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Supplementary Figure 1

Flow chart of dose level patient enrollment

Supplementary Data from First-in-Human Phase I/II ICONIC Trial of the ICOS Agonist Vopratelimab Alone and with Nivolumab: ICOS-High CD4 T-Cell Populations and Predictors of Response

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Supplementary Figure 3

Purpose: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including that of hepatocellular carcinoma (HCC), and is associated with poor prognosis. Endoglin is essential for angiogenesis, and its expression is induced by hypoxia and VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 mAb that inhibits angiogenesis and causes antibody-dependent cellular cytotoxicity and apoptosis of proliferating endothelium.Experimental Design: Patients with HCC (Child–Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, and 15 mg/kg every 2 weeks given with sorafenib 400 mg twice daily. Correlative biomarkers included DCE-MRI and plasma levels of angiogenic factors, including soluble endoglin. Pharmacokinetics were assessed in serum.Results: Twenty-six patients were enrolled, of whom 25 received treatment, 15 with cirrhosis. Hep B/C: 3/15; M:F 19:6; mean age of 60 (range, 18–76); 1 DLT (grade 3 AST) occurred at 10 mg/kg. The most frequent toxicity was low-grade epistaxis, a known toxicity of TRC105. One patient experienced an infusion reaction and was replaced. One patient with coronary stenosis developed a fatal myocardial infarction, and one patient developed G3 cerebral tumor hemorrhage. MTD was not established and DL4 (15 mg/kg) was expanded. The overall response rate in 24 evaluable patients at all 4 dose levels was 21% [95% confidence interval (CI), 7.1–42.2], and 25% (95% CI, 8.7–49.1) in patients with measureable disease. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median progression-free survival (PFS) for 24 patients evaluable for PFS was 3.8 months (95% CI, 3.2–5.6 months); median overall survival was 15.5 months (95% CI, 8.5–26.3 months).Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity to date (PR rate 25%) was observed, and the study is now continuing to recruit in the phase II stage as a multicenter study to confirm activity of the combination. Clin Cancer Res; 23(16); 4633–41. ©2017 AACR.

Supplementary Figure 2

Purpose:The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors.Patients and Methods:In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed.Results:ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-high (ICOS-hi) CD4 T cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), P = 0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified that demonstrated improvement in clinical outcomes, including OS (P = 0.0062).Conclusions:Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized phase II non–small cell lung cancer trial.See related commentary by Lee and Fong, p. 3633

Purpose:Prospective human data are lacking regarding safety, efficacy, and immunologic impacts of different radiation doses administered with combined PD-L1/CTLA-4 blockade.Patients and Methods:We performed a multicenter phase II study randomly assigning patients with metastatic microsatellite stable colorectal cancer to repeated low-dose fractionated radiation (LDFRT) or hypofractionated radiation (HFRT) with PD-L1/CTLA-4 inhibition. The primary endpoint was response outside the radiation field. Correlative samples were analyzed using multiplex immunofluorescence (IF), IHC, RNA/T-cell receptor (TCR) sequencing, cytometry by time-of-flight (CyTOF), and Olink.Results:Eighteen patients were evaluable for response. Median lines of prior therapy were four (range, 1–7). Sixteen patients demonstrated toxicity potentially related to treatment (84%), and 8 patients had grade 3–4 toxicity (42%). Best response was stable disease in 1 patient with out-of-field tumor shrinkage. Median overall survival was 3.8 months (90% confidence interval, 2.3–5.7 months). Correlative IF and RNA sequencing (RNA-seq) revealed increased infiltration of CD8+ and CD8+/PD-1+/Ki-67+ T cells in the radiation field after HFRT. LDFRT increased foci of micronuclei/primary nuclear rupture in two subjects. CyTOF and RNA-seq demonstrated significant declines in multiple circulating immune populations, particularly in patients receiving HFRT. TCR sequencing revealed treatment-associated changes in T-cell repertoire in the tumor and peripheral blood.Conclusions:We demonstrate the feasibility and safety of adding LDFRT and HFRT to PD-L1/CTLA-4 blockade. Although the best response of stable disease does not support the use of concurrent PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population, biomarkers provide support that both LDFRT and HFRT impact the local immune microenvironment and systemic immunogenicity that can help guide future studies.

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Supplementary table 1 and Supplementary figure legends.

