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Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating provider and do not account for individual variation among patients. See Appendix 1 (online only) for disclaimers and other important information. Updates are published regularly and can be found at https://ascopubs.org/nsclc-da-living-guideline .

Adavosertib selectively inhibits Wee1, which regulates intra-S and G2/M cell-cycle checkpoints. This study investigated dosing schedules for adavosertib monotherapy, determining the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients with advanced solid tumors.Patients received oral adavosertib qd or bid on a 5/9 schedule (5 days on treatment, 9 days off) in 14-day cycles, or qd on one of two 5/2 schedules (weekly, or for 2 of 3 weeks) in 21-day cycles. Safety, efficacy, and pharmacokinetic analyses were performed.Sixty-two patients (female, 64.5%; median age, 61.5 years; most common primary tumors: lung [24.2%], ovary [21.0%]) received treatment (qd schedules, n = 50; bid schedules, n = 12) for 1.8 months (median). Median time to maximum adavosertib concentration was 2.2–4.1 h; mean half-life was 5–12 h. Adverse events (AEs) caused dose reductions, interruptions and discontinuations in 17 (27.4%), 25 (40.3%) and 4 (6.5%) patients, respectively. Most common grade ≥ 3 AEs were anemia, neutropenia (each n = 9, 14.5%) and diarrhea (n = 8, 12.9%). Seven (11.3%) patients experienced 10 treatment-related serious AEs (pneumonia n = 2 [3.2%], dehydration n = 2 [3.2%], anemia n = 1 [1.6%], febrile neutropenia n = 1 [1.6%], and thrombocytopenia n = 1 [1.6%]). Overall objective response rate was 3.4% (2/58); disease control rate was 48.4% (30/62); median progression-free survival was 2.7 months.MTDs were 125 mg (bid 5/9) and 300 mg (qd 5/9 and 5/2 for 2 of 3 weeks); RP2D was 300 mg (qd 5/2 for 2 of 3 weeks). The safety profile was manageable, acceptable, and generally concordant with the known safety profile.

Background This was an open-label, multicenter, single-arm phase Ib dose-escalation study of oral LCL161 administered in combination with oral topotecan in patients with relapsed/refractory small cell lung cancer (SCLC) and select gynecological cancers. Methods Cohorts of 3-6 patients initiated treatment with LCL161 and topotecan in escalating doses. LCL161 was administered orally on days 1, 8, and 15 of each 21-day cycle; topotecan was administered orally for the first 5 days of each 21-day cycle. Results A total of 35 patients were enrolled in 6 cohorts; 30 patients were female; 4 patients had SCLC and 19 patients had ovarian cancer. Median prior lines of therapy were 3 (1-10). Median duration of treatment was 7.1 weeks (0.1-174). The most frequent grade 3/4 treatment-related adverse events were thrombocytopenia (51.43%) and anemia (31.43%). ORR was 9.7%; 58% of patients had SD. The study was stopped early before the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) were determined. Conclusion The addition of LCL161 to oral topotecan caused more myelosuppression when dosed together than what was associated with either drug alone. Moreover, the drug combination did not improve outcomes. The study was terminated early (ClinicalTrials.gov Identifier: NCT02649673).

High tumor mutational burden (TMB-H) correlates with improved immunotherapy response. We assessed atezolizumab 1,200 mg every 3 weeks for TMB-H tumors from MyPathway (NCT02091141), a phase IIa multibasket study. One hundred twenty-one patients had advanced solid tumors with TMB ≥10 mut/Mb by any Clinical Laboratory Improvement Amendments (CLIA)–certified assay. The preplanned primary endpoint was objective response rate (ORR) in patients with TMB ≥16 mut/Mb tumors by FoundationOne TMB testing [F1(CDx)]. Patients with F1(CDx) TMB ≥10 and Significance:Atezolizumab monotherapy had promising, durable clinical activity across a variety of advanced solid tumor types in patients with TMB ≥16 mut/Mb tumors lacking other suitable treatment options and who were immunotherapy-naïve at enrollment, regardless of microsatellite instability status. Limited activity was observed in tumors with TMB ≥10 and See related commentary by Maron and Klempner, p. 602.This article is highlighted in the In This Issue feature, p. 587

Supplementary Figure from Atezolizumab Treatment of Tumors with High Tumor Mutational Burden from MyPathway, a Multicenter, Open-Label, Phase IIa Multiple Basket Study

Supplementary Data from Atezolizumab Treatment of Tumors with High Tumor Mutational Burden from MyPathway, a Multicenter, Open-Label, Phase IIa Multiple Basket Study

PURPOSE The phase III PACIFIC trial compared durvalumab with placebo in patients with unresectable, stage III non–small-cell lung cancer and no disease progression after concurrent chemoradiotherapy. Consolidation durvalumab was associated with significant improvements in the primary end points of overall survival (OS; stratified hazard ratio [HR], 0.68; 95% CI, 0.53 to 0.87; P = .00251) and progression-free survival (PFS [blinded independent central review; RECIST v1.1]; stratified HR, 0.52; 95% CI, 0.42 to 0.65; P < .0001), with manageable safety. We report updated, exploratory analyses of survival, approximately 5 years after the last patient was randomly assigned. METHODS Patients with WHO performance status 0 or 1 (any tumor programmed cell death-ligand 1 status) were randomly assigned (2:1) to durvalumab (10 mg/kg intravenously; administered once every 2 weeks for 12 months) or placebo, stratified by age, sex, and smoking history. Time-to-event end point analyses were performed using stratified log-rank tests. Medians and landmark survival rates were estimated using the Kaplan-Meier method. RESULTS Seven hundred and nine of 713 randomly assigned patients received durvalumab (473 of 476) or placebo (236 of 237). As of January 11, 2021 (median follow-up, 34.2 months [all patients]; 61.6 months [censored patients]), updated OS (stratified HR, 0.72; 95% CI, 0.59 to 0.89; median, 47.5 v 29.1 months) and PFS (stratified HR, 0.55; 95% CI, 0.45 to 0.68; median, 16.9 v 5.6 months) remained consistent with the primary analyses. Estimated 5-year rates (95% CI) for durvalumab and placebo were 42.9% (38.2 to 47.4) versus 33.4% (27.3 to 39.6) for OS and 33.1% (28.0 to 38.2) versus 19.0% (13.6 to 25.2) for PFS. CONCLUSION These updated analyses demonstrate robust and sustained OS and durable PFS benefit with durvalumab after chemoradiotherapy. An estimated 42.9% of patients randomly assigned to durvalumab remain alive at 5 years and 33.1% of patients randomly assigned to durvalumab remain alive and free of disease progression, establishing a new benchmark for standard of care in this setting.

Purpose: This study assessed the efficacy, safety, and pharmacokinetics of adavosertib in combination with four chemotherapy agents commonly used in patients with primary platinum-resistant ovarian cancer. Patients and Methods: Women with histologically or cytologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer with measurable disease were enrolled between January 2015 and January 2018 in this open-label, four-arm, multicenter, phase II study. Patients received adavosertib (oral capsules, 2 days on/5 days off or 3 days on/4 days off) in six cohorts from 175 mg once daily to 225 mg twice daily combined with gemcitabine, paclitaxel, carboplatin, or pegylated liposomal doxorubicin. The primary outcome measurement was overall response rate. Results: Three percent of patients (3/94) had confirmed complete response and 29% (27/94) had confirmed partial response. The response rate was highest with carboplatin plus weekly adavosertib, at 66.7%, with 100% disease control rate, and median progression-free survival of 12.0 months. The longest median duration of response was in the paclitaxel cohort (12.0 months). The most common grade ≥3 adverse events across all cohorts were neutropenia [45/94 (47.9%) patients], anemia [31/94 (33.0%)], thrombocytopenia [30/94 (31.9%)], and diarrhea and vomiting [10/94 (10.6%) each]. Conclusions: Adavosertib showed preliminary efficacy when combined with chemotherapy. The most promising treatment combination was adavosertib 225 mg twice daily on days 1–3, 8–10, and 15–17 plus carboplatin every 21 days. However, hematologic toxicity was more frequent than would be expected for carboplatin monotherapy, and the combination requires further study to optimize the dose, schedule, and supportive medications.

