INTRODUCTION:In CheckMate 227 Part 1, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with metastatic NSCLC, regardless of tumor programmed death-ligand 1 (PD-L1) expression. Here, we report post hoc exploratory systemic and intracranial efficacy outcomes and safety by baseline brain metastasis status at 5 years' minimum follow-up. METHODS:Treatment-naive adults with stage IV or recurrent NSCLC without EGFR or ALK alterations, including asymptomatic patients with treated brain metastases, were enrolled. Patients with tumor PD-L1 greater than or equal to 1% were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy; patients with tumor PD-L1 less than 1% were randomized to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy groups. Assessments included OS, systemic and intracranial progression-free survival per blinded independent central review, new brain lesion development, and safety. Brain imaging was performed at baseline (all randomized patients) and approximately every 12 weeks thereafter (patients with baseline brain metastases only). RESULTS:Overall, 202 of 1739 randomized patients had baseline brain metastases (nivolumab plus ipilimumab: 68; chemotherapy: 66). At 61.3 months' minimum follow-up, nivolumab plus ipilimumab prolonged OS versus chemotherapy in patients with baseline brain metastases (hazard ratio = 0.63; 95% confidence interval: 0.43-0.92) and in those without (hazard ratio = 0.76; 95% confidence interval: 0.66-0.87). In patients with baseline brain metastases, 5-year systemic and intracranial progression-free survival rates were higher with nivolumab plus ipilimumab (12% and 16%, respectively) than chemotherapy (0% and 6%). Fewer patients with baseline brain metastases developed new brain lesions with nivolumab plus ipilimumab (4%) versus chemotherapy (20%). No new safety signals were observed. CONCLUSIONS:With all patients off immunotherapy for more than or equal to 3 years, nivolumab plus ipilimumab continued to provide a long-term, durable survival benefit in patients with or without brain metastases. Intracranial efficacy outcomes favored nivolumab plus ipilimumab versus chemotherapy. These results further support nivolumab plus ipilimumab as an efficacious first-line treatment for patients with metastatic NSCLC, regardless of baseline brain metastasis status.

First-line immunotherapy has been shown to significantly improve survival in patients with advanced/metastatic NSCLC. The anti-PD-1 antibody pembrolizumab alone showed superior efficacy over chemotherapy in untreated patients with advanced NSCLC and PD-L1 expression ≥50%, yet most patients will eventually experience progression. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate composed of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a topoisomerase I inhibitor payload via a plasma-stable, tetrapeptide-based, cleavable linker.

9099 Background: PERLA (NCT04581824) is a global, randomized, Phase II, double-blind study assessing the efficacy and safety of chemotherapy (CT) combined with programmed death 1 (PD-1) inhibitors dostarlimab (dostCT) and pembrolizumab (pembCT) as first-line (1L) treatment (tx) for patients (pts) with metastatic non-oncogene-driven, non-squamous, NSCLC. DostCT had similar efficacy and safety to pembCT [1]. Exploratory analyses of patient-reported outcomes (PROs) from PERLA have been conducted. Methods: In PERLA, pts with ECOG status 0–1 were randomized 1:1 to receive ≤35 cycles (C) of dostCT or pembCT Q3W (CT was ≤35 cycles [C] of 500 mg/m 2 pemetrexed every 3 weeks [Q3W] and ≤4C of cisplatin or carboplatin). PROs were collected at baseline (BL), Q3W until C4, Q9W until C16, Q12W until end of tx and at 30-day safety follow-up. Change from BL in EORTC QLQ-C30 & QLQ-LC13 were analyzed using a longitudinal mixed model, with a ≥10-point change from BL considered clinically meaningful; scores were categorized as improved, stable, or worsened. Time to deterioration (TTD) in QLQ-C30 and selected QLQ-LC13 symptoms were estimated using Kaplan–Meier methods. Results: Analysis populations for dostCT/pembCT included 102/99 pts for QLQ-C30 and 96/90 pts for QLQ-LC13. Completion rates for QLQ-C30 and QLQ-LC13 were >80% up to C4 in both tx arms, decreasing after C7. At C13, 55.0% [n=33/60] and 54.2% [n=32/59] of dostCT pts, and 37.1% [n=23/62] and 