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Purpose To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer. Patients and Methods In a phase II trial, 99 patients were randomly assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m2) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks. Results Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels. Conclusion Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. PURPOSE The phase III ADAURA (ClinicalTrials.gov identifier: NCT02511106 ) primary analysis demonstrated a clinically significant disease-free survival (DFS) benefit with adjuvant osimertinib versus placebo in EGFR-mutated stage IB-IIIA non–small-cell lung cancer (NSCLC) after complete tumor resection (DFS hazard ratio [HR], 0.20 [99.12% CI, 0.14 to 0.30]; P < .001). We report an updated exploratory analysis of final DFS data. METHODS Overall, 682 patients with stage IB-IIIA (American Joint Committee on Cancer/Union for International Cancer Control, seventh edition) EGFR-mutated (exon 19 deletion/L858R) NSCLC were randomly assigned 1:1 (stratified by stage, mutational status, and race) to receive osimertinib 80 mg once-daily or placebo for 3 years. The primary end point was DFS by investigator assessment in stage II-IIIA disease analyzed by stratified log-rank test; following early reporting of statistical significance in DFS, no further formal statistical testing was planned. Secondary end points included DFS in stage IB-IIIA, overall survival, and safety. Patterns of recurrence and CNS DFS were prespecified exploratory end points. RESULTS At data cutoff (April 11, 2022), in stage II-IIIA disease, median follow-up was 44.2 months (osimertinib) and 19.6 months (placebo); the DFS HR was 0.23 (95% CI, 0.18 to 0.30); 4-year DFS rate was 70% (osimertinib) and 29% (placebo). In the overall population, DFS HR was 0.27 (95% CI, 0.21 to 0.34); 4-year DFS rate was 73% (osimertinib) and 38% (placebo). Fewer patients treated with osimertinib had local/regional and distant recurrence versus placebo. CNS DFS HR in stage II-IIIA was 0.24 (95% CI, 0.14 to 0.42). The long-term safety profile of osimertinib was consistent with the primary analysis. CONCLUSION These updated data demonstrate prolonged DFS benefit over placebo, reduced risk of local and distant recurrence, improved CNS DFS, and a consistent safety profile, supporting the efficacy of adjuvant osimertinib in resected EGFR-mutated NSCLC.

PURPOSE Resistance to immune checkpoint inhibition (ICI) in advanced non–small-cell lung cancer (NSCLC) represents a major unmet need. Combining ICI with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types. METHODS In this randomized phase II Lung-MAP nonmatch substudy (S1800A), patients ineligible for a biomarker-matched substudy with NSCLC previously treated with ICI and platinum-based chemotherapy and progressive disease at least 84 days after initiation of ICI were randomly assigned to receive ramucirumab plus pembrolizumab (RP) or investigator's choice standard of care (SOC: docetaxel/ramucirumab, docetaxel, gemcitabine, and pemetrexed). With a goal of 130 eligible patients, the primary objective was to compare overall survival (OS) using a one-sided 10% level using the better of a standard log-rank (SLR) and weighted log-rank (WLR; G[rho = 0, gamma = 1]) test. Secondary end points included objective response, duration of response, investigator-assessed progression-free survival, and toxicity. RESULTS Of 166 patients enrolled, 136 were eligible (69 RP; 67 SOC). OS was significantly improved with RP (hazard ratio [80% CI]: 0.69 [0.51 to 0.92]; SLR one-sided P = .05; WLR one-sided P = .15). The median (80% CI) OS was 14.5 (13.9 to 16.1) months for RP and 11.6 (9.9 to 13.0) months for SOC. OS benefit for RP was seen in most subgroups. Investigator-assessed progression-free survival (hazard ratio [80% CI]: 0.86 [0.66 to 1.14]; one-sided SLR, P = .25 and .14 for WLR) and response rates (22% RP v 28% SOC, one-sided P = .19) were similar between arms. Grade ≥ 3 treatment-related adverse events occurred in 42% of patients in the RP group and 60% on SOC. CONCLUSION This randomized phase II trial demonstrated significantly improved OS with RP compared with SOC in patients with advanced NSCLC previously treated with ICI and chemotherapy. The safety was consistent with known toxicities of both drugs. These data warrant further evaluation.