Supplemental Data legends

Purpose:Despite the expansion of immune checkpoint inhibitor (ICI) indications, the relationship between ICI dose and toxicity or response is not well established. To understand this correlation, we performed a meta-analysis of ICI trials that used dose escalation.Experimental Design:We searched PubMed and abstracts presented at (inter)national meetings for trials using FDA-approved ICIs. The reported rates of grade 3–5 adverse events (G3–5 AE), immune-related adverse events (irAE), and response were correlated with doses within each ICI using marginal exact generalized linear models.Results:A total of 74 trials (7,469 patients) published between January 2010 and January 2017 were included. For ipilimumab, the incidence of G3–5 AEs was 34% with a significant 27% reduced risk in lower doses (P = 0.002). However, no relationship was observed between dose and irAEs or response. For nivolumab, the incidence of G3–5 AEs was 20.1% which was lower in non–small cell lung cancer (NSCLC) compared with renal cell carcinoma (RCC) or melanoma (P ≤ 0.05) with no dose-toxicity relationship. In melanoma and NSCLC, a dose–response association was observed, which was not observed in RCC. For pembrolizumab, the incidence of G3–5 AEs was 13.3%, which was lower in melanoma compared with NSCLC (P = 0.03) with no dose-toxicity relationship. In melanoma, lower dose levels correlated with decreased odds of response (P = 0.01), a relationship that was not observed in NSCLC.Conclusions:Our analysis shows a lack of consistent dose-toxicity or dose–response correlation with ICIs. Therefore, dose escalation is not an appropriate design to conduct ICI studies. Here we present an innovative trial design for immune-modulating agents.

Supplementary Data and Methods

Supplemental Table 3. Bacterial vector vaccine trials and their grade 3/4 vaccine-related toxicities.

Background: National guidelines including NCCN and ASCO clearly state the indication of genomic profiling for all patients diagnosed with advanced or metastatic breast cancer. Despite this, there remains a large gap between those guidelines and real-world practice. Increasing numbers of therapies have been approved or are under investigation for specific genomic mutations including PIK3CA, NTRK, BRCA, and most recently immunotherapy based on PD-L1 and microsatellite status. Accordingly, it is critical that advanced and metastatic breast cancer patients are offered and receive genomic testing. We explored patients’ knowledge and perception of genomic testing as well as their testing status using the Outcomes4MeTM app, a digital application that helps breast cancer patients engage in their care. Methodology: The study was conducted virtually on the Outcomes4MeTM mobile app. Eligible patients (n=203) had stage III/IV breast cancer and resided in the United States. Participants were surveyed on their awareness of Comprehensive Genomic Profiling (CGP), if they have been tested, incentives and barriers to testing, and their willingness to talk to their doctors to learn more/initiate genomic testing. Participants were also able to access educational content on CGP through the app. Analyzed data included: tested vs not tested, cancer subtype and stage, geographic location, and time since diagnosis. Results: Participants represented all 4 breast cancer subtypes, were well-distributed in time since diagnosis, and were located across 43 states. 105 (52%) of patients were HR+HER2-, 152 (75%) were metastatic, and 51 (25%) were stage III/advanced. Most patients (59%) were at least somewhat aware of the availability of CGP and 60% of participants were at least somewhat familiar with CGP. However, only 56 out of 203 eligible surveyed patients (28%) had been tested. Of those patients that were not tested (n=147), only 73 patients (50%) were at least somewhat aware or familiar with CGP. Further, 88% of patients that were not tested said they were interested in genomic testing and 85% said they were likely to ask their doctor about getting genomic testing, after learning about CGP. Conclusion: Despite under-testing, many advanced and metastatic patients are interested in learning more and getting genomic testing. These results are important because they demonstrate the discrepancy between patients’ willingness to get genomic testing and the extent of genomic testing being offered to patients. They also highlight the importance of educational digital apps such as the Outcomes4MeTM app in raising awareness and providing access to CGP, which can ultimately improve outcomes. In fact, many studies have shown that ~40% of patients with HR+HER2- advanced breast cancer have a PIK3CA mutation, where now a new therapy (alpelisib) targeting this mutation is FDA approved. Additional data needs to be collected to identify barriers to genomic testing and how to overcome such barriers to decrease the gap with current guidelines. Chart 1: Results from patient-reported surveysDimension ValueN (%)StageStage IV (Metastatic)152 (75)Stage III (Advanced)51 (25)SubtypeHR+HER2-105 (52)HR+HER2+36 (18)HR-HER2-30 (15)HR-HER2+12 (6)Unknown20 (10)Time from Diagnosis5 years37 (18)Testing StatusHad genomic testing56 (28)Did not have genomic testing147 (72)AwarenessVery aware or somewhat aware of CGP120 (59)Not very aware or not at all aware of CGP83 (41)FamiliarityVery familiar or somewhat familiar with CGP123 (60)Not very familiar or not at all familiar with CGP80 (40)Interest in GCP (non-tested)Very interested or somewhat interested129 (88)Not very interested or not at all interested18 (12)Likeliness of talking to their Doctor (non-tested)Very likely or somewhat likely125 (85)Not very likely or not at all likely22 (15)HR+HER2- (stage III/IV)Tested34 (32)Not Tested71 (68)Interest in learning more about GCP (non-tested HR+HER2-)Very interested or somewhat interested64 (90)Not very interested or not at all interested7 (10)Likeliness to talk to their doctor about CGP (non-tested HR+HER2-)Very likely or somewhat likely60 (85)Not very likely or not at all likely11 (15) Citation Format: Amanda G Stroiney, Osama E Rahma, Maya R Said. Understanding genomic testing in real-world populations at outcomes4Me (GENOME) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-42.

