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PURPOSE Small-cell lung cancer (SCLC) is an aggressive malignancy with limited treatments. Delta-like ligand 3 (DLL3) is aberrantly expressed in most SCLC. Tarlatamab (AMG 757), a bispecific T-cell engager molecule, binds both DLL3 and CD3 leading to T-cellb–mediated tumor lysis. Herein, we report phase I results of tarlatamab in patients with SCLC. PATIENTS AND METHODS This study evaluated tarlatamab in patients with relapsed/refractory SCLC. The primary end point was safety. Secondary end points included antitumor activity by modified RECIST 1.1, overall survival, and pharmacokinetics. RESULTS By July 19, 2022, 107 patients received tarlatamab in dose exploration (0.003 to 100 mg; n = 73) and expansion (100 mg; n = 34) cohorts. Median prior lines of anticancer therapy were 2 (range, 1-6); 49.5% received antiprogrammed death-1/programmed death ligand-1 therapy. Any-grade treatment-related adverse events occurred in 97 patients (90.7%) and grade b % 3 in 33 patients (30.8%). One patient (1%) had grade 5 pneumonitis. Cytokine release syndrome was the most common treatment-related adverse event, occurring in 56 patients (52%) including grade 3 in one patient (1%). Maximum tolerated dose was not reached. Objective response rate was 23.4% (95% CI, 15.7 to 32.5) including two complete and 23 partial responses. The median duration of response was 12.3 months (95% CI, 6.6 to 14.9). The disease control rate was 51.4% (95% CI, 41.5 to 61.2). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.1 to 5.4) and 13.2 months (95% CI, 10.5 to not reached), respectively. Exploratory analysis suggests that selecting for increased DLL3 expression can result in increased clinical benefit. CONCLUSION In patients with heavily pretreated SCLC, tarlatamab demonstrated manageable safety with encouraging response durability. Further evaluation of this promising molecule is ongoing.

PURPOSE We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non–small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status. METHODS Adults with stage IV/recurrent non–small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life. RESULTS At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed. CONCLUSION With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non–small-cell lung cancer. [Media: see text]

Over the last decade, the use of targeted therapies and immune therapies led to drastic changes in the management lung cancer and translated to improved survival outcomes. This growing arsenal of therapies available for the management of non-small cell lung cancer added more complexity to treatment decisions. The genomic profiling of tumors and the molecular characterization of the tumor microenvironment gradually became essential steps in exploring and identifying markers that can enhance patient selection to facilitate treatment personalization and narrow down therapy options. The advent of innovative diagnostic platforms, such as next-generation sequencing and plasma genotyping (also known as liquid biopsies), has aided in this quest. Currently, programmed cell death ligand 1 expression remains the most recognized and fully validated predictive biomarker of response to immune checkpoint inhibitors. Other markers such as tumor mutational burden, tumor infiltrating lymphocytes, driver mutations, and other molecular elements of the tumor microenvironment bear the potential to be predictive tools; however, the majority are still investigational. In this review, we describe the advances noted thus far on currently validated as well as novel emerging biomarkers that have the potential to guide the use of immunotherapy agents in the management of non-small cell lung cancer.

A proinflammatory diathesis, as measured by the neutrophil to lymphocyte ratio (NLR), heralds an adverse disease course for non-small cell lung cancer (NSCLC).This post hoc analysis used data from the phase 3 OAK trial (NCT02008227), which randomized previously treated patients with NSCLC to atezolizumab or docetaxel. The main objective was assessing the differential impact of the pretreatment NLR on overall survival according to the treatment modality. In addition, patients' genomic characteristics were assessed according to their inflammatory status with a circulating free DNA (cfDNA) next-generation sequencing (NGS) analysis.In all, 600 and 575 patients with NLR data were included in the atezolizumab and docetaxel cohorts, respectively, with a median NLR of 4 (interquartile range, 2.6-6.7) for the pooled population. An NLR ≥4 was associated with a positive smoking status (88.6% vs. 78.1%; p .01), male sex (66.4% vs. 57.6%; p = .01), a worse performance status (71.3% vs. 55.2%; p .01), a higher number of metastatic sites (63.2% vs. 51.6%; p = .01), squamous histology (32.1% vs. 21.4%; p .01), and tissue KRAS mutations (30% vs. 18.7%; p = .02) but not with programmed death ligand 1 (PD-L1) expression or the tissue epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) status. A pretreatment NLR ≥4 was more strongly associated with mortality after atezolizumab (adjusted hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.35-2.01) versus docetaxel (HR, 1.32; 95% CI, 1.08-1.60; multivariable [MVA] interaction p = .08). The HR for an increased risk of death for PD-L1-negative/NLR ≥4 patients (compared with PD-L1-positive/NLR 4 patients) was significantly higher in the atezolizumab cohort (MVA interaction p = .01). The exclusion of EGFR/ALK-positive patients further increased the prognostic ability of the baseline NLR in favor of atezolizumab (MVA interaction p = .02). Pretreatment cfDNA data from NGS showed that patients with a high blood tumor mutation burden (cutoff, 16 mut/Mb) had a higher median NLR (4.6 vs. 3.7; p = .01). After adjustments for multiple comparisons, none of the selected variants of interest (EGFR, KRAS, TP53, KEAP1, STK11, SMARCA4, ARID1A, and targeted DNA damage response and repair genes) were significantly associated with the NLR.A low baseline NLR identified patients with NSCLC who derived a greater survival benefit from atezolizumab in comparison with those identified in the docetaxel cohort. The NLR could complement PD-L1 expression in tailoring treatment in this setting.