9060 Background: Inactivating STK11 genomic alterations are prevalent in non-squamous (nsq) NSCLC and define a patient (pt) subgroup with poor prognosis and inferior response to immune checkpoint inhibitors (CPIs). PARP inhibitors (PARPi) can potentiate response to CPIs in preclinical models. We conducted a single arm Phase II study within Lung-MAP to evaluate the efficacy and safety of talazoparib in combination with avelumab in patients (pts) with previously treated nsq NSCLC harboring pathogenic STK11 genomic alterations. Methods: Eligibility: STK11 pathogenic somatic mutation or bi-allelic loss on tumor identified via LUNGMAP screening; stage IV or recurrent nsq NSCLC, receipt of one prior line of anti-PD-1/anti-PD-L1 therapy and platinum-based chemotherapy for stage IV or recurrent disease (sequentially or in combination) and disease progression > 42 days following treatment initiation, a ECOG PS of 0-1, adequate organ function and no previous PARPi exposure. Pts received talazoparib (1000 mg PO daily) plus avelumab (800 mg IV Q2W). Co-primary objectives were to evaluate the best objective response rate (ORR) and disease control rate at 12 weeks (DCR12) after study registration, assessed by RECISTv1.1. Rejection of an ORR of 10% required ≥ 8 responses or rejection of a DCR12 of 30% required ≥18 w/ disease control at 12 weeks and ≥4 responses. Results: 47 pts enrolled from January 16 - November 16, 2020; 42 pts met eligibility (50% male, 50% female). 54% of pts had PD-L1 TPS < 1%. The median TMB was 8.83 Mut/Mb and 45% of pts had KRAS mutations. 52% of the pts had received ≥2 prior lines of treatment for stage IV disease. As of the November 24, 2021 data cutoff, 3 pts remain on treatment, the ORR was 2% (n = 1) and the DCR12 was 40% (n = 17). 26 pts (62%) had SD as best objective response. One responding pt remained on treatment for > 14 mo. The median progression-free survival (39 events) was 2.7 mo (95% CI, 1.6-3.9 mo) and the median overall survival (30 events) was 7.6 mo (95% CI, 6.3-12.2 mo). There were no reported grade 5 treatment toxicities and most grade 3-4 toxicities were hematologic. Additional biomarker analysis to assess effects of key co-mutations on clinical outcomes will be presented. Conclusions: Treatment with talazoparib and avelumab did not meet the pre-specified threshold for efficacy in previously treated STK11-mutant NSCLC in this biomarker-driven Phase II study, though durable disease stabilization was observed. Further studies are required to determine optimal therapeutic approaches for this challenging subset of NSCLC pts. Funding: NIH/NCI grants U10CA180888, U10CA180819. Talazoparib was provided by Pfizer. Avelumab was provided by Pfizer, as part of an alliance between Pfizer and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100004755). Clinical trial information: NCT04173507.

9046 Background: Immune checkpoint blockade (ICB) has become a standard pillar of treatment for lung cancer. However, only ̃20% of unselected patients can achieve durable clinical benefits. We performed immunogenomic profiling of tissue specimens from a randomized Phase III trial S1400I on metastatic lung squamous cell carcinoma (SCC) to evaluate if there were factors associated with better prognoses with ICB from single-agent versus combined targeting PD-1/CTLA-4 and evaluate if any differentiated between the treatments. Methods: We utilized FFPE tumor tissue submitted for Lung-MAP screening provided by the SWOG bank. SCC samples from 82 eligible patients treated with combined nivolumab+ipilimumab (N+I) or single agent nivolumab (N) were subjected to multiplex immunofluorescence (mIF, n = 82) and NanoString (ncounter PanCancer Immune Profiling Panel, n = 32). Cell density phenotypes (cells/mm2) were defined using image analysis of staining for cytokeratin, CD3, CD8, granzyme B, CD45RO, FOXP3, PD1, PD-L1, and CD68. Immunogenomic features were associated with response, PFS, and OS derived from data provided by the LungMap team to the CIDC portal. For statistical analyses, non-parametric tests were utilized to assess associations of cell phenotypes versus continuous or categorical variables, and log-rank test analysis was performed to identify cell phenotypes or genes correlated with survival. Results: In both arms higher densities of total CD3+CD45RO+ T cells ( P= 0.041), CD3+PD-1+ T cells ( P= 0.024) and CD3+CD8+PD-1 T cells in stroma ( P= 0.042) and CD3+CD8+GZMB+ T cells in the tumor compartment ( P= 0.011) were positively associated with PFS. In the N+I arm but not in the N arm, higher densities of CD3+CD8+GZMB+ T cells in the tumor compartment were associated with better PFS ( P= 0.015) and higher densities of stroma CD3+CD8-FOXP3+ T cells with worse OS. Spatial analysis showed that the presence of CD8+GZMB+ T cells close to malignant cells (median, ≤19.27 µm) was associated with better PFS ( P= 0.037) in N+I arm and cluster analysis showed low clustering of cells in TMB-high vs. TMB-low tumors (P < 0.01). Gene expression profiling demonstrated that myeloid infiltration, immune recruitment, and inflammation genes were associated with a positive clinical outcome ( P< 0.05). In both arms, BLNK, CD163, FCGR2A were associated with better OS ( P< 0.01), IRF1 and BLNK were associated with increased PFS ( P< 0.01). In the N+I arm but not in the N arm, we observed significantly higher CD45 immune cell scores, including CD8 T cells and neutrophils, in responders versus non-responders. Conclusions: Our findings suggest a potential advantage in PFS and OS with an increased presence of cytotoxic immune cells and genes associated with the recruitment and proliferation of these cell types before therapy.