35.7% [n=20/56] of pembCT pts completed QLQ-C30 and QLQ-LC13, respectively. Overall, least squares (LS) mean QLQ-C30 and QLQ-LC13 scores remained stable up to C13. Relative to BL, average pt functioning (e.g., physical, role) and cancer symptoms (e.g., pain, cough, dyspnea) were stable through C13 (~1 yr on tx); no clinically meaningful difference in LS mean QLQ-C30 or QLQ-LC13 scores were observed between tx arms. Across most QLQ-C30 and QLQ-LC13 subscales, >60% pts in both tx arms had stable or improved responses up to C13. At C13, meaningful improvements in chest pain and dyspnea were reported in a higher % of dostCT pts (34.4% [n=11/32] and 40.6% [n=13/32], respectively) than pembCT pts (10.0% [n=2/20] and 25.0% [n=5/20], respectively). TTD for QLQ-C30 and QLQ-LC13 subscales were comparable between tx arms, except for longer median TTD in dyspnea in dostCT pts (N=96) than pembCT pts (N=90) (4.24 vs 1.54 months; HR 0.64 [95% CI: 0.44–0.93]). Conclusions: HRQoL was similar and stable through C13 in both tx arms. These results supplement efficacy and safety data reported in PERLA and support further investigation of dostarlimab as an appropriate PD-1 inhibitor for use in combination with standard of care and novel therapies in metastatic NSCLC. References: 1. Peters, S et al. IOTECH 2022;16(S1):100162 Funding:GSK (213403). Editorial support provided by Fishawack Health, funded by GSK. Clinical trial information: NCT04581824 .

TPS8611 Background: Small cell lung cancer (SCLC) is an aggressive malignancy for which very few patients achieve long term disease control; response to most treatments is transient and second line treatment options are limited. Delta-like ligand 3 (DLL3) is a Notch ligand aberrantly expressed on the surface of up to 85% of SCLC cells and minimally expressed in normal tissues, making it an attractive therapeutic target. Tarlatamab is a bispecific T cell engager (BiTE) molecule designed to bind DLL3 on target cancer cells and CD3 on T cells, thereby driving T cell-dependent killing of tumor cells. Results from the first-in-human study in patients with relapsed/refractory SCLC (DeLLphi-300; NCT03319940) demonstrate tarlatamab efficacy in pretreated patients with confirmed responses in 23% of patients and median duration of response > 12 months. 1 Median overall survival (OS) was 13.2 months. Grade ≥ 3 treatment-related AEs (TRAEs) occurred in 31% of patients and TRAEs resulted in discontinuation in 4% of patients. This promising efficacy/safety profile is being evaluated further in a phase 2, open-label study in patients with relapsed/refractory SCLC after ≥2 lines of prior treatment (DeLLphi-301; NCT05060016). Methods: NCT05740566 is a randomized, open-label, phase 3 study of tarlatamab compared with standard of care (SOC) in ~700 patients with relapsed SCLC after platinum-based first-line chemotherapy. Patients will be randomized 1:1 to receive tarlatamab or SOC therapy (lurbinectedin or topotecan in US, Canada, Australia, Singapore, Korea; amrubicin in Japan; topotecan in all countries except Japan), stratified by prior anti-programmed cell death 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) exposure, chemotherapy-free interval, presence of brain metastases, and SOC (topotecan/amrubicin vs lurbinectedin). The primary objective is to compare the efficacy of tarlatamab with SOC on prolonging OS. Key secondary endpoints include comparison of progression free survival (PFS) based on investigator assessment per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and patient-reported outcomes (PRO) including disease-related symptoms, physical function, and global health status of quality of life. Key eligibility criteria include adults with histologically or cytologically confirmed relapsed SCLC who progressed following 1 platinum-based regimen. Patients must have measurable lesions as defined per RECIST 1.1 within the 21-day screening period and must have adequate organ function. Exclusions include untreated or symptomatic central nervous system metastases, history of immune checkpoint inhibitor use resulting in severe immune-mediated adverse event, and previous history of NSCLC. Enrollment is ongoing. References 1. Paz-Ares L, et al. J Clin Oncol. DOI:1200/JCO.22.02823. Clinical trial information: NCT05740566 .