Purpose: Objectives of this dose-finding study were to determine the MTD and recommended phase II dose (RP2D) of the first-in-class anti-activin receptor-like kinase 1 (ALK-1) monoclonal antibody PF-03446962, and assess safety and antitumor activity in patients with advanced solid tumors.Experimental Design: This open-label, multicenter study was based on a 3+3 design. PF-03446962 was administered biweekly by intravenous infusion, at doses ranging from 0.5 to 15 mg/kg.Results: Forty-four patients received treatment with PF-03446962. Dose-limiting toxicities observed during dose escalation included grade 3 increased amylase, grade 3/4 increased lipase, and grade 3/4 thrombocytopenia. The MTD was determined to be 10 mg/kg. The RP2D was set at 7 mg/kg for patients with advanced solid tumors, based on the observed safety, pharmacokinetics, and antitumor activity. The most-frequent treatment-related, all-grade adverse events included thrombocytopenia (20.5%), fatigue (15.9%), and nausea, increased amylase, and increased lipase (each 11.4%). Treatment-related telangiectasia was noted in 7% of patients, suggesting in vivo inhibition of the ALK-1 pathway. None of the deaths was deemed to be treatment-related. Three (6.8%) patients with advanced hepatocellular carcinoma, renal cell carcinoma, or non–small cell lung cancer achieved a partial response, and 12 (27.3%) patients had stable disease, across dose levels. Contrast-enhanced ultrasound analysis of tumor vascularity showed reduction in tumor perfusion in 2 patients with stable disease following treatment with PF-03446962.Conclusions: The clinical activity demonstrated in this study points to PF-03446962 as a novel approach to antiangiogenic therapy, with manageable safety profile and single-agent, antitumor activity in patients with advanced solid tumors. Clin Cancer Res; 22(9); 2146–54. ©2015 AACR.

Figure S1 from Detection of NRG1 Gene Fusions in Solid Tumors

Table S1. Descriptions of NRG1 Fusions Identified. *Novel fusion. Abbreviations: NSCLC, non-small cell lung cancer; PDAC, pancreatic ductal adenocarcinoma; GBC, gallbladder cancer (cholangiocarcinoma); CRC, colorectal cancer. RCC, renal cell carcinoma; NET, neuroendocrine tumor.

Figure S1 - PDF file 23K, Mean serum siltuximab concentration following the first dose of 12 mg/kg by disease type in patients evaluable for pharmacokinetics analysis in cohorts 3, 5, and 6. Abbreviations: CD, Castleman's disease; Inf, infusion; MM, multiple myeloma; NHL, non-Hodgkin's lymphoma

Supplementary Methods - PDF file 88K, Supplementary methods for pharmacokinetic analyses and pharmacodynamic analyses

Additional Methods; Tables and Figure [1]Supplementary Methods: Contrast-enhanced ultrasound (CE-US) [2]Supplementary Table S1. Pharmacokinetic characteristics of PF-03446962 following single-dose administration in cycle 1 [3]Supplementary Table S2. Best overall tumor response in patients treated with PF-03446962 [4]Supplementary Figure S1. Telangiectasia observed in patients treated with PF-03446962.

Purpose:NRG1 gene fusions are rare but potentially actionable oncogenic drivers that are present in some solid tumors. Details regarding the incidence of these gene rearrangements are lacking. Here, we assessed the incidence of NRG1 fusions across multiple tumor types and described fusion partners.Experimental Design:Tumor specimens submitted for molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)–certified genomics laboratory and that underwent fusion testing by anchored multiplex PCR for targeted RNA sequencing were retrospectively identified. The overall and tumor-specific incidence was noted, as was the specific fusion partner.Results:Out of 21,858 tumor specimens profiled from September 2015 to December 2018, 41 cases (0.2%) harbored an NRG1 fusion. Multiple fusion partners were identified. Fusion events were seen across tumor types. The greatest incidence was in non–small cell lung cancer (NSCLC, 25), though this represented only 0.3% of NSCLC cases tested. Other tumor types harboring an NRG1 fusion included gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer.Conclusions:NRG1 fusions can be detected at a low incidence across multiple tumor types with significant heterogeneity in fusion partner.See related commentary by Dimou and Camidge, p. 4865

Purpose: To evaluate the safety and pharmacokinetics of siltuximab, an anti–interleukin-6 chimeric monoclonal antibody (mAb) in patients with B-cell non-Hodgkin lymphoma (NHL), multiple myeloma, or Castleman disease.Experimental Design: In an open-label, dose-finding, 7 cohort, phase I study, patients with NHL, multiple myeloma, or symptomatic Castleman disease received siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks. Response was assessed in all disease types. Clinical benefit response (CBR; composite of hemoglobin, fatigue, anorexia, fever/night sweats, weight, largest lymph node size) was also evaluated in Castleman disease.Results: Sixty-seven patients received a median of 16 siltuximab doses for a median of 8.5 (maximum 60.5) months; 29 were treated 1 year or longer. There was no dose-limiting toxicity, antibodies to siltuximab, or apparent dose–toxicity relationship. The most frequently reported possible drug-related adverse events were thrombocytopenia (25%), hypertriglyceridemia (19%), neutropenia (19%), leukopenia (18%), hypercholesterolemia (15%), and anemia (10%). None of these events led to dose delay/discontinuation except for neutropenia and thrombocytopenia (n = 1 each). No treatment-related deaths occurred. C-reactive protein (CRP) suppression was most pronounced at 12 mg/kg every 3 weeks. Mean terminal-phase half-life of siltuximab ranged 17.73 to 20.64 days. Thirty-two of 37 (86%) patients with Castleman disease improved in 1 or more CBR component; 12 of 36 evaluable Castleman disease patients had radiologic response [complete response (CR), n = 1; partial response (PR), n = 11], including 8 of 19 treated with 12 mg/kg; 2 of 14 (14%) evaluable NHL patients had PR; 2 of 13 (15%) patients with multiple myeloma had CR.Conclusion: No dose-related or cumulative toxicity was apparent across all disease indications. A dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease and the sustained CRP suppression. Randomized studies are ongoing in Castleman disease and multiple myeloma. Clin Cancer Res; 19(13); 3659–70. ©2013 AACR.

Supplementary Table S1 - PDF file Percent change from baseline in serum C-reactive protein concentration (mg/L) in Cohort 7

Background HER2 alteration (mutation and/or amplification) is associated with poor survival in NSCLC and can mediate resistance to EGFR tyrosine kinase inhibitors. Methods We retrospectively analyzed de-identified molecular information from 12,946 NSCLC samples that underwent next-generation sequencing (NGS) with Caris Life Sciences. The objectives were to determine the prevalence and type of HER2 alterations with and without EGFR as a co-mutation. Insurance claims were utilized to obtain outcomes data. Results Three hundred and twenty-one patients (2.5%) had HER2 alteration: mutation in 197 patients and amplification in 134. Median age was 65 years and 62% were female. A total of 84% were adenocarcinoma. HER2 exon 20 insertion was most common (69%). A total of 1551 (12%) patients had EGFR mutations. Among samples with EGFR mutations, 24 (1.5%) had concurrent HER2 alteration (8 with HER2 mutation and 16 with amplification). Among 8 patients who had both EGFR and HER2 mutations, 3 had EGFR exon 19 deletions and exon 8 HER2 mutation (S310F). One-third of the patients (7/21) with HER2 extracellular domain (ECD) mutation had co-occurring EGFR mutations. All 7 were S310. Patients with concurrent EGFR mutation and HER2 amplification had longer median time on treatment with EGFR TKI(s) than those with EGFR mutation without HER2 amplification (HR 2.284, P =.004). Conclusion A minority of NSCLC samples with EGFR mutations had HER2 alterations. In patients with both mutations, exon 21 mutations for EGFR and exon 8 mutations for HER2 were common. It will be critical to continue to accumulate valuable clinical data for further real-world outcomes analysis.