9004 Background: Resistance to immune checkpoint inhibitor (ICI) therapy develops in most patients (pts) with advanced non-small cell lung cancer (NSCLC). Tumors that develop resistance to ICI constitute a major unmet need. Combined ICI and VEGF/VEGF receptor inhibition have shown benefit in multiple tumor types through immune modulation. We evaluated pembrolizumab and ramucirumab (P+R) in advanced, ICI-exposed NSCLC, under the aegis of Lung-MAP, a master protocol for pts with stage IV, previously treated NSCLC. Pt characteristics and treatment toxicities were presented at ASCO 2021. Methods: S1800A was a randomized phase II trial for pts ineligible for a biomarker-matched substudy with acquired resistance to ICI defined as previous ICI therapy for at least 84 days with progressive disease (PD) on or after therapy. Eligibility stipulated PD on prior platinum-based doublet therapy (sequential or in combination with ICI) and ECOG PS of 0-1. Pts were stratified by PD-L1 expression, histology, and intent to receive ramucirumab in the standard of care (SOC) arm and were randomized to P+R or SOC (investigator’s choice of docetaxel+R; docetaxel, pemetrexed, gemcitabine). With a goal of 144 total/130 eligible pts, the primary objective was to compare overall survival (OS) between the arms using a 1-sided 10% level log-rank test upon 90 deaths. Secondary endpoints included response, duration of response, investigator assessed-progression free survival and toxicity. Results: From May 17, 2019 to November 16, 2020, 166 pts were enrolled with 137 eligible (69 P+R; 68 SOC [45 +R, 23 w/o R]). Main causes for ineligibility were lack of PD on ICI or chemotherapy (6 SOC, 6 P+R), > 1 line of ICI (2 P+R), ICI discontinued due to toxicity (2 SOC), or lack of measurable disease (2 SOC, 1 P+R). OS was significantly improved with P+R (HR: 0.61 [0.38-0.97], 1-sided p-value = 0.019; median [95% CI] OS of 15.0 (13.2-17) months (mo) for P+R and 11.6 (8.5-13.8) mo in SOC arm). Progression-free survival (PFS) was not different between the arms (HR: 0.86 [0.57-1.31], 1-sided p-value=0.25; median PFS (95% CI) of 4.5 (4.0-6.9) mo for P+R and 5.2 (4.0-6.6) mo in SOC arm). ORR was not different between the arms (p=0.28). OS benefit for P+R was seen in most subgroups. Analysis of survival based on genomic alterations, tumor mutational burden and PD-L1 will be presented. Conclusions: Pembrolizumab + ramucirumab in pts with advanced NSCLC previously treated with chemotherapy and immunotherapy led to improved OS compared to SOC. Discordance of ORR and PFS from OS has been reported in prior ICI trials (Rittmeyer et al. Lancet 2017). This is the first trial in the 2nd line setting without a chemotherapy backbone to demonstrate a potential survival benefit compared to SOC regimens including docetaxel and ramucirumab using the Lung-MAP platform. Clinical trial information: NCT03971474.