CAFs are an important component of the tumour microenvironment. TGFβ-induced CAFs have been associated with poor prognosis in several indications. In IMpower010, adjuvant atezo showed significant DFS benefit vs BSC in resected early-stage NSCLC after chemotherapy (chemo), leading to approval of atezo after platinum-based chemo for resected (R0) PD-L1 TC ≥1% or ≥50% (SP263) stage II-IIIA NSCLC. We report results from exploratory analyses to identify predictive biomarkers for atezo outcomes using IMpower010 RNA sequencing (RNAseq) data. The IMpower010 study design and primary data have been reported ( Felip, Lancet 2021 ). The predictive effects of features including cell-type and -state gene signatures for DFS (atezo vs BSC) were evaluated from baseline (resection) tumour samples. Relevant features were identified based on variable importance scores calculated by generalised random forests method. Median DFS was estimated using Kaplan-Meier curves; HRs were estimated by Cox regressions. Of the 1005 randomised pts (ITT), 500 comprised the RNAseq biomarker-evaluable population. The TGFβ CAF gene signature had the highest variable importance. DFS HRs (95% CI) were 0.54 (0.37, 0.80) and 0.94 (0.63, 1.41) in the TGFβ CAF-high (≥ median) and -low (< median) populations (Table). Improved outcomes with atezo vs BSC in the TGFβ CAF-high population were driven by shorter DFS in the BSC arm. Baseline characteristics were generally balanced across populations. Exploratory analyses of IMpower010 RNAseq data showed that the TGFβ CAF-high population had improved DFS with atezo vs BSC, regardless of histology or PD-L1 expression level. These data suggest that after surgical resection, pts with enrichment of the TGFβ CAF gene signature may have improved DFS after adjuvant atezo vs BSC.Table: 1264MOAtezo median DFS, moBSC median DFS, moDFS HR (vs BSC) 95% CIITTn=507 NRn=498 37.20.81 0.66, 0.99RNAseq BEPn=248 36.1n=252 30.40.71 0.54, 0.94TGFβ CAF-lown=123 NRn=127 37.30.94 0.63, 1.41TGFβ CAF-highn=125 NRn=125 29.70.54 0.37, 0.80TGFβ CAF-high, squamousn=61 NRn=62 41.40.48 0.26, 0.89TGFβ CAF-high, nonsquamousn=64 36.1n=63 24.70.60 0.36, 0.99TGFβ CAF-high, PD-L1 TC ≥1%n=74 NRn=69 35.30.49 0.29, 0.84TGFβ CAF-high, PD-L1 TC <1%n=51 NRn=56 28.60.64 0.36, 1.14BEP, biomarker evaluable population; NR, not reached; TGFβ, transforming growth factor beta. Open table in a new tab

Background: IMpower010 (NCT02486718) demonstrated significantly improved disease-free survival (DFS) with adjuvant atezolizumab versus best supportive care (BSC) following platinum-based chemotherapy in the programmed death-ligand 1 (PD-L1)-positive and all stage II-IIIA non-small-cell lung cancer (NSCLC) populations, at the DFS interim analysis. Results of the first interim analysis of overall survival (OS) are reported here.Patient and methods: The design, participants, and primary-endpoint DFS outcomes have been reported for this phase III, open-label, 1 : 1 randomised study of atezolizumab (1200 mg q3w; 16 cycles) versus BSC after adjuvant platinum-based chemotherapy (1-4 cycles) in adults with completely resected stage IB (>= 4 cm)-IIIA NSCLC (per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system, 7th edition). Key secondary endpoints included OS in the stage IB-IIIA intent-to-treat (ITT) population and safety in randomised treated patients. The first pre-specified interim analysis of OS was conducted