Mesothelioma is a rare and fatal cancer with limited therapeutic options until the recent approval of combination immune checkpoint blockade. Here we report the results of the phase 2 PrE0505 trial (NCT02899195) of the anti-PD-L1 antibody durvalumab plus platinum-pemetrexed chemotherapy for 55 patients with previously untreated, unresectable pleural mesothelioma. The primary endpoint was overall survival compared to historical control with cisplatin and pemetrexed chemotherapy; secondary and exploratory endpoints included safety, progression-free survival and biomarkers of response. The combination of durvalumab with chemotherapy met the pre-specified primary endpoint, reaching a median survival of 20.4 months versus 12.1 months with historical control. Treatment-emergent adverse events were consistent with known side effects of chemotherapy, and all adverse events due to immunotherapy were grade 2 or lower. Integrated genomic and immune cell repertoire analyses revealed that a higher immunogenic mutation burden coupled with a more diverse T cell repertoire was linked to favorable clinical outcome. Structural genome-wide analyses showed a higher degree of genomic instability in responding tumors of epithelioid histology. Patients with germline alterations in cancer predisposing genes, especially those involved in DNA repair, were more likely to achieve long-term survival. Our findings indicate that concurrent durvalumab with platinum-based chemotherapy has promising clinical activity and that responses are driven by the complex genomic background of malignant pleural mesothelioma., In a phase 2 trial, the combination of chemotherapy with durvalumab, an anti-PD-L1 antibody, exhibited promising clinical activity in patients with previously untreated, unresectable mesothelioma, with additional analyses providing insights into genomic and immunologic features potentially associated with response.

Background Nuclear protein transport is essential in guiding the traffic of important proteins and RNAs between the nucleus and cytoplasm. Export of proteins from the nucleus is mostly regulated by Exportin 1 (XPO1). In cancer, XPO1 is almost universally hyperactive and can promote the export of important tumor suppressors to the cytoplasm. Currently, there are no studies evaluating XPO1 amplifications and mutations in NSCLC and the impact on outcomes. Methods Tumor samples were analyzed using next-generation sequencing (NGS) (NextSeq, 592 Genes), immunohistochemistry (IHC), and whole transcriptome sequencing (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Survival was extracted from insurance claims data and calculated from time of tissue collection to last contact using Kaplan-Meier estimate. Results Among 18,218 NSCLC tumors sequenced, 26 harbored XPO1 mutations and 24 had amplifications. XPO1 mutant tumors were more likely to have high TMB (79% vs. 52%, p = 0.007) and less likely to have high PD-L1 (32% vs. 68%, p = 0.03). KRAS co-mutations were seen in 19% (n = 5) and EGFR co-mutations were rare (n = 2). Among the 17,449 NSCLC tumors with clinical data, there were 24 XPO1 mutant. Comparison of survival between XPO1 mutant and WT showed a negative association with a hazard ratio (HR) of 1.932 (95% CI: 1.144–3.264 p = 0.012). XPO1 amplification was not associated with survival. Conclusions XPO1 pathogenic mutations were associated with a poor survival in NSCLC. Although XPO1 mutations are rare in NSCLC, further studies to assess its associations with treatment responses are warranted.

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.

Non-small cell lung cancer (NSCLC) has limited treatment options. Expression of the RNA-binding protein (RBP) Musashi-2 (MSI2) is elevated in a subset of non-small cell lung cancer (NSCLC) tumors upon progression, and drives NSCLC metastasis. We evaluated the mechanism of MSI2 action in NSCLC to gain therapeutically useful insights. Reverse phase protein array (RPPA) analysis of MSI2-depleted versus control KrasLA1/+; Trp53R172HΔG/+ NSCLC cell lines identified EGFR as a MSI2-regulated protein. MSI2 control of EGFR expression and activity in an NSCLC cell line panel was studied using RT-PCR, Western blots, and RNA immunoprecipitation. Functional consequences of MSI2 depletion were explored for cell growth and response to EGFR-targeting drugs, in vitro and in vivo. Expression relationships were validated using human tissue microarrays. MSI2 depletion significantly reduced EGFR protein expression, phosphorylation, or both. Comparison of protein and mRNA expression indicated a post-transcriptional activity of MSI2 in control of steady state levels of EGFR. RNA immunoprecipitation analysis demonstrated that MSI2 directly binds to EGFR mRNA, and sequence analysis predicted MSI2 binding sites in the murine and human EGFR mRNAs. MSI2 depletion selectively impaired cell proliferation in NSCLC cell lines with activating mutations of EGFR (EGFRmut). Further, depletion of MSI2 in combination with EGFR inhibitors such as erlotinib, afatinib, and osimertinib selectively reduced the growth of EGFRmut NSCLC cells and xenografts. EGFR and MSI2 were significantly co-expressed in EGFRmut human NSCLCs. These results define MSI2 as a direct regulator of EGFR protein expression, and suggest inhibition of MSI2 could be of clinical value in EGFRmut NSCLC.