8583 Background: Immunotherapy has shown efficacy in the treatment of recurrent, extensive-stage small cell lung cancer (ES-SCLC). In the Checkmate 032 trial, ipilimumab and nivolumab combination therapy resulted in a 21% objective response rate in relapsed SCLC. At present, there are no biomarkers used in clinical practice to predict treatment responsiveness in SCLC. Ipilimumab and nivolumab act by blocking key co-inhibitory immune pathways of CTLA-4 and PD-1/PD-L1, respectively, leading to reinvigoration of anti-tumor cytotoxic T cell responses and a decrease in immune suppressive tumor infiltrating leukocytes. The ratio of intratumor Teff (CD8+) cells to Treg (CD4+/Foxp3+) cells (Teff/Treg) could be a more reliable biomarker than effector cell infiltration alone. Methods: In this open-label, single arm trial, we enrolled patients with ES-SCLC who previously received platinum-based chemotherapy; prior anti-PD-1 /PD-L1 therapy was allowed. Patients were treated with nivolumab 1 mg/kg and ipilimumab 3 mg/kg, for a total of 4 doses each and received nivolumab 480 mg beginning with cycle 5, every 4 weeks until progression, unacceptable toxicity or study discontinuation. On-study biopsies were performed prior to initiation of therapy and during week 4 for the biomarker primary objective—to correlate disease response with intratumor Teff/Treg changes. Secondary objectives include determining ORR, DOR, PFS, and OS. Results: Twenty-two patients (median age 63.5 [range 54-80] years, ECOG 0/1/2 [41%/50%/9%], sex M/F [45%/55%]) were enrolled and received treatment. Fourteen (64%) had paired biopsies while on treatment. Fifteen patients were evaluable per RECIST with an ORR of 13% (2/15, 2 partial responses [13%]) and DCR was 40% (6/15, 4 stable disease [27%]). Grade 3 treatment-related adverse events (TRAEs) occurred in 9/22 [40%]. Grade 4 TRAEs occurred in 2/22 [9%] (elevated lipase and elevated bilirubin) and Grade 5 TRAEs occurred in 1/22 patients (hepatic failure). Out of the 9 patients previously treated with anti- PD-1/PD-L1 therapy, 1 had a partial response and 2 had stable disease. Multiplexed quantitative immunofluorescence analysis revealed changes of both CD8+ effector T cells and Tregs in the tumor micro-environment associated with clinical benefit to immunotherapy. Conclusions: Combination immunotherapy with ipilimumab and nivolumab shows clinical efficacy in relapsed extensive-stage SCLC, including those previously treated with anti-PD-1/PDL-1 therapy. Obtaining paired biopsies was shown to be successful in this prospective trial to study the tumor microenvironment in SCLC tumors treated with checkpoint inhibitors. Early biomarker evaluation during week 4 shows local immunomodulatory effect of treatment and supports exploration as predictive biomarker in this population. Clinical trial information: 03670056.

6543 Background: A major goal of Lung-MAP, a biomarker-driven master protocol conducted within the National Clinical Trials Network of the NCI using a public-private partnership, was to improve access to novel therapeutics. Representative enrollment of patient sub-groups in clinical trials is essential for improving confidence that trial findings are valid and applicable to all patients. We examined the representativeness of patients enrolled in Lung-MAP by demographic and area-level measures compared to patients in other advanced non-small cell lung cancer (NSCLC) trials and with the US NSCLC population. Methods: We analyzed data on patients enrolled to Lung-MAP between 2014-2020 according to sex, age ( < 65 years v. ≥ 65 years), race (White v. Black v. Asian), ethnicity (Hispanic v. not Hispanic), residence (rural v. urban), insurance type (Medicaid or no insurance v. private), and neighborhood socioeconomic deprivation (quintiles of Area Deprivation Index score). Rates were compared to SWOG-led NSCLC trials conducted between 2001-2020 (date range to provide sufficient power) and, where possible, to US NSCLC population rates using Surveillance, Epidemiology, and End Results (SEER) registry data (2014-2018). Two-sided tests of proportions at the 5% level were used for all comparisons. Results: 3,556 patients enrolled to Lung-MAP were compared to 2,267 patients enrolled to SWOG-led NSCLC studies. Lung-MAP patients were more likely to be ≥ 65 years old (57.2% v. 46.7%; p