after 251 deaths in the ITT population. Exploratory analyses included OS by baseline PD-L1 expression level (SP263 assay).Results: At a median of 45.3 months' follow-up on 18 April 2022, 127 of 507 patients (25%) in the atezolizumab arm and 124 of 498 (24.9%) in the BSC arm had died. The median OS in the ITT population was not estimable; the stratified hazard ratio (HR) was 0.995 [95% confidence interval (CI) 0.78-1.28]. The stratified OS HRs (95% CI) were 0.95 (0.74-1.24) in the stage II-IIIA (n = 882), 0.71 (0.49-1.03) in the stage II-IIIA PD-L1 tumour cell (TC) >= 1% (n = 476), and 0.43 (95% CI 0.24-0.78) in the stage II-IIIA PD-L1 TC >= 50% (n = 229) populations. Atezolizumab-related adverse event incidences remained unchanged since the previous analysis [grade 3/4 in 53 (10.7%) and grade 5 in 4 (0.8%) of 495 patients, respectively].Conclusions: Although OS remains immature for the ITT population, these data indicate a positive trend favouring atezolizumab in PD-L1 subgroup analyses, primarily driven by the PD-L1 TC >= 50% stage II-IIIA subgroup. No new safety signals were observed after 13 months' additional follow-up. Together, these findings support the positive benefit-risk profile of adjuvant atezolizumab in this setting.

The Phase III IMpower010 (NCT02486718) study showed a statistically significant disease-free survival (DFS) benefit with adjuvant atezolizumab vs best supportive care (BSC) following platinum-based chemotherapy for patients with PD-L1 tumour cells (TC) ≥1% (by SP263) stage II-IIIA and in all patients with stage II-IIIA NSCLC (Felip et al. Lancet 2021). High tissue tumour mutational burden (TMB-H) has been associated with clinical response to some immune checkpoint inhibitors across indications. Here we present the exploratory analysis of DFS by TMB and PD-L1 expression levels in patients with resected stage II-IIIA NSCLC from the IMpower010 study.

IMpower010 (NCT02486718) showed a statistically significant benefit in primary-endpoint disease-free survival (DFS) with adjuvant atezo vs BSC in resected stage II-IIIA PD-L1 tumour cell (TC) ≥1% (SP263) NSCLC after platinum-based chemotherapy. This finding led to the approval of atezo in this setting in the US, China, Japan and other countries and to its approval for stage II-IIIA PD-L1 TC ≥50% NSCLC in the EU and other countries. At the first pre-specified interim analysis (IA) of OS (cutoff 18 Apr 2022), the secondary endpoint of OS in the ITT population was not mature, but OS is of clinical interest in this curative setting; in pts with stage II-IIIA and stage II-IIIA PD-L1 ≥1% NSCLC, the respective OS HRs were 0.95 (95% CI: 0.74, 1.24) and 0.71 (95% CI: 0.49, 1.03) (Wakelee JTO 2022; 17:S2).

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

BackgroundIMpower010 (NCT02486718) showed that adjuvant atezo improved disease-free survival (DFS) vs BSC in pts with PD-L1 tumour cell (TC) ≥1% stage II-IIIA NSCLC. While a ctDNA positive (+) status post-surgery (Post-OP ctDNA) conferred poor prognosis, atezo was beneficial vs BSC irrespective of Post-OP ctDNA status (Zhou ESMO-IO 2021). The current exploratory analysis evaluated (1) association of atezo clinical outcomes by PD-L1 status and Post-OP ctDNA status and (2) association of ctDNA clearance post-chemo and pre-atezo cycle 1 day 1 (Post-chemo ctDNA), as well as post-atezo/BSC treatment (on-treatment), with DFS by arm in atezo