Supplementary Figure S1. CA125 response to lifastuzumab vedotin in ovarian cancer patients. All patients with radiographic responses also had {greater than or equal to}50 decrease in CA125 from baseline levels.

Purpose: This study was conducted to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the i.v. pan-aurora kinase inhibitor PHA-739358, danusertib, in patients with advanced solid tumors.Experimental Design: In part 1, patients received escalating doses of danusertib (24-hour infusion every 14 days) without filgrastim (granulocyte colony-stimulating factor, G-CSF). Febrile neutropenia was the dose-limiting toxicity without G-CSF. Further dose escalation was done in part 2 with G-CSF. Blood samples were collected for danusertib pharmacokinetics and pharmacodynamics. Skin biopsies were collected to assess histone H3 phosphorylation (pH3).Results: Fifty-six patients were treated, 40 in part 1 and 16 in part 2. Febrile neutropenia was the dose-limiting toxicity in part 1 without G-CSF. Most other adverse events were grade 1 to 2, occurring at doses ≥360 mg/m2 with similar incidence in parts 1 and 2. The maximum tolerated dose without G-CSF is 500 mg/m2. The recommended phase 2 dose in part 2 with G-CSF is 750 mg/m2. Danusertib showed dose-proportional pharmacokinetics in parts 1 and 2 with a median half-life of 18 to 26 hours. pH3 modulation in skin biopsies was observed at ≥500 mg/m2. One patient with refractory small cell lung cancer (1,000 mg/m2 with G-CSF) had an objective response lasting 23 weeks. One patient with refractory ovarian cancer had 27% tumor regression and 30% CA125 decline.Conclusions: Danusertib was well tolerated with target inhibition in skin at ≥500 mg/m2. Preliminary evidence of antitumor activity, including a partial response and several occurrences of prolonged stable disease, was seen across a variety of advanced refractory cancers. Phase II studies are ongoing. (Clin Cancer Res 2009;15(21):6694–701)

Supplementary tables S1-S3 and Supplementary figures S1-Se

Purpose:This study assessed the efficacy, safety, and pharmacokinetics of adavosertib in combination with four chemotherapy agents commonly used in patients with primary platinum-resistant ovarian cancer.Patients and Methods:Women with histologically or cytologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer with measurable disease were enrolled between January 2015 and January 2018 in this open-label, four-arm, multicenter, phase II study. Patients received adavosertib (oral capsules, 2 days on/5 days off or 3 days on/4 days off) in six cohorts from 175 mg once daily to 225 mg twice daily combined with gemcitabine, paclitaxel, carboplatin, or pegylated liposomal doxorubicin. The primary outcome measurement was overall response rate.Results:Three percent of patients (3/94) had confirmed complete response and 29% (27/94) had confirmed partial response. The response rate was highest with carboplatin plus weekly adavosertib, at 66.7%, with 100% disease control rate, and median progression-free survival of 12.0 months. The longest median duration of response was in the paclitaxel cohort (12.0 months). The most common grade ≥3 adverse events across all cohorts were neutropenia [45/94 (47.9%) patients], anemia [31/94 (33.0%)], thrombocytopenia [30/94 (31.9%)], and diarrhea and vomiting [10/94 (10.6%) each].Conclusions:Adavosertib showed preliminary efficacy when combined with chemotherapy. The most promising treatment combination was adavosertib 225 mg twice daily on days 1–3, 8–10, and 15–17 plus carboplatin every 21 days. However, hematologic toxicity was more frequent than would be expected for carboplatin monotherapy, and the combination requires further study to optimize the dose, schedule, and supportive medications.

Purpose:This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody–drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E).Patients and Methods:LIFA was administered to patients with non–small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D).Results:Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline).Conclusions:LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.

Supplementary Data from A Phase I Dose-Escalation Study of Danusertib (PHA-739358) Administered as a 24-Hour Infusion with and without Granulocyte Colony-Stimulating Factor in a 14-Day Cycle in Patients with Advanced Solid Tumors

Supplementary Figure S2. Representative NaPi2b ICH images for PROC and NSCLC patients.

Supplementary Table S1. Adverse events regardless of relationship to study drug occurring in 10 or more patients Supplementary Table S2. Adverse events grades 3-5 regardless of relationship to study drug occurring in 2 or more patients Supplementary Table S3. Pulmonary adverse events by frequency of occurrence in all patients regardless of relationship to study drug Supplementary Table S4. Pulmonary adverse events of NCI-CTCAE grade 3 or higher by frequency of occurrence in all patients regardless of relationship to study drug Supplementary Table S5. Mean (standard deviation) of the pharmacokinetic parameters for antibody-conjugated MMAE in plasma Supplementary Table S6. Mean (standard deviation) of the pharmacokinetic parameters for total antibody in plasma Supplementary Table S7. Mean (standard deviation) of the pharmacokinetic parameters for unconjugated MMAE in plasma Supplementary Table S8. Response outcomes and duration

PURPOSE Molecular biomarkers informing disease diagnosis, prognosis, and treatment decisions in patients with breast cancer are being uncovered by next-generation sequencing (NGS) technologies. In this study, we survey how NGS is used for patients with breast cancer in real-world settings with a focus on physician behaviors and sequencing results. METHODS We conducted a retrospective analysis of patients with breast cancer who received NGS testing from commercial vendors as part of standard of care from 2014 to 2019. A total of 2,635 NGS reports from 2,316 unique breast cancer patients were assessed. Hormone receptor and human epidermal growth factor receptor 2 statuses were abstracted from patient medical records. Comparative gene amplification and mutation frequencies were analyzed using Pearson's correlation and Lin's concordance statistics. RESULTS The number of physicians ordering NGS tests for patients with breast cancer increased more than six-fold from 2014 to 2019. Tissue- and plasma-based tests were ordered roughly equally by 2019, with plasma-based testing ordered most frequently in hormone receptor–positive subtypes. Patients with triple-negative breast cancer were most likely to receive NGS testing. Gene amplifications including ERBB2 were detected less frequently in our real-world data set as compared to previous genomic landscape studies, whereas the opposite was true for gene mutations including ESR1. Pathogenic mutations in the PI3K pathway (38.6%) and DNA damage repair pathway (11.0%) were frequently reported. Alterations were also reported across other cellular pathways. CONCLUSION Overall, we found that an increasing number of physicians in community settings are adopting NGS in the care of patients with breast cancer. Discrepancies between our real-world NGS data and previous genomic landscape studies are likely owed to the prevalence of plasma-based testing in community oncology clinics, as the reference data were from tissue-based NGS alone.