Introduction In cohort G of KEYNOTE-021 (NCT02039674), first-line pembrolizumab plus pemetrexed-carboplatin significantly improved the objective response rate and progression-free survival versus chemotherapy alone with manageable toxicity in advanced nonsquamous NSCLC. We report the long-term outcomes from this study. Methods Patients with previously untreated advanced nonsquamous NSCLC without sensitizing EGFR or ALK alterations were randomly assigned 1:1 to receive open-label pemetrexed 500 mg/m2 plus carboplatin at area under the concentration-time curve of 5 mg/mL/min (four cycles) with or without pembrolizumab 200 mg (up to 2 years), with optional pemetrexed maintenance, each administered every 3 weeks. Eligible patients could crossover from the chemotherapy arm to pembrolizumab monotherapy after progression. Responses were assessed per the Response Evaluation Criteria in Solid Tumors version 1.1. Results After the median time of 49.4 months from randomization to data cutoff, objective response rate (58% versus 33%) and progression-free survival (median: 24.5 versus 9.9 mo; hazard ratio: 0.54; 95% confidence interval: 0.35‒0.83) remained improved with pembrolizumab combination (n = 60) versus chemotherapy (n = 63), regardless of programmed death ligand 1 status. Median overall survival was 34.5 versus 21.1 months (hazard ratio: 0.71; 95% confidence interval: 0.45‒1.12), despite a 70% crossover rate from chemotherapy alone to anti‒programmed death (ligand) 1 therapy. Among the 12 patients who completed 2 years of pembrolizumab, 92% were alive at data cutoff; the estimated 3-year duration of response rate was 100%. Grade 3 to 5 treatment-related adverse events occurred in 39% of patients receiving pembrolizumab combination and 31% receiving chemotherapy. Conclusions First-line pembrolizumab plus pemetrexed-carboplatin continued to show improved response and survival versus chemotherapy alone in advanced nonsquamous NSCLC, with durable clinical benefit in patients who completed 2 years of therapy. No new safety signals were observed with longer follow-up.

Over the past year, the combination of platinum-based chemotherapy and immunotherapy has become the standard of care for patients with metastatic non-small-cell lung cancer with any programmed death ligand 1 tumor proportion score. There is preclinical evidence demonstrating potential synergistic immunomodulation with combination therapy by enhancing immune-mediated tumor death and by disrupting the immunosuppressive tumor microenvironment that prevents immune detection. This potential synergy or complementary activity has been demonstrated in clinical trials showing improved and durable responses with chemo-immunotherapy.

[Introduction] In CheckMate 227, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death-ligand 1 (PD-L1) greater than or equal to 1% (primary end point) or less than 1% (prespecified descriptive analysis). We report results with minimum 4 years' follow-up., [Methods] Adults with previously untreated stage IV or recurrent NSCLC were randomized (1:1:1) to nivolumab plus ipilimumab, nivolumab, or chemotherapy (PD-L1 ≥1%); or to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1, [Results] After 54.8 months' median follow-up, OS remained longer with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 greater than or equal to 1% (hazard ratio = 0.76; 95% confidence interval: 0.65–0.90) and PD-L1 less than 1% (0.64; 0.51–0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 ≥1%); and 24% versus 10% (PD-L1, [Conclusions] At more than 4 years' minimum follow-up, with all patients off immunotherapy treatment for at least 2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable long-term efficacy in patients with advanced NSCLC. No new safety signals were identified. Immune-mediated AEs occurred early and resolved quickly with guideline-based management. Discontinuation of nivolumab plus ipilimumab due to TRAEs did not have a negative impact on the long-term benefits seen in all randomized patients., This study was supported by Bristol Myers Squibb and Ono Pharmaceutical Company Ltd.

Purpose of the study: Smoking is detrimental to treatment outcomes for both smoking and non-smoking-related cancers, and tobacco cessation is an integral part of comprehensive cancer care. Through the support of a competitive grant funded by the NCI’s Cancer Center Cessation Initiative, Fox Chase Cancer Center (FCCC) optimized their Tobacco Treatment Program (TTP). Within the first year of optimization, TTP’s reach increased tenfold by implementing an automated tobacco registry through a nightly EMR feed that proactively reaches all new cancer patients who have used tobacco in the last 30 days. This registry serves as a repository and referral source for the optimized program and includes demographic information and smoking status of all new patients who use tobacco. Within the first year of the program at FCCC, the registry was comprised of 70% white (W) and 20% black (B). FCCC TTP has since expanded to the broader Temple University Health System (TUHS) to increase smoking cessation and cancer prevention efforts within a predominantly underrepresented population that often face higher rates of tobacco use and barriers to quitting. Description: Patients are referred to TTP in 3 ways (survey from the tobacco registry, a provider referral from the newly implemented BPA, or self-referral from AVS and marketing materials in three languages). The TTP provides access to evidence-based smoking cessation resources, motivational interviewing with a health educator, treatment with Advanced Practice Tobacco Specialists, and access to NRTs. A REDCap Case Management System was utilized to collect programmatic data that includes scheduled TTP appointments, no-show rates, prescribing data, and readiness to quit. These data have allowed us to evaluate access disparities between B and W patients that will further be explored with the broader expansion to TUHS. Results: Within the first year of optimization, there were no significant differences in number of appointments, no-show rates, and NRT prescriptions between B and W patients. The maximum number of appointments for B patients was 9 compared to 11 W, and TTP had an overall no-show rate of 22% (W patients had a no-show rate of 23%, and B patients had a lower no-show rate of 15%). Additionally, 60% of W patients scheduled TTP visits compared to 50% of B patients. Over 85% of B/W patients were prescribed NRTs, and the breakdown of what was prescribed (patch, gum, lozenge, Chantix, Zyban) did not differ by race. Conclusions: While access to services is comparable in B/W populations, there may be approaches to increase B patients scheduling and explore access all patient populations, particularly as we expand our services throughout TUHS. We will examine barriers to scheduling appointments for B patients as they were less likely than W patients to schedule a TTP appointment. The expansion to TUHS will allow us to provide tobacco cessation and explore differences across sociodemographic factors and further explain utilization/access to TTP. Citation Format: Alison C. Brecher, Cassidy Kenny, Donna Edmondson, Allison Zambon, Linda Fleisher, Hossein Borghaei. Addressing disparities and barriers to care between Black and White cancer patients who use tobacco [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B002.