and BSC pts.MethodsOf 1005 randomized pts, 600 were evaluated for Post-OP ctDNA using the Signatera (Natera) RUO test. 118 of 600 pts were Post-OP ctDNA+. Of these, 103 pts were evaluated for ctDNA Post-chemo ctDNA and on-treatment at Wk 6 (C3; n=94), Wk 12 (C5; n=85), Wk 18 or 21 (C7/8; n=73) and Wk 42 or 45 (C15/16; n=46). PD-L1 TC subgroups <1%, ≥1%, 1-49% and ≥50% were determined using the VENTANA SP263 assay.ResultsRegardless of Post-OP ctDNA status, atezo was associated with improved DFS vs BSC in PD-L1+ subgroups (TC ≥1%, 1-49%, ≥50%) but not the PD-L1− subgroup (TC <1%). 62.1% (64/103) of Post-OP ctDNA+ pts were cleared (ctDNA−) at Post-chemo ctDNA, which was linked to improved DFS. Atezo improved DFS vs BSC regardless of ctDNA clearance at Post-chemo ctDNA (Cleared: DFS, 31.3 (atezo) vs 13.3 mo (BSC); HR [95% CI], 0.7 [0.37, 1.34] vs Not cleared: DFS, 4.2 vs 3.9 mo; 0.67 [0.34, 1.32]). Longitudinal assessment of ctDNA+ pts at Post-chemo ctDNA showed that atezo maintained ctDNA levels over time, while an approximate 10× increase was observed with BSC. The median time to convert to ctDNA+ in pts who were ctDNA− at Post-chemo ctDNA was longer with atezo vs BSC (not reached vs 4.67 mo; HR, 0.60 [95% CI: 0.31, 1.17]). Similarly, improved DFS was seen with atezo vs BSC in these pts (31.3 vs 13.3 mo; HR, 0.7 [95% CI: 0.37, 1.34]).ConclusionsAdjuvant atezo is linked to improved DFS vs BSC in early NSCLC in PD-L1+ subgroups regardless of ctDNA status. Chemo ctDNA clearance is associated with longer DFS and atezo may control ctDNA levels and delay disease recurrence better than BSC.Clinical trial identificationNCT02486718.Editorial acknowledgementMedical writing support for this abstract was provided by Michael Williams, PhD, of Health Interactions, Inc. and funded by F. Hoffmann-La Roche, Ltd.Legal entity responsible for the studyF. Hoffmann-La Roche, Ltd.FundingF. Hoffman-La Roche, Ltd.DisclosureE. Felip: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Roche, Janssen, Merck Sharp & Dohme, Merck Serono, Pfizer, PeerVoice, Springer, Touch Medical; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Roche, GlaxoSmithKline, Medical Trends, Peptomyc, Puma Biotechnology, Regeneron, Sanofi, Takeda; Other, Institutional, Research Grant, Research Grant: Oncology Innovation, Merck Healthcare KGAa, Fundacion Merck Salud; Other, Personal, Member of the Board of Directors, Independent Member of the Board: GRIFOLS. M. Srivastava: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Roche. M. Reck: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Novartis, Merck, Roche, Sanofi; Financial Interests, Personal, Advisory Board: Mirati, Pfizer, Sanofi, Amgen, AstraZeneca, Boehringer Ingelheim, BMS, MSD, Roche. H. Wakelee: Financial Interests, Institutional, Research Grant, Research Funding: ACEA Biosciences, Arrys Therapeutics, AstraZeneca/MedImmune, BMS, Celgene, Clovis Oncology, Genentech/Roche, Merck, Novartis, Pharmacyclics, Seagen, Xcovery, Helsinn; Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen, Daiichi Sankyo, Blueprint, Mirati; Non-Financial Interests, Personal, Advisory Board: Merck, Genentech/Roche; Other, Personal, Leadership Role, President: IASLC; Other, Personal, Leadership Role, Executive Committee: ECOG-ACRIN. N.K. Altorki: Financial Interests, Institutional, Research Grant, PI: AstraZeneca, Janssen; Financial Interests, Personal, Other, Steering