Both immune checkpoint inhibitors (ICI) and antiangiogenesis agents have changed the landscape of cancer treatment in the modern era. While antiangiogenesis agents have demonstrated activities in tumors with high vascularization, including renal cell carcinoma and colorectal cancer, the effect of ICIs has been seen mainly in immunologically recognized tumors, with highly immune-infiltrative lymphocytes. The main challenge in the drug development of ICIs is moving their activities to noninflamed tumors and overcoming resistance that is driven, in part, by the immune-suppressive microenvironment. Angiogenesis factors drive immune suppression by directly suppressing the antigen-presenting cells as well as immune effector cells or through augmenting the effect of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM). Those suppressive immune cells can also drive angiogenesis, creating a vicious cycle of impaired immune activation. The combination of bevacizumab and ipilimumab was the first to show the promising effect of antiangiogenesis and ICIs. A plethora of similar combinations has entered the clinic since then, confirming the promising effects of such approach.

Despite the major role that metastasis plays in the morbidity and mortality of melanoma, stereotyped patterns of metastasis and drivers of its organotropism in melanoma are still not well characterized, limited by a dearth of sequencing data in well-annotated clinical melanoma samples. To address these open questions, we performed an integrative analysis of clinical and genomic features from 243 patients with metastatic melanoma treated at Dana Farber Cancer Institute (DFCI). Tumor biopsies were sequenced with OncoPanel, a next-generation sequencing panel that identifies mutations in 331 cancer genes. Presence of site metastases was evaluated radiographically pre-treatment for each patient; sites include lymph node (64% of cohort), soft tissue (59%), lung (57%), liver (32%), brain (24%), bone (22%), mesentery (12%), adrenal gland (9%), spleen (7%), and other metastatic sites (13%). Metastases showed significant co-occurrences (e.g. bone and lung, OR 2.8, 95% CI = [2.3, 3.3], p < 0.01; adrenal and mesentery, OR 4.4, 95% CI = [3.8, 5.0], p < 0.01) and exclusions (lymph node and brain, OR 0.5, 95% CI = [0.2, 0.8], p = 0.02). We performed unsupervised hierarchical clustering of patients with cutaneous melanoma (n = 203) by metastatic site pattern using a Euclidean distance metric weighted to favor uncommon metastatic sites, yielding five stereotypic patterns of metastasis, characterized by: (1) co-occurrence of adrenal, mesenteric, and abdominal metastases (n=19); (2) liver metastases (n=33); (3) low metastatic burden (n=80); (4) co-occurrence of lung, brain, and mesentery metastases (n=42); and (5) co-occurrence of bone and lung metastases (n=29). Clustering is stable, with highly concordant cluster assignments in repeated subsampling of the data. Patients with cutaneous melanoma (n=203) exhibited both site-specific and pattern-specific genomic correlates of metastatic organotropism that persist after correction for mutational burden. Tumors from patients with liver metastases showed significantly higher prevalence (p < 0.05) of mutation compared to patients without liver metastases in KMT2D (56% vs 18%), BCL6 (22% vs 0%), TMPRSS2 (22% vs 0%), ARID1B (33% vs 4%), MET (33% vs 4%), and AXL (44% vs 11%), with similar enrichment in the liver met-predominant metastatic cluster, implicating dysregulation of histone and protein deacetylation pathways in liver metastatic organotropism (p < 0.01). Numerous additional mutational correlates were found for the remaining nine metastatic sites and all five metastatic patterns, and validation in an orthogonal dataset is ongoing. We present robust stereotypic patterns of metastasis and both site- and pattern-specific genomic correlates of organotropism in metastatic melanoma. By leveraging a valuable clinical/genomic data set, we nominate genetic correlates of organotropism for functional validation and potential therapeutic targets. Citation Format: William H. Ge, Giuseppe Tarantino, Emily Robitschek, Michael P. Manos, Lauren Eastman, Olivia Ouyang, Patrick Ott, Ann W. Silk, Osama E. Rahma, Alexander Gusev, Rizwan Haq, Elizabeth I. Buchbinder, Megan L. Insco, Stephen Hodi, Eliezer Van Allen, David Liu. Stereotypic patterns and genomic correlates of organotropism in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2846.

Purpose: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including that of hepatocellular carcinoma (HCC), and is associated with poor prognosis. Endoglin is essential for angiogenesis, and its expression is induced by hypoxia and VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 mAb that inhibits angiogenesis and causes antibody-dependent cellular cytotoxicity and apoptosis of proliferating endothelium. Experimental Design: Patients with HCC (Child–Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, and 15 mg/kg every 2 weeks given with sorafenib 400 mg twice daily. Correlative biomarkers included DCE-MRI and plasma levels of angiogenic factors, including soluble endoglin. Pharmacokinetics were assessed in serum. Results: Twenty-six patients were enrolled, of whom 25 received treatment, 15 with cirrhosis. Hep B/C: 3/15; M:F 19:6; mean age of 60 (range, 18–76); 1 DLT (grade 3 AST) occurred at 10 mg/kg. The most frequent toxicity was low-grade epistaxis, a known toxicity of TRC105. One patient experienced an infusion reaction and was replaced. One patient with coronary stenosis developed a fatal myocardial infarction, and one patient developed G3 cerebral tumor hemorrhage. MTD was not established and DL4 (15 mg/kg) was expanded. The overall response rate in 24 evaluable patients at all 4 dose levels was 21% [95% confidence interval (CI), 7.1–42.2], and 25% (95% CI, 8.7–49.1) in patients with measureable disease. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median progression-free survival (PFS) for 24 patients evaluable for PFS was 3.8 months (95% CI, 3.2–5.6 months); median overall survival was 15.5 months (95% CI, 8.5–26.3 months). Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity to date (PR rate 25%) was observed, and the study is now continuing to recruit in the phase II stage as a multicenter study to confirm activity of the combination. Clin Cancer Res; 23(16); 4633–41. ©2017 AACR.