PURPOSE Next-generation sequencing (NGS) testing is being incorporated into routine standard of care for patients with cancer. Immune checkpoint inhibitors (CPIs) are approved for use in both tumor-specific and tumor-agnostic indications. We sought to determine tumor type–specific or tumor-agnostic correlations between mutations detected by NGS and response to CPIs. MATERIALS AND METHODS A retrospective analysis of 26,004 patient records with NGS data available was conducted. Time to treatment failure and overall survival analyses were performed. Hazard ratios and associated statistics were computed in the R programming language. The study was considered exempt from internal review board review and data were considered nonhuman subjects. RESULTS Response to CPIs varied between tumor types with melanoma and lung cancer performing relatively better on CPIs than other tumor types. Within tumor types, response to CPIs was stratified by mutations in specific genes. Tumor-agnostic markers including high tumor mutation burden and microsatellite instability-high were also associated with longer time to treatment failure on CPIs. Importantly, within the high tumor mutation burden and microsatellite instability-high groups, mutations in individual genes correlate with response to CPIs. CONCLUSION The results from commercial NGS panels may be used to stratify patients for response to CPIs. In tumors where CPIs show relatively low efficacy, there may be distinct patient populations—based on gene mutation status—that are predicted to have better response to CPIs. Likewise, there may be distinct patient populations who do relatively worse on CPIs within tumor types known to respond well to CPIs.

This first-in-human phase I study (NCT03179436) investigated anti-cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody quavonlimab and anti-programmed death 1 monoclonal antibody pembrolizumab in patients with advanced solid tumors. The study was conducted in two parts: dose-escalation (part 1) and dose-confirmation (part 2). First-line treatment with quavonlimab + pembrolizumab conferred encouraging antitumor activity (objective response rate [ORR], 28%-40%) and was generally well tolerated (grade ≥ 3 treatment-related adverse events [TRAEs] were lowest with quavonlimab 25 mg every 6 weeks [Q6W] at 30% and highest with quavonlimab 75 mg Q3W at 57%) in non-small cell lung cancer. We present data from patients with extensive-stage small cell lung cancer (SCLC) receiving second-line or later therapy.Patients with stage III/IV SCLC received quavonlimab 75 mg Q6W plus pembrolizumab 200 mg Q3W for ≤ 2 years. Primary endpoints were safety and tolerability; ORRs as assessed by blinded independent central review per Response Evaluation Criteria In Solid Tumorsv1.1 was a secondary endpoint. Progression-free survival (PFS), overall survival (OS), and the correlation of response with PD-L1 expression were exploratory endpoints.Forty patients with extensive-stage SCLC received treatment; median follow-up was 13 months. Dose-limiting toxicity occurred in 4 patients (10%). TRAEs occurred in 80% of patients; grade 3 events occurred in 33% of patients and no grade 4/5 events were reported. Confirmed ORRs (95% CI) were 18% (7-33) among all patients, 7% (1-34) for PD-L1-positive tumors (n = 14), and 19% (5-42) for PD-L1-negative tumors (n = 21). Response duration ranged from 2.9 to 19.1+ months. Median PFS was 2.0 months; 6-month PFS rate was 26%. Median OS was 11.0 months; 6-month OS rate was 66%.Encouraging antitumor activity was observed with quavonlimab + pembrolizumab in patients with extensive-stage SCLC; responses were observed in PD-L1-positive and PD-L1-negative tumors. The combination was tolerable with manageable toxicities.

Summary Background Systemic therapies for metastatic biliary tract cancers are few, and patients have a median overall survival of less than 1 year. MyPathway evaluates the activity of US Food and Drug Administration-approved therapies in non-indicated tumours with potentially actionable molecular alterations. In this study, we present an analysis of patients with metastatic biliary tract cancers with HER2 amplification, overexpression, or both treated with a dual anti-HER2 regimen, pertuzumab plus trastuzumab, from MyPathway. Methods MyPathway is a non-randomised, multicentre, open-label, phase 2a, multiple basket study. Patients aged 18 years and older with previously treated metastatic biliary tract cancers with HER2 amplification, HER2 overexpression, or both and an Eastern Cooperative Oncology Group performance status of 0–2 were enrolled from 23 study sites in the USA and received intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) plus trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). The primary endpoint was investigator-assessed objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary outcome and adverse events were analysed in all patients who received at least one dose of pertuzumab and trastuzumab. This trial is registered with ClinicalTrials.gov , NCT02091141 , and is ongoing. Findings 39 patients enrolled in the MyPathway HER2 biliary tract cancer cohort between Oct 28, 2014, and May 29, 2019, were evaluable for anti-tumour activity by the March 10, 2020, data cutoff date. Median follow-up was 8·1 months (IQR 2·7–15·7). Nine of 39 patients achieved a partial response (objective response rate 23% [95% CI 11–39]). Grade 3–4 treatment-emergent adverse events were reported in 18 (46%) of 39 patients, most commonly increased alanine aminotransferase and increased aspartate aminotransferase (each five [13%] of 39). Treatment-related grade 3 adverse events were reported in three (8%) of 39 patients, including increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, and blood bilirubin. Serious treatment-emergent adverse events were observed in ten (26%) of 39 patients, of which only abdominal pain occurred in more than one patient (two [5%] of 39). There were no treatment-related serious adverse events, treatment-related grade 4 events, or deaths. Interpretation Treatment was well tolerated in patients with previously treated HER2-positive metastatic biliary tract cancer. The response rate is promising for the initiation of randomised, controlled trials of pertuzumab plus trastuzumab in this patient population. Funding F Hoffmann-La Roche–Genentech.

PURPOSE: Insufficient characterization of the optimal multidisciplinary team and lack of understanding of barriers to quality care are unmet needs in the management of stage III or IV non–small-cell lung cancer (NSCLC). A national survey was conducted to inform the design and execution of process improvement plans and address identified barriers. METHODS: A steering committee of multidisciplinary specialists and representation from patient advocacy collaborated for a comprehensive, double-blind, web-based survey (January-April 2019) to obtain insights on care delivery for patients with advanced NSCLC in a diverse set of US community cancer programs. RESULTS: Overall, 639 responses (160 unique cancer programs across 44 US states) were included; 41% (n = 261) of respondents indicated an absence of a thoracic multidisciplinary clinic in their cancer program. Engagement in shared decision making was significantly associated with the presence of navigation and radiation oncology disciplines ( P ≤ .04); 19.2% and 33.3% of respondents belonged to cancer programs with no lung cancer screening and no protocol for biomarker testing, respectively. The frequency of tumor board meetings negatively correlated with time to complete disease staging ( P = .03); the average time to first therapeutic intervention in newly diagnosed patients was 4 weeks. The most challenging barriers to quality care included insufficient quantity of biopsy material for biomarker testing, lack of primary care provider referrals, and diagnostic costs. CONCLUSION: Improving the quality of advanced NSCLC care, including optimization of a multidisciplinary team framework, may surmount barriers to care coordination, diagnosis and staging, and treatment planning, consequently improving adherence to evolving standards of care.

Living guidelines are routinely updated guidelines that are developed for selected topic areas with rapidly evolving evidence that drives frequent change in clinical practice. These guidelines are updated on a regular schedule, based on the work of a standing panel that reviews the literature on a continuous basis. Updates will be made regularly and can be found at https://ascopubs.org/nsclc-da-living-guideline . PURPOSE To provide evidence-based recommendations updating the 2021 ASCO and Ontario Health (Cancer Care Ontario) guideline on systemic therapy for patients with stage IV non–small-cell lung cancer (NSCLC) with driver alterations. METHODS ASCO updated recommendations on the basis of an ongoing systematic review of randomized control trials from 2020 to 2021. RESULTS This guideline update reflects changes in evidence since the previous update. Two studies provide the evidence base. Outcomes of interest include efficacy and safety. RECOMMENDATIONS For patients with an anaplastic lymphoma kinase rearrangement, a performance status (PS) of 0-2, and previously untreated NSCLC, clinicians should offer alectinib or brigatinib or lorlatinib. For patients with an anaplastic lymphoma kinase rearrangement, a PS of 0-2, and previously untreated NSCLC, if alectinib, brigatinib, or lorlatinib are not available, clinicians should offer ceritinib or crizotinib. For patients with a RET rearrangement, a PS of 0-2, and previously untreated NSCLC, clinicians may offer selpercatinib or pralsetinib. In second line, for patients with a RET rearrangement who have not received RET-targeted therapy, clinicians may offer selpercatinib or pralsetinib. Additional information is available at www.asco.org/thoracic-cancer-guidelines .

Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC.CheckMate 331 is a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS).Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy [median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11]. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%.Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.

Objectives: The JAVELIN Lung 200 phase 3 trial did not meet its primary endpoint of improving overall survival (OS) with avelumab vs docetaxel in patients with platinum-treated PD-L1+ NSCLC. We report post hoc analyses assessing the effects of subsequent immune checkpoint inhibitor (ICI) treatment on OS. Material and methods: Patients with stage IIIB/IV NSCLC progressed following platinum-doublet therapy were randomized to receive avelumab or docetaxel. OS was analyzed in the PD-L1+ population (?1% of tumor cells) and full analysis set (PD-L1+ or PD-L1-). Effects of subsequent ICI (after permanent discontinuation of study treatment) on OS were analyzed using a preplanned naive sensitivity analysis and post hoc inverse probability of censoring weighting (IPCW) analysis. Subgroups with or without subsequent ICI treatment were analyzed using descriptive statistics. Results: In the avelumab and docetaxel arms, a subsequent ICI was received by 16/396 (4.0 %) and 104/396 (26.3 %) after a median of 10.5 months (range, 3.9?20.4) and 5.7 months (range, 0.1?24.4), respectively. Some subgroups showed trends for higher subsequent ICI treatment, including patients with non-squamous NSCLC (avelumab arm, 4.3 % vs docetaxel arm, 32.1 %) or with a baseline ECOG performance status of 0 (6.3 % vs 31.3 %); those enrolled in the early recruitment wave (11.6 % vs 54.3 %), or enrolled in the US/Western Europe (2.8 % vs 45.5 %) or Asia (11.0 % vs 35.4 %); and non-white patients (10.1 % vs 35.0 %). The hazard ratio for OS with avelumab vs docetaxel was lower in the IPCW analysis than in the naive sensitivity analysis (PD-L1+ population: 0.80 [95 % CI, 0.62-1.04] vs 0.86 [95 % CI, 0.68-1.09], respectively). Conclusion: In the JAVELIN Lung 200 trial, avelumab showed clinical activity as second-line treatment for patients with advanced NSCLC. Post hoc analyses suggest that the primary OS analysis may have been confounded by subsequent ICI use in the docetaxel arm. ClinicalTrials.gov identifier: NCT02395172. Merck KGaA, Darmstadt, Germany This work was supported by Merck KGaA, Darmstadt, Germany, as part of an alliance between Merck KGaA and Pfizer. Employees of the sponsor are coauthors of this manuscript, who contributed to the design, execution, and interpretation of the analyses being reported, writing the report, and the decision to submit the article for publication, along with other coauthors

Background: High-dose interleukin-2 (HD IL-2) induces durable clinical responses in a subset of patients with melanoma and RCC, but severe toxicity limits its therapeutic utility. Early clinical data from several not-α IL-2Rβγ agonists suggest better tolerability but lower objective response rates compared to historical HD IL-2 data.1-2 In patients, these not-α IL-2s demonstrate a profound NK cell bias, while retaining activity on Tregs, and exhibiting limited CD8+ T cell expansion.3-5AB248 is a CD8+ selective IL-2 that demonstrates more than 500-fold selectivity for CD8+ T cells over other immune cell types. AB248 has demonstrated a highly differentiated preclinical profile, with compelling anti-tumor activity and less toxicity when given alone and in combination with anti-PD1 in multiple murine tumor models. These data suggest that AB248 may have an improved therapeutic index compared to broad-acting IL-2Rβγ agonists by increasing CD8+ T cell expansion and activation, avoiding NK cell-driven toxicity and avoiding Treg-mediated immunosuppression. Here we introduce the first-in-human study which aims to investigate AB248 when administered alone and in combination with pembrolizumab in subjects with advanced solid tumors who failed prior standard of care therapies. Methods: This open-label phase 1a/b study consisting of a dose escalation and expansion phase aims to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of AB248 alone or in combination with pembrolizumab in subjects with locally advanced/metastatic tumors, including melanoma, renal cell carcinoma, NSCLC and SCCHN, who failed prior therapies, including prior anti-PD(L)1, as well as in first-line SCCHN during the expansion phase. Key eligibility criteria include age ≥18 years, ECOG ≤1, measurable disease per RECIST v1.1, adequate end-organ function, and no autoimmune disease. The dose escalation phase will follow the Bayesian Optimal Interval (BOIN) design and enroll subjects at multiple dose levels and schedules for the AB248 monotherapy and pembrolizumab combination portion. Upon identifying suitable dose and schedule based on the totality of cumulative data including safety, PK, PD and preliminary efficacy, additional subjects will be enrolled in indication specific cohorts in the expansion phase according to the Simon 2-stage design. The primary objectives for this study are to assess the safety and tolerability of AB248 alone or in combination with pembrolizumab. Secondary objectives include assessing the PK, PD changes, immunogenicity, and antitumor activity. Exploratory objectives include evaluating the potential response-predictive and/or associated changes in immune cells, blood, and tissue biomarkers. Tumor assessments will be performed every 6 weeks for the first 30 weeks and every 9 weeks thereafter. Adverse events will be assessed by CTCAE v5.0. The study is currently open for enrollment in the dose escalation phase at multiple sites in the US. Citation Format: Elizabeth I. Buchbinder, David R. Spigel, Costantine Albany, Michael Chisamore, Kelly D. Moynihan, Xiaohan Liu, Christopher DelNagro, Matt Axt, Andrea Pirzkall. An open-label, phase 1a/b study of AB248, a CD8+ selective IL-2 mutein fusion protein, alone or in combination with pembrolizumab in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT250.

Background: NRG1 fusions represent a rare and potentially actionable oncogenic alteration found in ~0.2% of solid tumors. Seribantumab is a fully human anti-HER3 IgG2 monoclonal antibody that blocks aberrant NRG1 fusion protein binding to HER3 thereby preventing ligand-dependent activation and dimerization resulting in complete inhibition of the PI3K/AKT and MAPK downstream signaling pathways. Seribantumab has shown significant anti-tumor activity in PDX models and in patients (pts) with solid tumors harboring NRG1 fusions. Methods: CRESTONE (NCT04383210) is a phase 2 study of seribantumab in adult pts with solid tumors harboring NRG1 fusions who received at least one prior therapy and were naïve to ERBB-targeted therapy (Cohort 1); pts previously treated with ERBB-targeted therapies (exploratory Cohort 2) and pts with tumors harboring additional molecular alterations (exploratory Cohort 3). Here, we present updated efficacy results for pts in Cohort 1 dosed at 3 g IV QW. Safety data are evaluated for pts enrolled in Cohort 1 and exploratory Cohorts 2 and 3. Results: As of Dec 2, 2022, 51 pts were enrolled across all cohorts with 30 pts in Cohort 1 dosed at 3 g IV QW. Median age was 62 years (range 19-84); median prior lines of therapy was 2 (range 1-7); tumor types included non-small cell lung cancer (NSCLC, n=30), pancreatic adenocarcinoma (PDAC, n=6), biliary tract/cholangiocarcinoma (CCA, n=6), breast (n=4), and others (n=5); 15 different NRG1 fusion partners were identified with CD74 (22%) and SLC3A2 (16%) as the most frequently reported. In the overall safety population, 41 pts (80%) reported at least one treatment-related adverse event (TRAE). The most common TRAEs (occurring in ≥20% of pts) were diarrhea (41%), fatigue (29%), rash (24%), and nausea (22%). Four pts (8%) experienced Gr 3/4 TRAEs; no Gr 5 TRAEs. The safety profile for Cohort 1 was similar to the overall safety population. Among the 30 pts in Cohort 1, 22 were evaluable for investigator assessed (INV) response per RECIST v1.1; 2 pts (9%) had confirmed complete response (CR), 6 pts (27%) had confirmed partial response (PR), and 13 pts (59%) had stable disease (SD) as their best overall response (BOR). The INV objective response rate (ORR, confirmed PR + CR) was 36% and disease control rate (DCR, confirmed PR+CR+SD) was 95%. The overall duration of response ranged from 1.4 to 17.2 months. In pts with NSCLC, the INV-ORR was 39% and DCR was 94%. Conclusions: Seribantumab has an acceptable safety and tolerability profile as a single agent in pts with solid tumors harboring NRG1 fusions. Updated efficacy data indicate seribantumab has robust and durable clinical activity, including CRs, across different tumor types harboring an NRG1 fusion and is a promising treatment option. Citation Format: Tejas Patil, Daniel R. Carrizosa, Mark E. Burkard, Karen L. Reckamp, Jayesh Desai, Young Kwang Chae, Stephen V. Liu, Kartik Konduri, Shirish M. Gadgeel, Jessica J. Lin, Parneet K. Cheema, David R. Spigel, Alison M. Schram, Valerie M. Jansen, Yasir Y. Elamin. CRESTONE: A Phase 2 study of seribantumab in adult patients with neuregulin-1 (NRG1) fusion positive locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT229.