Committee Member: Roche. E. Vallieres: Financial Interests, Personal, Speaker's Bureau: AstraZeneca, Oncocyte; Financial Interests, Personal, Advisory Board: BMS. H. Tanaka: Financial Interests, Personal, Speaker's Bureau: Chugai Pharmaceutical, AstraZeneca, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, AstraZeneca, MSD, Bristol Myers Squibb, Ono Pharmaceutical. S. McCune: Financial Interests, Institutional, Other, Support from Genentech as a research site for this trial: Genentech. E. Bennett, B.J. Gitlitz, V.A. McNally: Financial Interests, Personal, Full or part-time Employment: Roche; Financial Interests, Personal, Stocks/Shares: Roche. S. Novello: Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Speaker's Bureau: AMG, Roche, Takeda, Pfizer, AZ, Thermofisher, Novartis, Sanofi, BeiGene; Financial Interests, Personal, Advisory Role, Advisor: AMG, Roche, Takeda, Pfizer, AZ, Novartis, Sanofi, BeiGene. M. Ballinger: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Roche. W. Zou, B. Nabet, M. Das Thakur: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Roche. C. Zhou: Financial Interests, Personal, Invited Speaker: Roche China, Lily China, Boehringer Ingelheim, Sanofi, C-Stone, Qilu, Hengrui, Innovent Biologics, LUYE Pharma, TopAlliance Bioscience Inc, Amoy Diagnostics. All other authors have declared no conflicts of interest. BackgroundIMpower010 (NCT02486718) showed that adjuvant atezo improved disease-free survival (DFS) vs BSC in pts with PD-L1 tumour cell (TC) ≥1% stage II-IIIA NSCLC. While a ctDNA positive (+) status post-surgery (Post-OP ctDNA) conferred poor prognosis, atezo was beneficial vs BSC irrespective of Post-OP ctDNA status (Zhou ESMO-IO 2021). The current exploratory analysis evaluated (1) association of atezo clinical outcomes by PD-L1 status and Post-OP ctDNA status and (2) association of ctDNA clearance post-chemo and pre-atezo cycle 1 day 1 (Post-chemo ctDNA), as well as post-atezo/BSC treatment (on-treatment), with DFS by arm in atezo and BSC pts. IMpower010 (NCT02486718) showed that adjuvant atezo improved disease-free survival (DFS) vs BSC in pts with PD-L1 tumour cell (TC) ≥1% stage II-IIIA NSCLC. While a ctDNA positive (+) status post-surgery (Post-OP ctDNA) conferred poor prognosis, atezo was beneficial vs BSC irrespective of Post-OP ctDNA status (Zhou ESMO-IO 2021). The current exploratory analysis evaluated (1) association of atezo clinical outcomes by PD-L1 status and Post-OP ctDNA status and (2) association of ctDNA clearance post-chemo and pre-atezo cycle 1 day 1 (Post-chemo ctDNA), as well as post-atezo/BSC treatment (on-treatment), with DFS by arm in atezo and BSC pts. MethodsOf 1005 randomized pts, 600 were evaluated for Post-OP ctDNA using the Signatera (Natera) RUO test. 118 of 600 pts were Post-OP ctDNA+. Of these, 103 pts were evaluated for ctDNA Post-chemo ctDNA and on-treatment at Wk 6 (C3; n=94), Wk 12 (C5; n=85), Wk 18 or 21 (C7/8; n=73) and Wk 42 or 45 (C15/16; n=46). PD-L1 TC subgroups <1%, ≥1%, 1-49% and ≥50% were determined using the VENTANA SP263 assay. Of 1005 randomized pts, 600 were evaluated for Post-OP ctDNA using the Signatera (Natera) RUO test. 118 of 600 pts were Post-OP ctDNA+. Of these, 103 pts were evaluated for ctDNA Post-chemo ctDNA and on-treatment at Wk 6 (C3; n=94), Wk 12 (C5; n=85), Wk 18 or 21 (C7/8; n=73) and Wk 42 or 45 (C15/16; n=46). PD-L1 TC subgroups <1%, ≥1%, 1-49% and ≥50% were determined using the VENTANA SP263 assay. ResultsRegardless of Post-OP ctDNA status, atezo was associated with improved DFS vs BSC in PD-L1+ subgroups (TC ≥1%, 1-49%, ≥50%) but not the PD-L1− subgroup (TC <1%). 