Summary Background Phase 3 clinical data has shown higher proportions of patients with objective response, longer response duration, and longer overall survival with nivolumab versus docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We aimed to evaluate the long-term benefit of nivolumab and the effect of response and disease control on subsequent survival. Methods We pooled data from four clinical studies of nivolumab in patients with previously treated NSCLC (CheckMate 017, 057, 063, and 003) to evaluate survival outcomes. Trials of nivolumab in the second-line or later setting with at least 4 years follow-up were included. Comparisons of nivolumab versus docetaxel included all randomised patients from the phase 3 CheckMate 017 and 057 studies. We did landmark analyses by response status at 6 months to determine post-landmark survival outcomes. We excluded patients who did not have a radiographic tumour assessment at 6 months. Safety analyses included all patients who received at least one dose of nivolumab. Findings Across all four studies, 4-year overall survival with nivolumab was 14% (95% CI 11–17) for all patients (n=664), 19% (15–24) for those with at least 1% PD-L1 expression, and 11% (7–16) for those with less than 1% PD-L1 expression. In CheckMate 017 and 057, 4-year overall survival was 14% (95% CI 11–18) in patients treated with nivolumab, compared with 5% (3–7) in patients treated with docetaxel. Survival subsequent to response at 6 months on nivolumab or docetaxel was longer than after progressive disease at 6 months, with hazard ratios for overall survival of 0·18 (95% 0·12–0·27) for nivolumab and 0·43 (0·29–0·65) for docetaxel; for stable disease versus progressive disease, hazard ratios were 0·52 (0·37–0·71) for nivolumab and 0·80 (0·61–1·04) for docetaxel. Long-term data did not show any new safety signals. Interpretation Patients with advanced NSCLC treated with nivolumab achieved a greater duration of response compared with patients treated with docetaxel, which was associated with a long-term survival advantage. Funding Bristol-Myers Squibb.

Background S1400D is a biomarker-driven therapeutic substudy of Lung-MAP evaluating the fibroblast growth factor (FGF) receptor (FGFR) inhibitor AZD4547 in patients with FGF pathway-activated squamous cell. This is the first phase II trial to evaluate AZD4547 as a targeted approach in patients with previously treated FGFR-altered squamous cell NSCLC and is the first demonstration of successful implementation and conduct of a national umbrella protocol in this disease setting. Methods Eligible patients had tumoral FGFR alteration or mutation and had progressive disease after at least one line of platinum-based systemic therapy. Patients received AZD4547 80 mg twice daily orally. Primary endpoint was response by Response Evaluation Criteria in Solid Tumors version 1.1; secondary endpoints included progression-free survival, overall survival, and duration of response (DoR). Results Ninety-two patients were assigned to S1400D, 43 were enrolled, and 27 AZD4547-treated patients were evaluable. Evaluable patients were predominantly white (n = 24, 89%), median age 66 years (range, 49–88 years old), and female (n = 7, 26%). FGFR alterations included FGFR1 amplification (n = 23; 85%), FGFR3 amplification (n = 2; 7%), FGFR3 S249C (n = 2; 7%), and FGFR3 fusion (n = 1; 4%). Treatment with ADZ4547 was well tolerated; grade 3 adverse events occurred in six patients, and one patient had grade 4 sepsis. Of 27 response-evaluable patients, 1 patient with FGFR3 S249C had unconfirmed partial response with a DoR of 1.5 months and 1 patient with FGFR1 amplification had a confirmed partial response with a DoR of 2.9 months (7%, 95% confidence interval [CI]: 0%–17%). Median progression-free survival and overall survival for the AZD4547-treated cohort were 2.7 months (95% CI: 1.4– 4.5 months) and 7.5 months (95% CI: 3.7–9.3 months). Conclusions AZD4547 had an acceptable safety profile but minimal activity in this predominantly FGFR1/FGFR3–amplified cohort. Evaluation of other targeted agents in Lung-MAP is ongoing.

Purpose:NRG1 gene fusions are rare but potentially actionable oncogenic drivers that are present in some solid tumors. Details regarding the incidence of these gene rearrangements are lacking. Here, we assessed the incidence of NRG1 fusions across multiple tumor types and described fusion partners.Experimental Design:Tumor specimens submitted for molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)–certified genomics laboratory and that underwent fusion testing by anchored multiplex PCR for targeted RNA sequencing were retrospectively identified. The overall and tumor-specific incidence was noted, as was the specific fusion partner.Results:Out of 21,858 tumor specimens profiled from September 2015 to December 2018, 41 cases (0.2%) harbored an NRG1 fusion. Multiple fusion partners were identified. Fusion events were seen across tumor types. The greatest incidence was in non–small cell lung cancer (NSCLC, 25), though this represented only 0.3% of NSCLC cases tested. Other tumor types harboring an NRG1 fusion included gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer.Conclusions:NRG1 fusions can be detected at a low incidence across multiple tumor types with significant heterogeneity in fusion partner.See related commentary by Dimou and Camidge, p. 4865

In the last few years, immunotherapy has transformed the way we treat solid tumors, including melanoma, lung, head neck, breast, renal, and bladder cancers. Durable responses and long-term survival benefit has been experienced by many cancer patients, with favorable toxicity profiles of immunotherapeutic agents relative to chemotherapy. Cures have become possible in some patients with metastatic disease. Additional approvals of immunotherapy drugs and in combination with other agents are anticipated in the near future. Multiple additional immunotherapy drugs are in earlier stages of clinical development, and their testing in additional tumor types is under way. Despite considerable early success and relatively fewer side effects, the majority of cancer patients do not respond to checkpoint inhibitors. Additionally, while the drugs are generally well tolerated, there is still the potential for significant, unpredictable and even fatal toxicity with these agents. Improved biomarkers may help to better select patients who are more likely to respond to these drugs. Two key biologically important predictive tissue biomarkers, specifically, PD-L1 and mismatch repair deficiency, have been FDA-approved in conjunction with the checkpoint inhibitor, pembrolizumab. Tumor mutation burden, another promising biomarker, is emerging in several tumor types, and may also soon receive approval. Finally, several other tissue and liquid biomarkers are emerging that could help guide single-agent immunotherapy and in combination with other agents. Of these, one promising investigational biomarker is alteration or deficiency in DNA damage response (DDR) pathways, with altered DDR observed in a broad spectrum of tumors. Here, we provide a critical overview of current, emerging, and investigational biomarkers in the context of response to immunotherapy in solid tumors.

Objectives Combination immunotherapy may result in improved antitumor activity compared with single-agent treatment. We report results from dose-finding and dose-expansion cohorts of the phase 1/2 KEYNOTE-021 study that evaluated combination therapy with anti‒programmed death 1 (PD-1) antibody pembrolizumab plus anti‒cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody ipilimumab in patients with previously treated advanced non–small-cell lung cancer (NSCLC). Materials and methods Eligibility criteria stipulated histologically/cytologically confirmed advanced NSCLC and treatment failure on ≥1 prior systemic therapy (platinum-based chemotherapy or targeted therapy for patients with EGFR/ALK aberrations). In the dose-finding cohort, patients initially received pembrolizumab 10 mg/kg plus ipilimumab 1 or 3 mg/kg once every 3 weeks for 4 cycles followed by pembrolizumab 10 mg/kg monotherapy for up to 2 years. Based on emerging published data, subsequent patients received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg. Objective response rate (ORR; primary efficacy endpoint) was assessed per RECIST version 1.1 by blinded, independent central review. Phase 2 hypothesis that ORR would be greater than the 20% rate for historical controls was evaluated using the exact binomial test. Results Fifty-one patients were enrolled; 71% received ≥2 prior lines of therapy. No dose-limiting toxicities occurred at any dose level. Among patients who received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg (n = 44), ORR was 30% (95% CI, 17%–45%), but not statistically significantly >20% (P = 0.0858). Median progression-free survival in this group was 4.1 (95% CI, 1.4–5.8) months; median overall survival was 10.9 (95% CI, 6.1–23.7) months. With pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg, incidences of treatment-related adverse events, grade 3–5 treatment-related adverse events, and immune-mediated adverse events and infusion reactions were 64%, 29%, and 42%, respectively. Conclusions In patients with heavily pretreated advanced NSCLC, pembrolizumab plus ipilimumab showed evidence of antitumor activity, but was associated with meaningful toxicity.

PURPOSE CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non–small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients. CONCLUSION Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.

Introduction Cohort G of KEYNOTE-021 (NCT02039674) evaluated the efficacy and safety of pembrolizumab plus pemetrexed-carboplatin (PC) versus PC alone as first-line therapy for advanced nonsquamous NSCLC. At the primary analysis (median follow-up time 10.6 months), pembrolizumab significantly improved objective response rate (ORR) and progression-free survival (PFS); the hazard ratio (HR) for overall survival (OS) was 0.90 (95% confidence interval [CI]: 0.42‒1.91). Herein, we present an updated analysis. Methods A total of 123 patients with previously untreated stage IIIB/IV nonsquamous NSCLC without EGFR and/or ALK receptor tyrosine kinase gene (ALK) aberrations were randomized 1:1 to four cycles of PC with or without pembrolizumab, 200 mg every 3 weeks. Pembrolizumab treatment continued for 2 years; maintenance pemetrexed was permitted in both groups. Eligible patients in the PC-alone group with radiologic progression could cross over to pembrolizumab monotherapy. p Values are nominal (one-sided p Results As of December 1, 2017, the median follow-up time was 23.9 months. The ORR was 56.7% with pembrolizumab plus PC versus 30.2% with PC alone (estimated difference 26.4% [95% CI: 8.9%‒42.4%, p = 0.0016]). PFS was significantly improved with pembrolizumab plus PC versus PC alone (HR = 0.53, 95% CI: 0.33‒0.86, p = 0.0049). A total of 41 patients in the PC-alone group received subsequent anti‒programmed death 1/anti‒programmed death ligand 1 therapy. The HR for OS was 0.56 (95% CI: 0.32‒0.95, p = 0.0151). Forty-one percent of patients in the pembrolizumab plus PC group and 27% in the PC-alone group had grade 3 to 5 treatment-related adverse events. Conclusions The significant improvements in PFS and ORR with pembrolizumab plus PC versus PC alone observed in the primary analysis were maintained, and the HR for OS with a 24-month median follow-up was 0.56, favoring pembrolizumab plus PC.

Background: Alterations in the RAS pathway have been linked to tumorigenesis, apoptosis, metabolism and angiogenesis. Mutations of KRAS in NSCLC are more frequent and better characterized, however, other family members such as HRAS remain under investigated and RAS remains a challenging therapeutic target. HRAS has been indirectly targeted with tipifarnib, a farnesyltransferase inhibitor rendering HRAS inactive in head and neck tumors. Here, we characterize the incidence, genomic landscape, and clinical context of HRAS alterations in NSCLC. Methods: A total of 29,767 NSCLC tumor samples underwent comprehensive molecular profiling at Caris Life Sciences. Analyses included next generation sequencing of DNA (592 Gene Panel, NextSeq, or whole exome sequencing, NovaSeq), RNA (NovaSeq, whole transcriptome sequencing, WTS) and immunohistochemistry. MAPK activation was assessed using the MPAS gene expression signature. Wilcoxon, Fisher’s exact, or Dunnett’s tests were used to determined statistical significance (displayed as p value without and q value with multi-comparison correction). Overall survival was calculated from date of tissue collection to last contact from insurance claims data and used for Kaplan-Meier analysis. Comparisons were conducted between HRAS mutated tumors and the entire NSCLC general cohort (GC). Results: HRAS mutations (Hm) were detected in 128 of 29767 NSCLC samples (0.4%) and were significantly enriched in older patients (median age, 71 vs. 69 years; q Conclusions: HRAS mutations are detectable but uncommon events in NSCLC and significantly enriched in squamous histology. HRAS mutations often occur with PIK3CA co-mutations and trended towards higher activation of MAPK pathway and MSI-H frequency. This warrants further investigation on possible clinical applications of HRAS pathway inhibitors and utility of immune checkpoint inhibitors for this subset of NSCLC. Citation Format: Asaad Trabolsi, Estelamari Rodriguez, Samuel Alexander Kareff, Michael Korn, Joanne Xiu, Stephen Liu, Philip walker, Patrick Ma, Hirva Mamdani, Jorge Nieva, Hossein Borghaei, Chadi Nabhan, Misako Nagasaka, Sonam puri, Gilberto Lopes. Molecular characteristics of HRAS mutated non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 48.