Background: ICI are widely used in the treatment of various cancer types. It has been hypothesized that ICI could confer an increased risk of severe acute lung injury or other complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: We analyzed data from 113 patients with laboratory-confirmed COVID-19 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe, and Australia. Data collected included details on symptoms, comorbidities, medications, treatments and investigations for COVID-19, and outcomes (hospital admission, ICU admission, and mortality). Results: The median age was 63 years (range 27–86); 40 (35%) patients were female. Most common malignancies were melanoma (n=64, 57%), non-small cell lung cancer (n=19, 17%), and renal cell carcinoma (n=11, 10%); 30 (27%) patients were treated for early (neoadjuvant/adjuvant) and 83 (73%) for advanced cancer. Most patients received anti-PD-1 (n=85, 75%), combination anti-PD-1 and anti-CTLA-4 (n=15, 13%), or anti-PD-L1 (n=8, 7%) ICI. Comorbidities included cardiovascular disease (n=31, 27%), diabetes (n=17, 15%), and pulmonary disease (n=14, 12%). Symptoms were present in 68 (60%) patients; 46 (68%) had fever, 40 (59%) cough, and 23 (34%) dyspnea. Overall, ICI was interrupted in 58 (51%) patients. At data cutoff, 33 (29%) patients were admitted to hospital, 6 (5%) to ICU, and 9 (8%) patients died. COVID-19 was the primary cause of death in 7 patients, 3 of whom were admitted to ICU. Cancer types in patients who died were melanoma (2), non-small cell lung cancer (2), renal cell carcinoma (2), and others (3); all (9) patients had advanced cancer. Administered treatments were oxygen therapy (8), mechanical ventilation (2), vasopression (2), antibiotics (7), antiviral drugs (4), glucocorticoids (2), and anti-IL-6 (2). Of all hospitalized patients, 20 (61%) had been discharged and 4 (12%) were still in hospital at data cutoff. Conclusion: The mortality rate of COVID-19 in patients on ICI is higher than rates reported for the general population without comorbidities but may not be higher than rates reported for the cancer population. Despite these preliminary findings, COVID-19 patients on ICI may not have symptoms and a proportion may continue ICI. Correlative analyses are ongoing and will be presented. Citation Format: Aljosja Rogiers, Carlo Tondini, Joe M. Grimes, Megan H. Trager, Sharon Nahm, Leyre Zubiri, Neha Papneja, Arielle Elkrief, Jessica Borgers, April Rose, Johanna Mangana, Michael Erdmann, Ines Pires da Silva, Christian Posch, Axel Hauschild, Lisa Zimmer, Paola Queirolo, Caroline Robert, Karijn Suijkerbuijk, Paolo A. Ascierto, Paul Lorigan, Richard Carvajal, Osama E Rahma, Mario Mandala, Georgina V. Long. Clinical characteristics and outcomes of coronavirus 2019 disease (COVID-19) in cancer patients treated with immune checkpoint inhibitors (ICI) [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S02-01.