62.1% (64/103) of Post-OP ctDNA+ pts were cleared (ctDNA−) at Post-chemo ctDNA, which was linked to improved DFS. Atezo improved DFS vs BSC regardless of ctDNA clearance at Post-chemo ctDNA (Cleared: DFS, 31.3 (atezo) vs 13.3 mo (BSC); HR [95% CI], 0.7 [0.37, 1.34] vs Not cleared: DFS, 4.2 vs 3.9 mo; 0.67 [0.34, 1.32]). Longitudinal assessment of ctDNA+ pts at Post-chemo ctDNA showed that atezo maintained ctDNA levels over time, while an approximate 10× increase was observed with BSC. The median time to convert to ctDNA+ in pts who were ctDNA− at Post-chemo ctDNA was longer with atezo vs BSC (not reached vs 4.67 mo; HR, 0.60 [95% CI: 0.31, 1.17]). Similarly, improved DFS was seen with atezo vs BSC in these pts (31.3 vs 13.3 mo; HR, 0.7 [95% CI: 0.37, 1.34]). Regardless of Post-OP ctDNA status, atezo was associated with improved DFS vs BSC in PD-L1+ subgroups (TC ≥1%, 1-49%, ≥50%) but not the PD-L1− subgroup (TC <1%). 62.1% (64/103) of Post-OP ctDNA+ pts were cleared (ctDNA−) at Post-chemo ctDNA, which was linked to improved DFS. Atezo improved DFS vs BSC regardless of ctDNA clearance at Post-chemo ctDNA (Cleared: DFS, 31.3 (atezo) vs 13.3 mo (BSC); HR [95% CI], 0.7 [0.37, 1.34] vs Not cleared: DFS, 4.2 vs 3.9 mo; 0.67 [0.34, 1.32]). Longitudinal assessment of ctDNA+ pts at Post-chemo ctDNA showed that atezo maintained ctDNA levels over time, while an approximate 10× increase was observed with BSC. The median time to convert to ctDNA+ in pts who were ctDNA− at Post-chemo ctDNA was longer with atezo vs BSC (not reached vs 4.67 mo; HR, 0.60 [95% CI: 0.31, 1.17]). Similarly, improved DFS was seen with atezo vs BSC in these pts (31.3 vs 13.3 mo; HR, 0.7 [95% CI: 0.37, 1.34]). ConclusionsAdjuvant atezo is linked to improved DFS vs BSC in early NSCLC in PD-L1+ subgroups regardless of ctDNA status. Chemo ctDNA clearance is associated with longer DFS and atezo may control ctDNA levels and delay disease recurrence better than BSC. Adjuvant atezo is linked to improved DFS vs BSC in early NSCLC in PD-L1+ subgroups regardless of ctDNA status. Chemo ctDNA clearance is associated with longer DFS and atezo may control ctDNA levels and delay disease recurrence better than BSC.

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]

BackgroundIMpower010 met its primary DFS endpoint in PD-L1 TC ≥1% (SP263) stage II-IIIA NSCLC patients (pts) and all stage II-IIIA NSCLC pts (Felip, Lancet 2021). We report exploratory DFS outcomes by additional PD-L1 subgroups and EGFR/ALK status; we also assessed ctDNA status as a potential biomarker in this setting.MethodsEligible pts with resected (R0) stage IB-IIIA NSCLC received up to four 21-day cycles of chemo and were then randomised 1:1 to atezo 1200 mg Q3W (16 cycles) or BSC. Stratification factors included PD-L1 status by SP142. We analysed DFS by PD-L1 expression at different TC levels (SP263; <1%, ≥1%, 1-49%, ≥50%) and by EGFR/ALK status in stage II-IIIA pts. Plasma samples for ctDNA testing were collected after surgery but before adjuvant chemo and analysed using the Natera Signatera RUO assay.ResultsOf 1005 randomised pts, 979 (97%) were evaluable by SP263; of these, 859 had stage II-IIIA NSCLC. SP263 subgroups were balanced between arms. DFS improvement with atezo vs BSC was seen in all PD-L1+ subgroups (Table). When EGFR/ALK+ pts were excluded, numerical improvements in DFS HRs were seen in all PD-L1 subgroups except TC ≥50%, which remained at 0.43. 