9037 Background: Immune checkpoint inhibitors (ICI) are standard of care for advanced NSCLC. Even among patients with initial response, a majority ultimately progress, and rational combination approaches are needed to improve outcomes. CAN-2409 is a replication-deficient adenoviral gene construct that delivers the thymidine kinase gene, resulting in local conversion of a prodrug (valacyclovir) into a toxic metabolite. This leads to tumor cell lysis and immunization against the injected tumor and uninjected metastases. We have previously shown that monotherapy intra-tumoral (IT) delivery of CAN-2409 followed by oral valacyclovir in NSCLC patients is safe and results in CD8+ T cell infiltration in the injected tumor and activation of this cell population in tissue and peripheral blood. Methods: This open-label Ph2 experimental medicine clinical trial evaluates safety and clinical activity of IT CAN-2409 combined with ICI (± chemo) for stage III/IV NSCLC. Three cohorts are defined based on response to ICI at enrollment: stable disease (SD; Cohort 1; C1), progressive disease (PD) after ≥18 weeks (w) of ICI (Cohort 2; C2), or ICI refractory disease (RD; Cohort 3; C3). Two doses of CAN-2409 (5x1011 vp) are given 5-7w apart via bronchoscopic or percutaneous injection into a lung tumor, disease-positive lymph node or peripheral metastasis, followed by valacyclovir. Patients are assessed for safety, immunologic biomarkers (analysis in progress), and clinical response. Results: As of data cutoff (10Jan22), 28 patients received ≥1 dose of CAN-2409 (safety population). Median age was 70 years; 86% stage IV; 32% squamous; 11% PD-L1 >50%; 82% receiving pembrolizumab and 18% nivolumab. Study treatment and procedures were generally well tolerated. The most common TRAEs were Gr1/2, with fatigue, fever, and chills in 18-39% of patients; 1 patient had Gr3 fever. Twenty-two patients are alive and 6 patients died due to disease. Of the 14 RECIST evaluable patients who received 2 doses of CAN-2409, clinical response was seen in 4 patients (Table 1). Two PRs are ongoing (6w, 24w) and reduction in tumor size was observed in non-injected lesions. In C2, 6 of 7 patients achieving SD are ongoing with median duration of 13w (range 10-40w). Conclusions: The addition of CAN-2409 for patients with advanced NSCLC and inadequate response to front-line ICI (± chemo) appears to be well tolerated. Preliminary clinical data suggest that CAN-2409 induced a clinical response in 4/14 evaluable patients and produced disease stabilization in most patients entering the trial with PD, with evidence of abscopal effect in a subset of patients. Clinical trial information: NCT04495153. [Table: see text]

9044 Background: While Immune checkpoint blockade (ICB) is standard treatment for lung cancer there are limited biomarkers that predict benefit, pharmacokinetic on-treatment activity or explain progression. S1400I was a randomized Phase III trial of nivolumab(N)+ipilimumab(I) versus N (NCT02154490, PMID 34264316) for ICB naïve, previously treated stage IV or recurrent squamous cell lung cancer. We performed circulating serum protein analysis of serial blood specimens from patients enrolled in S1400I to evaluate if serum proteins levels changed over time, changes differed by treatment arm, and if they were associated with overall survival. Methods: 561 serial blood specimens (baseline, weeks (wk) 3, 7, 9, and progression [PD]) from 160 of 252 eligible patients enrolled to S1400I were analyzed for 92 immuno-oncology analytes with the Olink proximity extension assay. Protein levels were normalized with use of internal controls and quantified as log2 protein expression (denoted as NPX). Linear mixed models evaluated change in expression from baseline at each time point (wks 3,7,9 and PD), and NPX differences at baseline, wk3, and PD depending on best objective response. A Cox model was used to evaluate the association between baseline NPX and survival. Overall survival and longitudinal cytokine expression were jointly modeled using a linear mixed model to estimate dynamic biomarker changes in NPX and a Cox model for survival. The joint models for time-varying NPX values included a random intercept and modeled time using a natural spline with three knots. Significance was defined as P < 0.05. Results: Serum proteins PCDC1, CXCL9, and CXCL10 were increased from baseline at wks 3,7,9 and at PD. CCL19 was increased at wks 3 and 7 but not at wk 9 and PD. IL10 and IFNγ were increased at wk 3 but subsequently returned to baseline. Change in CXCL13 from baseline to PD was larger for N+I versus N. Baseline CCL23, CSF-1, IL6, and MUC-16 were associated with shorter survival (HR > 1). Joint modeling of survival with cytokines showed an increased risk of death (HR > 1) with higher longitudinal serum levels of CXCL13, MMP12, CSF-1, and IL8. Patients achieving objective response had higher IL4 and LAMP3 and lower IL6 and IL8 at baseline and wk 3 compared to non-responders. Conclusions: Measurements of blood circulating soluble proteins represent easily accessible biomarkers that may be useful as indicators of outcome, and that will need to be prospectively confirmed. Clinical trial information: NCT02154490.