Neuregulin-1 (encoded by NRG1) serves as a ligand for ERBB3 and can lead to dysregulated cellular proliferation in cases of NRG1 fusions. The reported incidence of NRG1 fusions in solid tumors is ~0.1-0.3% with enrichment in invasive mucinous adenocarcinoma of the lung and KRAS wildtype pancreatic adenocarcinoma. However, the real-world incidence of NRG1 fusions across diverse tumor types continues to evolve with the clinical implementation of comprehensive next-generation sequencing (NGS) methods including RNA based NGS. The true diversity and prognostic significance of specific NRG1 fusion partners has yet to be elucidated. We report on NRG1 fusions from a large clinico-genomic database of patients (pts) in community-based oncology settings where NGS is ordered as standard clinical practice. We conducted a retrospective, records-based analysis of pts across Sarah Cannon’s network of over 299 partner community-based oncology clinics to identify pts with NRG1 fusions detected by commercial NGS testing ordered as a part of standard of care from 1/1/2017 - 7/7/2022. NRG1 fusions were reported in 0.05% (19 of 40,857) of pts with commercial NGS test results across a range of tumor types including lung (59%; n=11/19), pancreas (11%; n=2), breast (5%; n=1), colorectal (5%), esophageal (5%), endometrial (5%), soft tissue liposarcoma (5%), and carcinoma of unknown primary (5%). NGS identifying an NRG1 fusion was performed in 5 (26%) pts with early stage disease while 11 (58%) pts had NGS testing after initial diagnosis of or progression to advanced/metastatic disease. A majority of pts harboring NRG1 fusions were female (68%; n=13). NRG1 fusions were detected by DNA (58%; n=11) and RNA based (42%; n=8) NGS from liquid (5%; n=1) and tissue biopsies (95%; n=18). A total of 11 different fusion partners were reported. CD74 was the most prevalent fusion partner and was primarily detected by DNA NGS including in one pt from liquid biopsy. Five novel, as yet to be described, fusion partners (CDK13, IL1RL2, FUT10, PPP2R2A, PIM3) were detected - 3 by RNA sequencing and 2 by DNA sequencing of NRG1 (versus sequencing of the fusion partner). TP53 (42%; n=8), CDKN2A (32%; n=6), and MTAP (16%; n=3) were the most frequently co-altered genes. Other notable co-altered genes included mutations in PIK3CA (11%; n=2), BRAF (5%; n=1), EGFR (5%), ALK (5%), and NRAS (5%). Immune biomarkers were largely negative, with 16% (n=3) PD-L1 positive, 0% MSI-high, and 5% (n=1) TMB-high cases. These data highlight the importance of comprehensive molecular profiling for pts with solid tumors, as NRG1 fusions occur across tumor types and stage of disease. Appropriate test selection is paramount as novel NRG1 fusions are more robustly detected by RNA over DNA NGS and are more routinely detected in tissue over liquid biopsies. Clinical trials investigating therapies to target NRG1 fusions are ongoing [CRESTONE (NCT04383210); eNRGy (NCT02912949)]. Citation Format: Emma G. Sturgill, Jaya Srivastava, Jessica Correia, Cooper Schumacher, Daniel Luckett, Cesar A. Perez, Judy S. Wang, Stephen G. Divers, Babar Bashir, Jennifer Johnson, Valerie M. Jansen, Andrew J. McKenzie, David R. Spigel. Identification of NRG1 fusions in patients with solid tumors: analysis from a real-world community oncology network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 921.

Background: Molecular biomarkers such as the expression status of hormone receptors (HR) and HER2 influence disease diagnosis, prognosis, and treatment decisions in breast cancer patients. Recent advances in genetic sequencing technologies and targeted therapies have revealed additional actionable biomarkers including PIK3CA, ESR1, and BRCA1/2; however, it remains unclear whether physicians in community-based clinics are universally adopting molecular profiling practices. Here, we describe the utility of next generation sequencing (NGS) in the care of breast cancer patients in community-based clinics with a focus on physician behaviors and molecular landscapes. Methods: Sarah Cannon provides clinical research services to medical oncology practices who order NGS panels as part of standard of care. Genospace, Sarah Cannon’s web-based precision medicine platform, links NGS test results with electronic medical records to identify and analyze clinico-genomic data of molecularly-profiled cancer patients. Here, a total of 2,673 NGS reports from 2,313 unique patients dated between January 2014 and December 2019 were analyzed. Hormone statuses were abstracted from physician notes using natural language processing capabilities and manual abstraction. Linear regression modeling was used for statistical analysis. Results: Physician ordering of NGS tests for breast cancer patients increased 6.3-fold from 2014 to 2019. Ordering of plasma-based NGS tests increased from 0.6% (versus 99.4% tissue) in 2014 to 47.0% (versus 53.0% tissue) in 2019. The time from initial diagnosis to NGS results increased from a median of 1008 days in 2015 to 1296 days in 2019 (p < 0.05), while the time from specimen collection to NGS test results (tissue only) decreased from 53 days in 2015 to 28 days in 2019 (p < 0.01). The majority of NGS-tested breast cancer patients were HR+/HER2- (62.6%), followed by HR-/HER2- (21.5%), HR+/HER2+ (8.4%), HR-/HER2+ (4.4%), and HER2 equivocal (3.0%). Plasma-based NGS testing was utilized more commonly in HR+ cancers (43.4% of HR+; 25.3% of HR-). In agreement with published studies, BRCA1 alterations were enriched in HR- cancers (1.7% of HR+; 6.6% of HR-) and BRCA2 alterations were enriched in HR+ cancers (6.4% of HR+; 3.2% of HR-). Amplifications in CCND1 (21.7% of HR+; 2.2% of HR-) and FGFR1 (18.1% of HR+; 6.2% of HR-) were also enriched in HR+ cancers, as were mutations in ESR1 (18.9% of HR+; 1.0% of HR-). PIK3CA mutations occurred most frequently in HR+ cancers (45.0%), but were also present in HR- cancers (20.9%). TP53 mutations were comparatively high in HR- cancers (42.9% of HR+; 94.8% of HR-). Conclusions: The usage of NGS for the care of breast cancer patients is increasing in community settings. Plasma-based NGS tests are ordered more frequently in HR+ cancers, likely as a result of difficult-to-biopsy and poor yield bone-only disease. Despite increased testing frequencies, NGS tests are ordered later-in-care which may be a reflection of earlier diagnosis or the development of more efficacious standard of care therapies in front line settings. The tissue specimens sent for sequencing are collected closer to the test date, indicating improved tissue processing systems and prioritization of fresh specimen collection for NGS testing. Overall, physicians are adopting NGS-testing as part of standard of care for breast cancer patients in the community setting and are discovering actionable mutations. Frequency of detection of molecular biomarkers in NGS-tested breast cancer patientsTissueTissueTissueTissuePlasmaPlasmaPlasmaPlasmaGeneAlterationHR+/HER2-HR-/HER2-HR+/HER2+HR-/HER2+HR+/HER2-HR-/HER2-HR+/HER2+HR-/HER2+ERBB2Amp1.1%0.5%45.4%67.9%0.0%0.8%10.4%45.5%CCND1Amp21.3%1.7%21.8%5.1%7.5%1.7%5.2%0.0%MYCAmp9.3%15.5%18.5%17.9%1.3%5.8%1.3%9.1%FGFR1Amp17.4%6.8%18.5%3.8%6.5%3.3%2.6%0.0%PIK3CAMutation43.8%19.1%49.6%32.1%49.5%25.0%50.6%30.3%ESR1Mutation19.4%1.2%13.4%0.0%41.7%4.2%31.2%0.0%BRCA1Mutation1.9%7.2%0.8%3.8%5.1%5.0%2.6%9.1%BRCA2Mutation6.7%3.6%5.9%1.3%8.8%5.8%14.3%3.0%ERBB2Mutation3.4%1.4%11.8%6.4%9.5%1.7%15.6%12.1%TP53Mutation42.2%94.7%51.3%93.6%65.8%96.7%68.8%93.9%PTENMutation8.8%10.6%2.5%3.8%12.6%10.8%7.8%6.1%PALB2Mutation1.6%1.2%0.8%0.0%0.2%0.0%0.0%0.0%MTORMutation0.7%0.2%0.8%0.0%2.7%0.0%0.0%0.0%ARID1AMutation9.0%4.8%12.6%2.6%11.0%11.7%7.8%3.0%KRASMutation3.2%3.1%0.8%2.6%6.5%8.3%5.2%6.1%AKT1Mutation6.5%3.4%2.5%1.3%7.5%6.7%1.3%0.0%n=856n=414n=119n=78n=602n=120n=77n=33 Citation Format: Emma Sturgill, Amanda Misch, Rebecca Lachs, Carissa Jones, Dan Schlauch, Suzanne Jones, Mythili Shastry, Denise Yardley, Howard Burris, David Spigel, Erika Hamilton, Andrew McKenzie. Physician adoption and molecular landscape of next-generation sequencing in breast cancer patients from community-based clinics [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 PS18-34.

We characterized the safety of first-line nivolumab plus ipilimumab (NIVO+IPI) in a large patient population with metastatic NSCLC and efficacy outcomes after NIVO+IPI discontinuation owing to treatment-related adverse events (TRAEs).We pooled data from three first-line NIVO+IPI studies (NIVO, 3 mg/kg or 240 mg every 2 wk; IPI, 1 mg/kg every 6 wk) in metastatic NSCLC (CheckMate 227 part 1, CheckMate 817 cohort A, CheckMate 568 part 1). Safety end points included TRAEs and immune-mediated adverse events (IMAEs) in the pooled population and patients aged 75 years or older.In the pooled population (N = 1255), any-grade TRAEs occurred in 78% of the patients, grade 3 or 4 TRAEs in 34%, and discontinuation of any regimen component owing to TRAEs in 21%. The most frequent TRAE and IMAE were diarrhea (20%; grade 3 or 4, 2%) and rash (17%; grade 3 or 4, 3%), respectively. The most common grade 3 or 4 IMAEs were hepatitis (5%) and diarrhea/colitis and pneumonitis (4% each). Pneumonitis was the most common cause of treatment-related death (5 of 16). Safety in patients aged 75 years or older (n = 174) was generally similar to the overall population, but discontinuation of any regimen component owing to TRAEs was more common (29%). In patients discontinuing NIVO+IPI owing to TRAEs (n = 225), 3-year overall survival was 50% (95% confidence interval: 42.6-56.0), and 42% (31.2-52.4) of 130 responders remained in response 2 years after discontinuation.First-line NIVO+IPI was well tolerated in this large population with metastatic NSCLC and in patients aged 75 years or older. Discontinuation owing to TRAEs did not reduce long-term survival.

Supplemental Digital Content is available in the text., CheckMate 218, a North American expanded access program (EAP), investigated nivolumab plus ipilimumab in patients with advanced melanoma. Safety and efficacy, including 2-year survival in clinically relevant patient subgroups, are reported. Eligible patients were aged ≥18 years with unresectable stage III/IV melanoma, an Eastern Cooperative Oncology Group performance status of 0/1, and no prior checkpoint inhibitors. Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction) followed by nivolumab 3 mg/kg every 2 weeks (maintenance) until progression or unacceptable toxicity or a maximum of 48 weeks. Safety and overall survival (OS) data were collected. This EAP included 754 treated patients from the USA (n = 580) and Canada (n = 174). Median follow-up time was 17.8 months. All-grade and grade 3–4 treatment-related adverse events were reported in 96% and 53% of patients and led to treatment discontinuation in 36% and 26% of patients, respectively. OS rates at 12 and 24 months were 82% [95% confidence interval (CI) 79–84] and 70% (95% CI 66–74), respectively. Twenty-four-month OS rates were 63% in patients aged ≥75 years, 56% in patients with elevated lactate dehydrogenase levels, 73% in patients with BRAF wild-type tumors, 70% in patients with BRAF mutant tumors, and 56% in patients with mucosal melanoma. In this EAP, nivolumab plus ipilimumab demonstrated high survival rates and safety outcomes consistent with those from randomized clinical trials, further supporting the use of this combination for advanced melanoma across multiple subgroups.

Background The efficacy and safety of the anti–programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab, as compared with those of platinum-based chemotherapy, as first-line trea...

Background Early cancer detection could identify tumors at a time when outcomes are superior and treatment is less morbid. This prospective case-control sub-study (from NCT02889978 and NCT03085888) assessed the performance of targeted methylation analysis of circulating cell-free DNA (cfDNA) to detect and localize multiple cancer types across all stages at high specificity. Participants and methods The 6689 participants [2482 cancer (>50 cancer types), 4207 non-cancer] were divided into training and validation sets. Plasma cfDNA underwent bisulfite sequencing targeting a panel of >100 000 informative methylation regions. A classifier was developed and validated for cancer detection and tissue of origin (TOO) localization. Results Performance was consistent in training and validation sets. In validation, specificity was 99.3% [95% confidence interval (CI): 98.3% to 99.8%; 0.7% false-positive rate (FPR)]. Stage I–III sensitivity was 67.3% (CI: 60.7% to 73.3%) in a pre-specified set of 12 cancer types (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile-duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach), which account for ∼63% of US cancer deaths annually, and was 43.9% (CI: 39.4% to 48.5%) in all cancer types. Detection increased with increasing stage: in the pre-specified cancer types sensitivity was 39% (CI: 27% to 52%) in stage I, 69% (CI: 56% to 80%) in stage II, 83% (CI: 75% to 90%) in stage III, and 92% (CI: 86% to 96%) in stage IV. In all cancer types sensitivity was 18% (CI: 13% to 25%) in stage I, 43% (CI: 35% to 51%) in stage II, 81% (CI: 73% to 87%) in stage III, and 93% (CI: 87% to 96%) in stage IV. TOO was predicted in 96% of samples with cancer-like signal; of those, the TOO localization was accurate in 93%. Conclusions cfDNA sequencing leveraging informative methylation patterns detected more than 50 cancer types across stages. Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies.