Vaccines targeting neoantigens identified from common tumor driver mutations are of increasing interest as evidence of clinical benefit builds, and opportunities to combine such vaccines with immune modulators are growing. Our individualized neoantigen vaccine (GRANITE) has shown clinical benefit and strong, consistent CD8 T cell induction in patients. We have developed an analogous off-the-shelf product (SLATE) targeting shared neoantigens that offers manufacturing simplicity and faster administration to patients with shared driver mutations. A Phase 1/2 trial of a heterologous prime/boost vaccine regimen using a chimpanzee adenovirus (ChAd) prime and self amplifying mRNA (SAM) boosts (SLATE, NCT03953235) was initiated to assess safety, tolerability, and immunogenicity in patients with advanced cancers. SLATE version 1 encodes 20 unique neoantigens to various shared driver mutations (KRAS, TP53, etc.). Patients were selected if their tumors harbored one of the 20 neoantigens encoded by the vaccine cassette and an HLA Class I allele that presents that neoantigen. Administration of ChAd prime and repeated administration of 30, 100, or 300µg SAM doses were safe and well tolerated in all subjects dosed (n=26), with no evidence of increasing reactogenicity with sequential dosing. Early efficacy signals (molecular responses; one unconfirmed RECIST response) were observed in NSCLC subjects all treated with and progressed on prior anti-PD(L)1. Analysis of T cell responses pre and post immunizations by ex vivo IFNγ ELISpot did not show robust responses to KRAS neoantigens across all patients. However, objective CD8 T cell responses to KRAS antigens post vaccination were detectable after in vitro stimulation, suggesting the induction of low-level KRAS specific T cell responses in vivo. In contrast, HLA-matched responses to TP53 neoantigens encoded by the vaccine were consistently detected via ex vivo ELISpot in these same patients. These data suggests that an immunodominant T cell response to the TP53 mutations may have outcompeted the response to the less immunogenic KRAS mutations restricted and presented by the same HLA in vivo. Differential surface peptide-HLA (pHLA) density may explain these discordant findings, and subsequent targeted mass spectrometry analyses revealed detection of TP53 pHLA complexes at a higher frequency compared to KRAS mutations in single HLA-allele cell lines. Redesigned vaccine cassettes excluding the TP53 epitopes and repeating KRAS epitopes demonstrated increased immune responses (ex vivo IFNγ ELISpot) compared to cassette version 1 in HLA transgenic mice, further supporting the tumor neoantigen immunodominance hierarchy observed in humans dosed with SLATE version 1. A re-designed product (SLATE v2) focusing exclusively on KRAS mutations (G12C, G12D, G12V and Q61H) is currently being assessed in phase 2 in patients with advanced KRAS-driven tumors. Citation Format: Amy R. Rappaport, Christine D. Palmer, Annie Shen, Claudia X. Dominguez, Meghan G. Hart, Lauren D. Kraemer, Sonia Koulavouth, Martina Marrali, Jason R. Jaroslavsky, Charmaine N. Nganje, Ciaran D. Scallan, Sue-Jean Hong, Leonid Gitlin, Monica Lane, Daniel V. Catenacci, Chrisann Kyi, David P. Carbone, Hossein Borghaei, Raphael Rousseau, Andrew Ferguson, Karin Jooss. Optimization of shared neoantigen vaccine design to increase vaccine potency: From bench to bedside and back [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3578.

Lung cancer holds second place in incidence and first place in mortality among all cancers, both in men and women, with metastasis contributing to the vast majority of deaths. Recently, expression of vascular endothelial growth factor receptor-2 (VEGFR2) on both endothelial and tumor cells was demonstrated as one of the key mechanisms contributing to growth of non-small cell lung cancer (NSCLC), the most common subtype of lung cancer. VEGFR2 dependent signaling is critical both for tumor autocrine functions related to NSCLC migration, and in paracrine control of tumor angiogenesis through action on tumor-proximal endothelial cells, suggesting a potential mechanism for growth control. Several drugs targeting VEGFR2 signaling pathway demonstrated their clinical efficacy in NSCLC setting, including VEGFR2 and VEGF-A inhibitors, VEGF-A/PIGF trap. Recently our group demonstrated that RNA-binding protein Musashi-2 (MSI2) is driving progression and metastasis of NSCLC. MSI2 regulates mRNA translation of multiple targets, its expression is upregulated in the metastasis-competent murine and human lung cancer cell lines and is progressively elevated in lung cancer samples. The goal of this study is to define the role of MSI2 in sustaining VEGFR2 signaling during NSCLC progression. Using reverse RNA immunoprecipitation (RIP) qPCR analysis, we demonstrate that MSI2 directly binds VEGFR2 mRNA. Reverse protein phase array (RPPA) of several NSCLC cell line models with expression or knockdown of MSI2 and subsequent direct validation showed that MSI2 strongly and positively regulates expression of VEGFR2. Subsequent mechanistical analysis revealed that MSI2 knockdown leads to decreased VEGFR2 protein and mRNA levels expression in several NSCLC cell lines in vitro, resulting in increased apoptosis via inhibition of VEGFR2 signaling pathway. To better characterize MSI2 biology, we’ve crossed the B6/129S4-Msi2tm1.1Cjl/J (M2) mice with B6/129S/Sv-Krastm3Tyj/J;Trp53tm1Brn/J (KP) mice and generated novel B6/129S/Sv-KP;Msi2-/- (KPM2) mouse model. Induction of tumorigenesis in KP mice using Cre adenovirus leads to development of lung adenocarcinoma. Induction of lung-specific Cre resulted in tumorigenesis in both KP and KPM2 mice. Interestingly, we observed significant decrease in both total lung tumor number and total lung tumor burden in KPM2 compared to KP mice. Next, we established three novel KP and KPM2 derived cell lines from mouse lung tumors and found that KPM2 cell lines demonstrate reduced proliferation capacity and VEGFR2 mRNA level relative to KP cell lines. Additional studies to understand an impact of MSI2 deletion in KP cell lines are ongoing. Taken together, MSI2 is a promising target for NSCLC treatment, as this protein regulates VEGFR2 signaling and apoptosis in cell models and contributes to KP tumorigenesis in vivo. Citation Format: Igor Bychkov, Alexander Deneka, Iuliia Topchu, Petr Makhov, Alexander Kudinov, Anna Nikonova, John Karanicolas, Erica Golemis, Christopher Lengner, Hossein Borghaei, Jyoti Patel, Yanis Boumber. MSI2 regulates VEGFR2 signaling and tumor progression in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 874.