Background: The MORPHEUS platform comprises multiple Phase Ib/II trials to identify early efficacy signals and safety of treatment combinations across cancers. Within MORPHEUS, atezolizumab (atezo), a PD-L1 inhibitor, was tested in combination with cobimetinib (cobi), a MEK1/2 inhibitor, in patients with advanced/metastatic (m) NSCLC, PDAC or GC. Methods: MORPHEUS-NSCLC (NCT03337698) enrolled patients who had disease progression during or after receiving a platinum-based regimen and a PD-L1/PD-1 checkpoint inhibitor. MORPHEUS-PDAC (NCT03193190) enrolled patients who had received 1 prior line of systematic therapy. MORPHEUS-GC (NCT03281369) enrolled HER2-negative patients who had not received prior chemotherapy. Patients enrolled in the atezo + cobi arms received atezo 840 mg q2w and cobi 40 mg daily on days 1-21 of each 28-day cycle. In MORPHEUS-GC, patients in the atezo + cobi arm also received mFOLFOX6. This arm started with a safety run-in during which cobi 40 mg could be dose escalated to 60 mg. Control treatments were docetaxel (75 mg/m2) in MORPHEUS-NSCLC and mFOLFOX6 or gemcitabine (100 mg/m2) plus nab-paclitaxel (125 mg/m2) in MORPHEUS-PDAC. The MORPHEUS-GC safety run-in did not have a control. Primary endpoints were objective response rate (ORR; investigator-assessed RECIST 1.1) and safety. Results: MORPHEUS-NSCLC (data cutoff, April 10, 2019): 15 patients received atezo + cobi, and 14 patients received control treatment. No responses were observed, and 7 patients had stable disease (SD) as best response in the treatment arm. In the control arm, 3 patients had partial response (PR), and 5 patients had SD as confirmed best response. All treated patients were evaluable for safety, with 67% of atezo + cobi and 93% of control patients experiencing a treatment-related adverse event (TRAE). Updated data from MORPHEUS-NSCLC will be presented. MORPHEUS-PDAC (data cutoff, September 7, 2018): 14 patients received atezo + cobi, and 15 patients received control treatment. There were no responses in either study arm, but 6 patients in the control arm had SD as confirmed best response. All treated patients were evaluable for safety, with 79% of atezo + cobi and 87% of control patients experiencing a TRAE. MORPHEUS-GC (data cutoff, July 11, 2019): 5 patients received atezo + cobi + mFOLFOX6 in the safety run-in after which this arm was terminated (due to internal re-prioritization, no safety concerns identified). Two patients had PR, and 3 patients had SD as confirmed best response. All 5 patients had a TRAE. Biomarker data will also be presented. Conclusions: No superior efficacy signals were identified with atezo + cobi in NSCLC, PDAC or GC. The safety of atezo + cobi was consistent with each agent's known safety profile, with no new safety signals identified. Citation Format: Byoung Chul Cho, Nathan Bahary, Johanna Bendell, Enriqueta Felip, Melissa Johnson, Yoon-Koo Kang, Farah Louise Lim, Teresa Macarulla, Gulam Manji, Do-Youn Oh, Osama Rahma, Simon Allen, Edward Cha, Denise Cotting, Hans-Joachim Helms, Jan Pintoffl, Pakeeza Sayyed, Xiaosong Zhang, Kyu-pyo Kim. Phase Ib/II open-label, randomized evaluation of atezolizumab + cobimetinib vs control in MORPHEUS-NSCLC (non-small cell lung cancer), MORPHEUS-PDAC (pancreatic ductal adenocarcinoma) and MORPHEUS-GC (gastric cancer) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT201.

Background: OX40 is a costimulatory receptor transiently expressed on the surface of activated T cells and some innate immune cells (e.g. NK cells). OX40 agonists have been shown to increase antitumor immunity and improve tumor-free survival in preclinical models, demonstrating increased efficacy when given in combination with a PD-1 inhibitor. GSK998 is a humanized IgG1 agonistic OX40 monoclonal antibody. Methods: ENGAGE-1 (NCT02528357) is a Phase 1 dose escalation study evaluating safety, PK, PD, and clinical activity of GSK998 (0.003-10 mg/kg IV Q3W) alone (Part 1) and in combination with pembrolizumab 200 mg IV Q3W (Part 2) in pts with previously treated advanced solid tumors: non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck, renal cell carcinoma, melanoma (MEL), bladder cancer, soft tissue sarcoma (STS), triple-negative breast cancer, and MSI-high colorectal carcinoma. Dose escalation used a continuous reassessment method and 4-week DLT period. Results: A total of 138 pts were enrolled (45 Part 1, 96 Part 2; 3 crossed over from Part 1). Two DLTs occurred in Part 2 only (G3 non-malignant pleural effusion 0.03 mg/kg; G1 myocarditis 10 mg/kg); MTD was not established. Most common (≥10%) treatment-related AEs (mostly G1-2) were diarrhea, fatigue (Part 1) and fatigue, nausea (Part 2). GSK998 demonstrated target engagement in the periphery as evidenced by PK and receptor occupancy (RO); a dose of 0.3 mg/kg was the threshold for linear PK & peripheral RO saturation over the 3-wk dose interval and was selected for further clinical evaluation in MEL, STS, and NSCLC in Part 2 expansion. Clinical responses and SD ≥24 weeks were observed in both PD-1/L1 naïve and experienced pts: Part 1 (1 PR, 1 SD; both 0.3 mg/kg) and Part 2 (2 CR, 7 PR, 9 SD; 0.01-3 mg/kg); Part 2 clinical responses were not correlated with baseline tumor PD-L1 expression levels; including one MEL pt with PD-L1 TPS=0 who progressed on prior CTLA-4/PD-1 treatment and had a CR (>18mo). Overall, peripheral and tumor expression of OX40 was low ( Citation Format: Sophie Postel-Vinay, Vincent K. Lam, Willeke Ros, Todd M. Bauer, Aaron R. Hansen, Daniel C. Cho, F. Stephen Hodi, Jan H.M. Schellens, Jennifer K. Litton, Sandrine Aspeslagh, Karen A. Autio, Frans L. Opdam, Meredith McKean, Neeta Somaiah, Stephane Champiat, Mehmet Altan, Anna Spreafico, Osama Rahma, Elaine M. Paul, Christoph M. Ahlers, Helen Zhou, Herbert Struemper, Shelby A. Gorman, Maura Watmuff, Kaitlin M. Yablonski, Niranjan Yanamandra, Michael J. Chisamore, Emmett V. Schmidt, Axel Hoos, Aurélien Marabelle, Jeffrey S. Weber, John V. Heymach. A first-in-human phase I study of the OX40 agonist GSK3174998 (GSK998) +/- pembrolizumab in patients (Pts) with selected advanced solid tumors (ENGAGE-1) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT150.

Background: Immune checkpoint inhibitors (ICI) such as anti-PD-1/PD-L1 antibodies have rapidly become a pivotal approach to cancer therapy. Nivolumab is an anti-PD1 antibody approved for treatment of melanoma, lung, renal cell, head and neck squamous, urothelial and increasing number of other solid and hematological malignancies. However, patients with history of autoimmune disorders are excluded from the majority of clinical trials testing ICI. Consequently, the risks of flare ups and worsening of pre-existing autoimmune disorders in patients with tumor types who otherwise stand to benefit from ICI therapy are largely unknown, posing a challenge for oncologists. We are conducting a phase Ib study to test the hypothesis that nivolumab can be safely administered to patients with varying severity of Dermatomyositis, Systemic Sclerosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Multiple Sclerosis and others autoimmune disorders (AIM-Nivo). Methods: AIM-Nivo is an open-label, multi-center ongoing phase Ib study with nivolumab 480mg IV every 28 days in patients with autoimmune diseases and advanced or metastatic solid tumors. The study has autoimmune disease-specific cohorts overseen by a multidisciplinary group of experts. The primary objective is to assess the overall safety and toxicity profile of nivolumab in patients with autoimmune disorders and advanced or metastatic solid tumors. Secondary objectives are to evaluate the antitumor efficacy, the impact of nivolumab on the autoimmune disease severity indices, and to explore potential biomarkers of response, resistance or toxicity. Key overall inclusion criteria include age ≥18 years, histologically confirmed advanced or metastatic solid tumors in which ICI are approved or have shown clinical activity, Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Key overall exclusion criteria include prior therapy with an anti-PD-1/PD-L1 antibodies. Specific eligibility criteria are defined for each disease-specific cohort. For each autoimmune disorder, severity level of the disease as defined by disease-specific severity indices will be assessed, and up to a total of 12 patients will be included in each disease cohort at each severity level. Primary endpoints are dose-limiting toxicities defined for each autoimmune disease-specific cohort, adverse events (AEs) and serious AEs. Continuous monitoring of toxicity will be conducted. Key secondary endpoints are best objective response, progression free and overall survival and cohort specific tumor tissue, blood and non-tumor tissue-based biomarkers. The AIM-Nivo trial opened in May 2019 and is currently enrolling patients in the participating sites through the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN). Clinical trial information: NCT03816345. Citation Format: Ecaterina E. Ileana Dumbrava, Maria Suarez-Almazor, Jeane Painter, Tanner M. Johanns, Michael L. Dougan, Laura Cappelli, Yinghong Wang, Clifton Bingham, Sarthak Gupta, Blake M. Warner, Osama Rahma, Jarushka Naidoo, Patrick A. Ott, David A. Hafler, Harriet Kluger, Arezou Khosroshahi, Rafeh Naqash, Lorinda Chung, Tamiko R. Katsumoto, Shivaani Kummar, Hussein Tawbi, Elad Sharon. A phase 1b study of nivolumab in patients with autoimmune disorders and advanced malignancies (AIM-NIVO) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT249.