Purpose: This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody–drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E). Patients and Methods: LIFA was administered to patients with non–small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D). Results: Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline). Conclusions: LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.

Neoantigens arising from mutations in tumor DNA provide targets for immune-based therapy. Here, we report the clinical and immune data from a Phase Ib clinical trial of a personalized neoantigen-vaccine NEO-PV-01 in combination with pemetrexed, carboplatin, and pembrolizumab as first-line therapy for advanced non-squamous non-small cell lung cancer (NSCLC). This analysis of 38 patients treated with the regimen demonstrated no treatment-related serious adverse events. Multiple parameters including baseline tumor immune infiltration and on-treatment circulating tumor DNA levels were highly correlated with clinical response. De novo neoantigen-specific CD4

RESILIENT (NCT03088813) is a phase 2/3 study assessing the safety, tolerability, and efficacy of liposomal irinotecan monotherapy in patients with small cell lung cancer and disease progression on/after first-line platinum-based therapy. Here, we present results from RESILIENT part 1. This open-label, single-arm, safety run-in evaluation with dose-exploration and dose-expansion phases included patients ≥18 years old with Eastern Cooperative Oncology Group performance status of 0/1; those with asymptomatic central nervous system metastases were eligible. The primary objectives were to evaluate safety and tolerability and recommend a dose for further development. Efficacy end points were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). During dose exploration, 5 patients received intravenous liposomal irinotecan at 85 mg/m2 (deemed not tolerable; dose-limiting toxicity) and 12 patients received 70 mg/m2 (deemed tolerable). During dose expansion, 13 additional patients received intravenous liposomal irinotecan at 70 mg/m2 . Of these 25 patients (median age [range], 59.0 [48.0-73.0] years, 92.0% with metastatic disease), 10 experienced grade ≥3 treatment-related treatment-emergent adverse events (TEAEs), most commonly diarrhea (20.0%) and neutropenia (16.0%), and 3 had serious treatment-related TEAEs, of whom 2 died. ORR was 44.0% (95% confidence interval [CI]: 24.40-65.07; 1 complete response, 10 partial responses) and median (95% CI) PFS and OS were 3.98 (1.45-4.24) months and 8.08 (5.16-9.82) months, respectively. Overall, no new safety signals were identified with liposomal irinotecan, and antitumor activity was promising. RESILIENT part 2, a randomized, controlled, phase 3 study of liposomal irinotecan versus topotecan, is ongoing. Small cell lung cancer (SCLC) is an aggressive disease with few treatment options after platinum-based therapy. Administering 1 option, irinotecan, as a "liposomal" formulation, may extend drug exposure and improve outcomes. The RESILIENT part 1 trial assessed the safety and efficacy of liposomal irinotecan in 25 adults with SCLC after disease progression despite platinum-based therapy. No new safety concerns were reported. The most common moderate-to-severe side effects were diarrhea (20% of patients) and neutropenia (16%). Tumors responded to treatment in 44% of patients. Average survival was 8.08 months, and time to disease progression was 3.98 months. Liposomal irinotecan trials are ongoing.

High tumor mutational burden (TMB-H) correlates with improved immunotherapy response. We assessed atezolizumab 1,200 mg every 3 weeks for TMB-H tumors from MyPathway (NCT02091141), a phase IIa multibasket study. One hundred twenty-one patients had advanced solid tumors with TMB ≥10 mut/Mb by any Clinical Laboratory Improvement Amendments (CLIA)–certified assay. The preplanned primary endpoint was objective response rate (ORR) in patients with TMB ≥16 mut/Mb tumors by FoundationOne TMB testing [F1(CDx)]. Patients with F1(CDx) TMB ≥10 and Significance: Atezolizumab monotherapy had promising, durable clinical activity across a variety of advanced solid tumor types in patients with TMB ≥16 mut/Mb tumors lacking other suitable treatment options and who were immunotherapy-naïve at enrollment, regardless of microsatellite instability status. Limited activity was observed in tumors with TMB ≥10 and See related commentary by Maron and Klempner, p. 602. This article is highlighted in the In This Issue feature, p. 587

738 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a devastating diagnosis with an overall 5-year survival rate of ~10%. Therapies targeting KRAS G12D, a prevalent molecular driver of PDAC, represent an active area of investigation with many agents currently in clinical development. This study characterizes the real-world clinico-genomic landscape of patients with KRAS G12D-mutated PDAC to inform ongoing therapeutic development and clinical trial design. Methods: We conducted a retrospective, records-based analysis of 2,805 patients with PDAC from across 299 community-based oncology clinics. All patients had broad-panel next generation sequencing (NGS) from commercial vendors performed as standard of care. Patients were stratified into KRASWT (26%), KRASG12D (31%), and KRASnon-G12D (43%) cohorts according to NGS results and assessed for co-mutations, overall survival, and time to chemotherapy failure. Results: The KRASG12D and KRASnon-G12D cohorts exhibited similar mutational landscapes with frequent alterations in TP53, CDKN2A, and SMAD4 ( > 20% frequency occurrence) and infrequent actionable co-mutations (i.e. ATM, MTAP, BRCA1/2, PIK3CA, and MYC; < 5% frequency occurrence). KRASG12D exhibited significantly decreased overall survival compared to KRASWT (m (95% CI); 32.4 months (27.6-37.6 months) [ KRASWT], 20.1 months (17.0-22.7 months) [ KRASG12D], 21.7 months (20.0-25.0 months) [ KRASnon-G12D]; Cox model p-value < 0.001) as well as significantly shortened time to chemotherapy failure compared to both KRASnon-G12D and KRASWT (m (95% CI); 10.8 months (9.6-11.6 months) [ KRASWT], 7.8 months (7.3-8.7 months) [ KRASG12D], 9.8 months (8.8-11.1 months) [ KRASnon-G12D]; Cox model p-value < 0.01). Within the KRASG12D cohort, no co-mutations were significantly associated with overall survival. Conclusions: This study demonstrates the acute need for KRAS G12D-targeted agents in the clinic, as patients with KRAS G12D-driven PDAC experience particularly poor patient outcomes and lack alternative molecular targets.