9075 Background: The therapeutic landscape in metastatic NSCLC has dramatically changed with approvals of immunotherapy agents in both treatment-naïve and previously treated cancer patients (pts) and irrespective of histology. Pts with tumors that develop resistance is a significant area of unmet need. Vascular endothelial growth factor (VEGF) has been shown to modulate the tumor immune microenvironment and combination immune checkpoint and VEGF/VEGF receptor inhibition have shown benefit in multiple tumor types. Lung-MAP is a master protocol for pts with stage IV, previously treated NSCLC. Pts who were not eligible for a biomarker-matched substudy enrolled in S1800A. The adverse event profile will be presented. Methods: S1800A is a phase II randomized trial for pts who previously received PD-1 or PD-L1 inhibitor therapy for at least 84 days and platinum-based doublet therapy with ECOG 0-1 stratified by PD-L1 expression, histology and intent to receive ramucirumab in the standard of care (SOC) arm. Pts were randomized 1:1 to pembrolizumab and ramucirumab P+R or SOC (docetaxel +R [SOC w R]; docetaxel, pemetrexed or gemcitabine [SOC wo R]). The primary endpoint was overall survival. Secondary endpoints included response, duration of response, investigator assessed-progression free survival and evaluation of toxicity. Results: From May 17, 2019 to November 16, 2020, 166 pts enrolled and 140 determined eligible [69 (49%) P+R; 46 (33%) SOC w R; 25 (18%) SOC wo R]. Treatments for those who received SOC wo R included 3 on docetaxel (19%); 12 on gemcitabine (75%); and on 1 on pemetrexed (6%). 131 were eligible for adverse event (AE) assessment. The most common AE were fatigue (38%), proteinuria (28%), hypertension (23%), diarrhea (22%) and hypothyroidism (22%) on P+R; fatigue (61%), anemia (48%), diarrhea (41%) and neutropenia (39%) on SOC w R and anemia (56%), leukopenia (56%), fatigue (44%) and neutropenia (44%) on SOC wo R. Grade ≥ 3 treatment-related AEs occurred in 32% of pts on P+R, 54% of pts on SOC w R and 56% of pts on SOC wo R. Cardiac and thromboembolic events occurred in 12% of pts on P+R, 11% of pts on SOC w R and 0% of pts on SOC wo R. Grade 5 AE occurred in 2 pts on P+R (respiratory failure and cardiac arrest), 3 pts on SOC w R (2 respiratory failure and sepsis) and 1 pt on SOC wo R (sepsis). Four patients were diagnosed with COVID-19 (1 on P+R and 3 on SOC) and 3 died (1 on P+R and 2 on SOC). Conclusions: Grade 3 toxicities were lower in P+R compared to SOC arms with or without R. Cardiac and thromboembolic events were similar in arms that included R. P+R was generally well-tolerated. Efficacy outcomes will be presented when data matures. Clinical trial information: NCT03971474.

9024 Background: While prior studies have shown robust efficacy leading to FDA approval of PARP inhibitors (PARPi) in BRCA-associated cancers, data in NSCLC are much less clear. S1900A, a LUNG-MAP substudy, evaluated the PARPi rucaparib in advanced stage NSCLC harboring BRCA1/2 mutations or genomic loss of heterozygosity (LOH) as a phenotypic marker of homologous recombination deficiency (HRD). Methods: Eligible patients (pts) were required to have a deleterious mutation in BRCA1/BRCA2 and/or high (≥21%) genomic LOH. Key eligibility criteria: advanced NSCLC patients (pts) with progression on or after platinum based chemotherapy and/or PD-(L)1 antibody and progressed on most recent line of systemic therapy, a Zubrod performance status of 0-1, adequate organ function, no ≥ grade 3 hypercholesterolemia, no previous PARPi exposure and no systemic therapy within 21 days of registration. Pts stratified by histology into two cohorts (squamous [sq] and non-squamous/mixed histology [nsq]). With 40 eligible pts per cohort, the design had 91% power to rule out an ORR of 15% if the true ORR was at least 35% at the 1-sided 5% level. A planned interim analysis on the first 20 pts evaluable for response per cohort required ≥ 3 responses to proceed to full enrollment. Results: 64 pts enrolled (27 sq cohort; 37 nsq cohort) of whom 59 are eligible. Median age 65.7 yrs; M/F 33/26 (56/44%); 98% of the pts received at least 1 prior line of treatment for stage IV disease. Biomarker selection included 36 pts (61%) LOH only, 4 pts (7%) BRCA1 only, 11 pts (19%) BRCA2 only, 4 pts (7%) BRCA1 + LOH high and 4 pts (7%) BRCA2 + LOH high. Both cohorts were closed for futility with insufficient responses in the interim analysis populations. In the full study, 4 responses (3 nsq/1 sq) were reported. ORR was 7% (95% CI: 0-13) (9% nsq/4% sq) and DCR was 62% (95% CI: 50-75) (62% nsq/64% sq); 3 of the 4 responders harbored BRCA1/2 mutations and 1 of 4 high LOH; ORR in BRCA1/2+ pts 3/23 (13%). Median PFS was 3.2 months (95% CI: 1.6-4.6) in nsq cohort and 2.9 months (95% CI 1.6-6.2) in sq cohort. Median OS was 7.8 months in nsq cohort and 7.9 months in sq cohort. The most frequent grade ≥3 adverse events were anemia (22%), lymphopenia (8%), fatigue (8%) and transaminitis (5%). Conclusions: S1900A failed to show the requisite level of efficacy for rucaparib in advanced NSCLC pts with high genomic LOH and/or a BRCA1/2 mutation. There were no new safety signals and hematologic toxicities were the most frequent adverse events. Genomic LOH as a phenotypic marker of HRD does not predict sufficient activity of rucaparib in NSCLC. These results stand in contrast to the high level of efficacy of PARPi in patients with BRCA-associated or high LOH cancers of other tumor types. Underlying biologic differences in the genomic characteristics of these cancers vs. NSCLC may be responsible. Studies examining this premise are ongoing. (NCT03845296). Clinical trial information: NCT03845296.

Purpose By applying the principles of real-time biopsy, biomarker-based, adaptively randomized studies in non–small-cell lung cancer (NSCLC) established by the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, we conducted BATTLE-2 (BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer), an umbrella study to evaluate the effects of targeted therapies focusing on KRAS-mutated cancers. Patients and Methods Patients with advanced NSCLC (excluding sensitizing EGFR mutations and ALK gene fusions) refractory to more than one prior therapy were randomly assigned, stratified by KRAS status, to four arms: (1) erlotinib, (2) erlotinib plus MK-2206, (3) MK-2206 plus AZD6244, or (4) sorafenib. Tumor gene expression profiling–targeted next-generation sequencing was performed to evaluate predictive and prognostic biomarkers. Results Two hundred patients, 27% with KRAS-mutated (KRAS mut+) tumors, were adaptively randomly assigned to erlotinib (n = 22), erlotinib plus MK-2206 (n = 42), MK-2206 plus AZD6244 (n = 75), or sorafenib (n = 61). In all, 186 patients were evaluable, and the primary end point of an 8-week disease control rate (DCR) was 48% (arm 1, 32%; arm 2, 50%; arm 3, 53%; and arm 4, 46%). For KRAS mut+ patients, DCR was 20%, 25%, 62%, and 44% whereas for KRAS wild-type patients, DCR was 36%, 57%, 49%, and 47% for arms 1, 2, 3, and 4, respectively. Median progression-free survival was 2.0 months, not different by KRAS status, 1.8 months for arm 1, and 2.5 months for arms 2 versus arms 3 and 4 in KRAS mut+ patients (P = .04). Median overall survival was 6.5 months, 9.0 and 5.1 months for arms 1 and 2 versus arms 3 and 4 in KRAS wild-type patients (P = .03). Median overall survival was 7.5 months in mesenchymal versus 5 months in epithelial tumors (P = .02). Conclusion Despite improved progression-free survival on therapy that did not contain erlotinib for KRAS mut+ patients and improved prognosis for mesenchymal tumors, better biomarker-driven treatment strategies are still needed.