600 pts were ctDNA evaluable; of these, 534 had stage II-IIIA NSCLC. ctDNA+ prevalence increased with disease stage (IB, 9%; II, 14%; IIIA, 29%). ctDNA+ vs ctDNA− stage II-IIIA pts had worse prognosis; improved DFS with atezo vs BSC was seen in both ctDNA+ and ctDNA− stage II-IIIA pts, with greater benefit in PD-L1 TC ≥1% vs <1% pts.ConclusionsTable: 2OStage II-IIIA ptsSP263 BEPTC <1%TC ≥1%TC 1-49%TC ≥50%AtezoBSCAtezoBSCAtezoBSCAtezoBSCn181202248228133114115114mDFS, mo36.137.0NR35.332.831.4NR35.7HRa 95% CI0.970.72, 1.310.660.49, 0.870.870.60, 1.260.430.27, 0.68SP263 BEP excluding EGFR/ALK+n15415821319710794106103mDFS, mo37.137.0NR36.0NR36.0NR37.3HRa 95% CI0.920.65, 1.300.620.45, 0.860.820.54, 1.250.430.26, 0.71ctDNA BEPctDNA−ctDNA+TC <1%bTC ≥1%bTC <1%bTC ≥1%bAtezoBSCAtezoBSCAtezoBSCAtezoBSCn941061249815223637mDFS, moNRNRNR37.35.18.021.87.2HRa 95% CI0.950.60, 1.500.570.36, 0.900.880.40, 1.910.540.31, 0.93BEP, biomarker-evaluable population; NR, not reached. a Unstratified HR. b By SP263. Open table in a new tab Clinical trial identificationNCT02486718.Editorial acknowledgementMedical writing assistance for this abstract was provided by Kia C. E. Walcott, PhD of Health Interactions and funded by F. Hoffmann-La Roche, Ltd.Legal entity responsible for the studyF. Hoffmann-La Roche, Ltd.FundingF. Hoffmann-La Roche, Ltd.DisclosureC. Zhou: Financial Interests, Personal, Invited Speaker: Roche China, Lily China, Boehringer Ingelheim, Sanofi, C-Stone, Qilu, Hengrui, Innovent Biologics, LUYE Pharma, TopAlliance Bioscience Inc, Amoy Diagnostics. M. Das Thakur, W. Zou: Financial Interests, Personal, Full or part-time Employment: Roche. M.K. Srivastava: Financial Interests, Personal, Full or part-time Employment: Genentech/Roche; Financial Interests, Personal, Stocks/Shares: Genentech/Roche. H. Xu: Financial Interests, Personal, Full or part-time Employment: Roche; Financial Interests, Personal, Stocks/Shares: Roche. M. Ballinger: Financial Interests, Personal, Full or part-time Employment: Genentech/Roche; Financial Interests, Personal, Stocks/Shares: Genentech/Roche. E. Felip: Financial Interests, Personal, Advisory Board: Pfizer, Merck Serono, Merck Sharp & Dohme, F. Hoffman-La Roche, Eli Lilly, Bristol Myers Squibb, AstraZeneca, AbbVie, Amgen, Bayer, Blue Print Medicines, Glaxo Smith Kline, Medical Trends, Peptomyc, Puma, Sanofi Genzyme, Syneos Health, Takeda; Financial Interests, Personal, Invited Speaker: PrIME Oncology, Springer, Touch Medical, Pfizer, Merck Serono, Janssen, Merck Sharpe & Dohme, F. Hoffmann-La Roche, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly; Financial Interests, Personal, Other, Grant: Grant for Medical Oncology Innovation (GOI); Financial Interests, Personal, Other, Grant: Fundacion Merck Salud. H. Wakelee: Financial Interests, Personal, Invited Speaker: AstraZeneca, Janssen, Daiichi Sankyo, Blueprint, Mirati, Helsinn; Financial Interests, Personal, Invited Speaker: Fishawack Facilitate LTD, Medscape, Research to Practice, MJH Holdings, Axis Medical Education, Nexus Oncology; Financial Interests, Personal, Other, Discussion of new data at conferences: Curio Science; Financial Interests, Personal, