foxp3 mRNA in paired tumor samples). The trial is currently recruiting. Clinical trial information: NCT04504669.

TPS8603 Background: SCLC is characterized by rapid growth and early development of metastases. Platinum-based first-line chemotherapy is associated with a high initial response rate; however, disease recurrence is common. Delta-like ligand 3 (DLL3) is a Notch ligand that is upregulated and aberrantly expressed on the cell surface in most SCLC, making it a compelling therapeutic target. Tarlatamab is an HLE BiTE immuno-oncology therapy designed to bind DLL3 on target cancer cells and CD3 on T cells, forming a cytolytic synapse inducing T cell activation and expansion and T cell-dependent killing of tumor cells. Interim results of an ongoing first-in-human study in patients with relapsed/refractory SCLC (NCT03319940) show preliminary evidence for tarlatamab efficacy in pretreated patients with confirmed partial responses in 20% of patients and duration of response of 8.7 months (Owonikoko TK, et al. Abstract 8510. Presented at: ASCO Annual Meeting, June 4–8, 2021; Virtual). Grade ≥ 3 treatment-related AEs (TRAEs) occurred in 27% of patients and TRAEs resulted in discontinuation in 5% of patients. This promising efficacy/safety profile supports further study of tarlatamab in SCLC. Methods: NCT05060016 is a phase 2, open-label study evaluating tarlatamab in patients with relapsed/refractory SCLC after two or more lines of prior treatment. Part 1 is a dose characterization phase in which subjects will be randomized 1:1 to two active doses of tarlatamab. Part 2 will continue enrollment for the selected target dose only based on interim analysis of Part 1. Key eligibility criteria include adults with histologically or cytologically confirmed SCLC whose disease progressed/recurred after two or more lines of prior treatment including at least 1 platinum-based regimen (including a PD-L1 inhibitor, if standard of care, with certain exceptions per protocol), treated brain metastases, ECOG performance status ≤1, and life expectancy ≥ 12 weeks in the opinion of the investigator. The primary endpoint for the primary analysis is ORR per RECIST 1.1 as assessed by blinded independent central review. Secondary objectives are to evaluate antitumor activity by additional measures (duration of response, progression-free survival, disease control rate and duration, overall survival), safety and tolerability, immunogenicity, and pharmacokinetics. Sites in North America, Asia and Europe are participating in the trial with subjects already enrolled and enrollment ongoing. Clinical trial information: NCT05060016.

Background Enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)–programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stag...