BackgroundB7-H6 is a member of the B7 family of immune receptors, which is expressed in several solid tumor types but very little expression can be detected in normal tissues.1 2 BI 765049 is a novel IgG-like bispecific T-cell engager designed to bind simultaneously to B7-H6 on tumor cells and CD3 on T cells, resulting in cytolytic synapse formation and tumor lysis. Preclinical studies have demonstrated that BI 765049 monotherapy induced dose-dependent anti-tumor activity in humanized in vivo CRC tumor models. Consistent with the mode of action, the treatment with BI 765049 led to target cell apoptosis, local T-cell activation/proliferation and cytokine production in the tumor tissue, with PD-(L)1 upregulation.3 Activation of the PD-(L)1 provides the rationale for combining BI 765049 with a PD1 inhibitor.MethodsNCT04752215 is a first-in-human, open-label, dose-escalation trial of BI 765049 ± the PD-1 inhibitor, ezabenlimab. Adults with advanced, unresectable and/or metastatic CRC, NSCLC, HNSCC, hepatocellular, gastric or pancreatic carcinoma are eligible. Patients must have failed on, or be ineligible, for standard therapies. B7-H6 positivity must be confirmed at screening by central review (immunohistochemistry assay) in archived tissues/in-study fresh biopsies (except CRC). Patients must have ≥1 evaluable lesion (modified RECIST 1.1) outside of the central nervous system and adequate organ function. The primary objective is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 765049 ± ezabenlimab, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD and preliminary efficacy of BI 765049 ± ezabenlimab. The trial may assess up to 4 dosing regimens: A (BI 765049 once every 3 weeks [q3w]); B1 (BI 765049 qw); B2 (BI 765049 qw with step-in doses); C (BI 765049 + ezabenlimab [q3w]). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control that will be fitted to binary toxicity outcomes using a hierarchical modelling approach to jointly model all dosing regimens. Treatment will be allowed to continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria or for a maximum duration of 36 months, whichever occurs first. Approximately 150–175 patients will be screened and ~120 patients enrolled. As of July 2021, patients are being recruited in early dose-escalation cohorts.AcknowledgementsMedical writing support for the development of this abstract, under the direction of the authors, was provided by Becky O’Connor, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim.Trial RegistrationNCT04752215ReferencesBrandt et al. J Exp Med 2009;206:1495–503.Boehringer Ingelheim. Data on file.Hipp et al. AACR Annual Meeting 2021.Ethics ApprovalThe trial will be carried out in compliance with the protocol, the ethical principles laid down in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good Clinical Practice (GCP) and the EU directive 2001/20/EC/EU regulation 536/2014.

96 Background: Despite the availability of molecularly-targeted agents for the treatment of many cancer types, gaps remain in integrating comprehensive precision oncology decision support tools and services into routine clinical practice. Molecular Tumor Boards (MTBs) have been shown to improve accurate incorporation of precision oncology and oncologic clinical trial enrolment into clinical practice. However, the traditional MTB model is a didactic meeting occurring at regular pre-scheduled cadences which may not align with treatment decisions or schedules of community-based general medical oncologists and advanced practice providers (APPs) without protected time away from clinic. Herein, we report on the utilization of an on-demand virtual MTB (vMTB) implemented at Tennessee Oncology (TO) powered by the Personalized Medicine (PM) team at the Sarah Cannon Research Institute (SCRI). Methods: “MolecularHelp” (MH) decision support services were implemented in September 2021 for oncology providers at TO – a network of over 100 oncologists and 86 APPs practicing across 34 clinics in Tennessee. The MH services request was a structured order that could be placed directly within the electronic health record (EHR) or through patient-protected email within the practice. MH orders initiated a virtual, on-demand interpretation of comprehensive genomic profiling (CGP) reports by a centralized vMTB run by SCRI's PM team and supported by Genospace, SCRI's precision medicine software platform. The PM team – comprised of pharmacologists, cell biologists, human geneticists, and molecular biologists – analyze CGP results and provide expert advice on both standard-of-care (SOC) and clinical research therapeutic options. Both SOC and clinical research targeted therapy options were relayed back to the treating physician and embedded within the EHR. Herein, we report key metrics including MH order frequency, average turnaround time, and subsequent clinical trial enrolment between September 2021 and March 2022. Results: CGP reports from 120 unique patients were reviewed by the vMTB during the collection period. MH orders were initiated by 30 TO providers from 14 different clinic locations across Middle and East Tennessee. The average turnaround time from referral to vMTB interpretation was less than 10 hours. Of the 120 patients reviewed, actionable mutations were identified by the MTB in 103 patients, of whom 27 subsequently enrolled onto clinical trials (15 phase 1 and 12 phase 2/3). Conclusions: An on-demand vMTB is feasible within an engaged community oncology practice with investments in bioinformatics, decision support software tools, and a team of precision oncology experts supported by a robust clinical trial menu. On-demand vMTBs can be widely adopted to enhance clinical trial enrolment. Future directions include studying the impact of vMTBs on patient outcomes over time.

Background Tumor mutation burden (TMB), a biomarker for immune checkpoint inhibitor (CPI) response, is reported by both blood- and tissue-based next-generation sequencing (NGS) vendors. However, the agreement between TMB from blood (bTMB) and tissue (tTMB) in real-world settings, both in absolute value and association with CPI response, is not known. Materials and Methods This study utilizes Sarah Cannon’s precision medicine platform, Genospace, to harmonize clinico-genomic data from 17 206 patients with cancer with NGS results from September 2015 to August 2021. A subset of patients have both bTMB and tTMB results. Statistical analyses are performed in R and include (1) correlation (r) and concordance (ρ) between patient-matched bTMB-tTMB pairs, (2) distribution of total bTMB and tTMB values, and (3) association of bTMB and tTMB with time to CPI therapy failure. Results In 410 patient-matched bTMB-tTMB pairs, the median bTMB (m = 10.5 mut/Mb) was significantly higher than the median tTMB (m = 6.0 mut/Mb, P < .001) leading to conflicting “high” and “low” statuses in over one-third of cases at a threshold of 10 mut/Mb (n = 410). Significant differences were observed in the distribution of bTMB values from blood-NGS vendors, with guardant health (GH) reporting higher (m = 10.5 mut/Mb, n = 2183) than Foundation Medicine (FMI, m = 3.8 mut/Mb, n = 462, P < .001). bTMB from GH required a higher threshold (≥40 mut/Mb) than bTMB from FMI (≥12 mut/Mb) in order to be associated with CPI response. Conclusions This study uncovers variability in bTMB reporting among commercial NGS platforms, thereby evidencing a need for assay-specific thresholds in identifying patients who may respond to CPI therapy.

Background Poly(ADP-ribose) polymerase (PARP) inhibitors may synergize with programmed cell death receptor-1 (PD-1) inhibitors to enhance adaptive and innate antitumor immune responses. In the phase 2 JASPER study (NCT04475939), the PARP inhibitor niraparib was evaluated in combination with the PD-1 inhibitor pembrolizumab in patients with metastatic and/or locally advanced non-small cell lung cancer (NSCLC). Methods Patients whose tumors had programmed cell death ligand 1 (PD-L1) tumor proportion scores (TPS) ≥50% (cohort 1) or 1%-49% (cohort 2) received first-line niraparib (200 mg once daily) plus pembrolizumab (200 mg every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR). Secondary end points included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Results Thirty-eight patients were enrolled in cohorts 1 and 2. In cohort 1, ORR (95% confidence interval [CI]) was 56.3% (9 of 16 patients; 29.9%-80.2%); 2 of 16 patients had complete responses and 7 of 16 had partial responses (PRs). In cohort 2, ORR was 20.0% (5.7%-43.7%) with 4 of 20 PRs. In cohorts 1 and 2, the median DoR was 19.7 months (95% CI, 4.2 months to not estimable [NE]) and 9.4 months (95% CI, 4.2 months to NE), the median PFS was 8.4 months (95% CI, 3.9-22.1 months) and 4.2 months (95% CI, 2.0-6.2 months), and the median OS was NE (95% CI, 6.0 months to NE) and 7.7 months (95% CI, 4.0-12.5 months), respectively. Grade ≥3 treatment-emergent adverse events occurred in 88.2% and 85.7% of patients in cohorts 1 and 2, respectively. Safety was consistent with known profiles of single-agent niraparib and pembrolizumab. Conclusions Niraparib plus pembrolizumab showed clinical activity in patients with advanced and/or metastatic NSCLC. Lay summary The JASPER clinical trial studied a new combination treatment for advanced or metastatic non-small cell lung cancer (NSCLC). Pembrolizumab, a drug approved for NSCLC, was given with niraparib. Previous research showed that these 2 drugs together might work better than either drug alone. This study found that more than half of patients with high levels of a tumor marker responded to the combination, and one-fifth of patients with lower levels of the marker responded. The types of side effects from the combination were similar to side effects from both drugs alone. These results support more research on this combination.