Background: Checkpoint inhibitors such as anti-PD-1 are ineffective as single agents for patients (pts) with PDAC. Preclinical data suggest that chemotherapy with agonistic CD40 antibodies can be combined with anti-PD-1 to trigger effective T cell immunity. We conducted a multi-center, open label clinical trial to evaluate the combination of APX005M with nivo and standard chemotherapy (gem and NP). Herein, we report safety and efficacy from the ongoing study. Methods: Pts with previously untreated PDAC were enrolled in 4 cohorts: Gem/NP/APX005M 0.1 mg/kg (B1), Gem/NP/APX005M 0.3 mg/kg (B2), Gem/NP/Nivo/APX005M 0.1 mg/kg (C1) and Gem/NP/Nivo/APX005M 0.3 mg/kg (C2). Primary objectives were to evaluate safety and determine the recommended Phase II dose (RP2D) of APX005M. Secondary objectives included tumor response and immune pharmacodynamics. Analyses were performed on dose-limiting toxicity (DLT)-evaluable subjects, defined as receiving 1 dose of APX005M and ≥ 2 doses of gem/NP during Cycle 1 and remaining on study through Cycle 2 Day 1. Results: N=30 pts dosed; 24 DLT-evaluable (6 per cohort). Median follow up is 32.2 weeks. N=13 (54%) pts experienced an AE leading to discontinuation, and 10 (42%) pts experienced a treatment-related serious AE. Two DLTs were observed, 1 each in cohorts B2 and C1 (grade 3 and 4 febrile neutropenia, respectively). AE rates were similar across cohorts. Four (17%) subjects died (2 each in Cohorts B1 and C1) due to disease progression (n=2) and AE (n=2, sepsis and septic shock in the setting of neutropenia). Within the DLT-evaluable population, best overall responses included 14 (58%) PR (11 confirmed, 3 unconfirmed), 8 (33%) SD, 1 (4%) PD and 1 (4%) NE. Post-baseline tumor assessments were available for 2 of the 6 DLT-inevaluable pts (best overall responses of SD and confirmed PR). Multiplexed IHC analysis of baseline tumors revealed a low CD8 T cell and high macrophage infiltrate. Analysis of circulating mutant KRAS DNA showed marked and rapid decrease with therapy in some pts. Immune profiling of PBMCs at baseline and on-treatment by CyTOF revealed remodeling of the myeloid compartment in response to treatment, with rapid activation of dendritic cells in most pts. Conclusions: Gem/NP/APX005M ± nivo demonstrated manageable safety profiles and promising antitumor activity in untreated metastatic PDAC pts. APX005M 0.3 mg/kg was selected as the dose for a randomized Phase II study in which the primary endpoint is 1-year overall survival. Clinical trial information: NCT02482168. Citation Format: Mark H. O'Hara, Eileen M. O'Reilly, Mick Rosemarie, Gauri Varadhachary, Zev A. Wainberg, Andrew Ko, George A. Fisher, Osama Rahma, Jaclyn P. Lyman, Christopher R. Cabanski, Erica L. Carpenter, Travis Hollmann, Pier Federico Gherardini, Lacey Kitch, Cheryl Selinsky, Theresa LaVallee, Ovid C. Trifan, Ute Dugan, Vanessa M. Hubbard-Lucey, Robert H. Vonderheide. A Phase Ib study of CD40 agonistic monoclonal antibody APX005M together with gemcitabine (Gem) and nab-paclitaxel (NP) with or without nivolumab (Nivo) in untreated metastatic ductal pancreatic adenocarcinoma (PDAC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT004.

Background: ICOS is a costimulatory molecule upregulated on activated T cells. JTX-2011 is an ICOS agonist antibody intended to stimulate primed CD4 T effector cells. JTX-2011 was assessed in pts with advanced solid tumors as monotherapy (mono) and combination (combo) with nivolumab (nivo) in the Phase I/II ICONIC trial (NCT02904226). Peripheral T cell phenotyping in ICONIC demonstrated emergence of an ICOS high (hi) subset of CD4 T cells associated with tumor reductions in mono and combo pts. In ex vivo studies, soluble JTX-2011 stimulated a polyfunctional cytokine response only in ICOS hi cells. Methods: Ad hoc flow cytometry phenotyping on PBMCs from a subset of pts with evaluable samples (n=50) was initiated retrospectively in early 2018 in ongoing pts, then prospectively on newly enrolled pts. Clinical characteristics and outcomes were analyzed, including unadjusted p-values for post-hoc statistical analyses. Phenotyping was also done on samples from pts treated with PD-1/L1 inhibitor (PD-1/L1i) mono collected outside of ICONIC. Results: Emergence of ICOS hi CD4 T effector cells (all FoxP3-, subset Tbet+ Ki67+) was observed in all pts with ≥30% target lesion tumor reduction by investigator assessment on mono and combo therapy (n=7). Emergence was seen in pts with stable target lesions (n=11/23) including loss of these cells with disease progression. ICOS hi cells were not seen in ICONIC pts with target lesion increase ≥20% (n=14), or in pts treated with PD-1/L1i mono, including responders. Emergence of ICOS hi CD4 T cells correlated with improved PFS and OS (Table). ICONIC Pt characteristicsICOS hi (N=18)ICOS low (N=32)≥3 prior therapies, n (%)13 (72.2)18 (56.3)Prior immunotherapy, n (%)6 (33.3)15 (46.9)Tumor type, n (%)Gastric n=9 (50), NSCLC n=3 (16.7), TNBC n=2 (11.1), Other n=4 (22.2)Gastric n=8 (25), NSCLC n=6 (18.8), TNBC n=4 (12.5), Other n=14 (43.8),Mono vs Combo, n (%)Mono n=2 (11.1), Combo n=16 (88.9)Mono n=11 (34.4), Combo n=21 (65.6)G3-4 treatment-related adverse events, n (%)1 (5.6)2 (6.3)Time on JTX-2011, median mths (range), p=0.00065.6 (1.45-18.4)1.41 (0.03-6.28)PFS, investigator and central imaging review, median mths, (investigator, p Conclusion: Emergence of a distinct ICOS hi population of peripheral CD4 T cells is associated with improved PFS and OS with JTX-2011 mono and combo therapy. Two JTX-2011 development paths are planned: (1) combo with agents that induce ICOS hi CD4 T cells; (2) use of potential putative biomarkers predictive of emergence of this T cell population and JTX-2011 response. Citation Format: Timothy Anthony Yap, Justin F. Gainor, Margaret K. Callahan, Gerald S. Falchook, Russell Kent Pachynski, Patricia LoRusso, Shivaani Kummar, Geoffrey Thomas Gibney, Howard A. Burris, Scott S. Tykodi, Osama E. Rahma, Tanguy Seiwert, Kyriakos P. Papadopoulos, Ellen Hooper, Christopher J. Harvey, Amanda Hanson, Sean Lacey, Rachel McComb, Courtney Hart, Haley Laken, Ty McClure, Elizabeth Trehu. Improved progression-free and overall survival (PFS/OS) in patients (pts) with emergence of JTX-2011 associated biomarker (ICOS high CD4 T cells) on the ICONIC trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT189.

Background: Immunotherapy has recently emerged as a promising modality in cancer treatment, but little is known about the application of this modality in pancreatic cancer (PC). Tumor-infiltrating lymphocytes (TILs) play a major role in anti-tumor immune responses, and their presence is correlated with survival in a variety of tumors. These TILs do not reach the PC cells in significant numbers due to the presence of stroma and a suppressive microenvironment. One of the leading causes for immune suppression is elevated expression of PD-L1 either by the tumor cells or the surrounding regulatory cells, resulting in dysfunction of TILs. Neoadjuvant chemoradiation therapy (CRT) has been advocated as a potential way to improve outcomes of patients with resectable or borderline resectable PC. More importantly, there is recent evidence to suggest that CRT can increase the presence of TILs in the PC microenvironment (PCME), leading to production of interferon-γ (IFN-γ), which could increase the expression of PD-L1 through a negative feedback loop. Accordingly, we hypothesize that blocking the PD-1 receptor will synergize with CRT to increase the density and activation of TILs in the PCME. Methods: This is a prospective multicenter randomized trial which will accrue subjects with resectable or borderline resectable pancreatic cancer who had not received prior treatment for PC. The primary objectives of the study are: (1) to determine the safety of neoadjuvant CRT in combination with Pembrolizumab. (2) To estimate the difference in the number of TILs in pancreatic cancer subjects receiving neoadjuvant CRT in combination with Pembrolizumab to the number of TILs in subjects receiving neoadjuvant CRT alone. This study will also investigate the effect of CRT+/-anti-PD-1 on the other effector and suppressive immune cells and immune checkpoints in PCME. Eligible subjects will be randomized 2:1 to the investigational treatment (Arm A) to receive Pembrolizumab administered IV every 3 weeks on days 1, 22, and 43 during concurrent CRT with capecitabine (825 mg/m2 orally twice daily, Monday through Friday, on days of radiation only) and radiation (50.4 Gy in 28 fractions over 28 days) or Arm B to receive only concurrent CRT with capecitabine. In all subjects, restaging CT scan or MRI will be performed at 4-6 weeks after completion of neoadjuvant treatment to determine resectability. Patients without local or distant disease progression will be taken to the operative room for planned surgery (within 2 weeks of imaging). Postoperatively, resected patients will receive off study standard of care adjuvant gemcitabine (1000mg/kg IV weekly for 3 out of 4 weeks for 6 months). Post operatively resected patients will be followed for up for PFS and OS for up to 2 years. Citation Format: Matthew H.G Katz, Todd W. Bauer, Gauri Rajani Varadhachary, Reid B. Adams, Amy R. Lankford, Gina Petroni, Timothy N. Bullock, Craig L. Slingluff, Osama E. Rahma. A randomized multicenter phase Ib/II study to assess the safety and the immunological effect of chemoradiation therapy (CRT) in combination with Pembrolizumab (anti-PD1) to CRT alone in patients with resectable or borderline resectable pancreatic canc [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT220. doi:10.1158/1538-7445.AM2015-CT220

Purpose: Peptide antigens have been administered by different approaches in cancer vaccine therapy, including direct injection or pulsed onto dendritic cells; however, the optimal delivery method is still debatable. In this study, we describe the immune response elicited by the wild-type (wt) p53 vaccine using two approaches. Experimental Design: Twenty-one HLA-A2.1 patients with stage III, IV, or recurrent ovarian cancer overexpressing the p53 protein with no evidence of disease were treated in two cohorts. Arm A received subcutaneous wt p53:264-272 peptide admixed with Montanide and GM-CSF. Arm B received wt p53:264-272 peptide-pulsed dendritic cells intravenously. Interleukin-2 (IL-2) was administered in both cohorts in alternative cycles. The immunologic response was assessed by ELISPOT and tetramer assays. Results: Nine of 13 patients (69%) in arm A and 5 of 6 patients (83%) in arm B had an immunologic response. The vaccine caused no serious systemic side effects. IL-2 administration resulted in grade 3 and 4 toxicities in both arms and directly induced expansion of T regulatory cells. The median overall survival was 40.8 and 29.6 months for arm A and B, respectively; the median progression-free survival was 4.2 and. 8.7 months, respectively. Conclusion: We demonstrated that using either vaccination approach could generate comparable specific immune responses against the wt p53 peptide with minimal toxicity. Accordingly, our findings support the utilization of the less demanding subcutaneous method. Furthermore, as IL-2 may add toxicity and induce T regulatory cells, which can suppress the immune response, therefore, it may not be needed in future trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2414.