LBA9025 Background: In CheckMate 227 part 1 (NCT02477826), 1L NIVO + IPI demonstrated long-term, durable survival benefit vs platinum-doublet chemo in patients (pts) with metastatic NSCLC regardless of tumor programmed death ligand 1 (PD-L1) expression level. Here we present the longest reported follow-up (5 y) of a phase 3 trial of 1L combination immunotherapy in metastatic NSCLC. Methods: Adults with previously untreated stage IV or recurrent NSCLC, no known EGFR/ ALK alterations , and an ECOG performance status ≤ 1 were enrolled and stratified by histology. Pts with tumor PD-L1 ≥ 1% were randomized 1:1:1 to NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), NIVO (240 mg Q2W), or chemo. Pts with tumor PD-L1 < 1% were randomized 1:1:1 to NIVO + IPI, NIVO (360 mg Q3W) + chemo, or chemo. Pts were treated until progression, toxicity, or ≤ 2 y for immunotherapy. Assessments included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and a novel efficacy endpoint, treatment-free interval. Treatment-free interval was measured in pts who discontinued study therapy (for any reason including treatment completion) and was defined as the time from last study dose to start of subsequent systemic therapy or death, whichever occurred first. Results: Minimum follow-up was 61.3 mo (database lock, Feb 15, 2022). In pts with tumor PD-L1 ≥ 1% (N = 1189), continued long-term OS benefit was seen with NIVO + IPI vs chemo (HR, 0.77 [95% CI, 0.66–0.91]); 5-y OS rates were 24% (NIVO + IPI), 17% (NIVO), and 14% (chemo). OS benefit also continued in pts with tumor PD-L1 < 1% (N = 550) for NIVO + IPI vs chemo (HR, 0.65 [95% CI, 0.52–0.81]); 5-y OS rates were 19% (NIVO + IPI), 10% (NIVO + chemo), and 7% (chemo). Clinical benefit with NIVO + IPI vs chemo was observed across additional efficacy endpoints in the overall population and in pts alive at 5 y (table). PFS, ORR, and DOR with NIVO and NIVO + chemo will be presented. Among pts alive at 5 y in the NIVO + IPI group, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) remained treatment-free ≥ 3 y after discontinuing study therapy; median (range) duration of NIVO ± IPI therapy was 17.7 (0-25.5) mo (PD-L1 ≥ 1%) and 9.5 (0-25.1) mo (PD-L1 < 1%). No new safety signals were observed. Conclusions: With a 5-y minimum follow-up, NIVO + IPI continues to provide long-term, durable clinical benefit vs chemo in previously untreated pts with metastatic NSCLC, regardless of PD-L1 expression. NIVO + IPI led to increased 5-y survivorship; the majority of these pts were treatment-free for ≥ 3 y post-treatment discontinuation. Clinical trial information: NCT02477826. [Table: see text]

8515 Background: Effective treatment options for SCLC remain limited and new treatment approaches are needed to improve outcome. We sought to validate the initial observation in cell lines and limited tissue samples of SCLC of a differential expression of cancer/testis (CT) antigens and TACSD2 gene that encodes surface protein, Trop2 across various subtypes of SCLC. We also tested whether overall surfaceome profile as previously described in other tumor types will show hierarchical priority of expression between transcriptionally defined SCLC subtypes. Methods: We conducted a comprehensive surfaceome profiling of SCLC samples using data generated by RNA sequencing (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). SCLC tumors were stratified into 5 subgroups (SCLC-A/N/Y/P and -mixed) based on the relative expression of the four transcription factors. Expression values were converted to z-scores (the expression value for each gene is normalized to the average expression of that specific gene such that the z-score reflects the number of standard deviations above or below the average). The highest positive z-score among the 4 transcription factors determined subgroup. If all transcription factor z-scores for a given sample were negative, the sample was assigned to ‘Mixed’ subgroup. Significance was tested by Chi-square, Fisher’s exact test, or Mann-Whitney U test. Results: We employed data generated from 674 SCLC samples; median age of 66 years and male (48.7%). The SCLC subtype distribution was 241 (35.8%), 120 (17.8%), 40 (5.9%), 143 (21.2%), 130 (19.3%) for types A, N, P, Y and mixed respectively. Supervised analysis for TACSTD2 expression showed highest levels in YAP1 subtype and was overall significantly increased in SCLC-Y (̃3-fold) and SCLC-P (̃2-fold) subtypes compared to A, N and mixed subtypes. Similarly, SCLC-Y subtype showed the highest median expression as well as the strongest correlation with most TACSTD2-interacting and regulatory genes. A top 10 list of candidate surface protein gene out of 3699 surfaceome genes was defined for each subtype based on the strength of correlation. The top candidate surface protein gene and CT antigen gene respectively by subtype were: SCN3A (r = 0.7033, p = 1.08E-101) and NOL4, (r = 0.574, p = 2.46E-60) for SCLC-A; SSTR2, (r = 0.742, p = 8.18E-119) and TMEFF1, (r = 0.3601, p = 4.53E-22) for SCLC-N; TMPRSS13 (r = 0.5699, p = 2.64E-59) and LY6K (r = 0.4778, p = 9.80E-40) for SCLC-P; and CYBRD1 (r = 0.8559, p = 1.18E-194) and CTAGE5 (r = 0.5521, p = 4.95E-55) for SCLC-Y. Conclusions: SCLC-Y subtype showed the highest expression of TACSTD2 and its interacting and regulatory genes. This subtype could serve as an enrichment factor for antibody-drug-construct targeting TROP2. Several candidate CT antigens and surfaceome genes showing strong correlation with lineage-defining transcription factors offer additional therapeutic targets in SCLC.

2630 Background: MDM2/MDM4 are implicated in hyperprogression after immune checkpoint blockade (ICB). Our preclinical studies showed reduced T-cell killing of MDM2-amplified tumor cells that was overcome by an MDM2 antagonist or gene knockdown, and we observed additional tumor killing by T-cells with MDM2 inhibition plus anti-PD1. We hypothesized that MDM2/4 gene amplification/overexpression correlates with resistance to ICB and investigated the association of MDM2/4 alterations to overall survival (OS) following ICB across multiple solid tumors. Methods: Solid tumors tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (NGS) were analyzed. MDM2/4 amplification (amp) was tested by NGS and determined as either amp4 (cutoff of >=4.0 copies) or amp6 (>=6.0) or amp8 (>=8.0). Real-world OS was obtained from insurance claims data and calculated from treatment start or tissue collection to last contact. Kaplan-Meier estimates were calculated for molecularly defined groups. X2/Fisher-Exact were used and significance determined as P-value adjusted for multiple comparisons (q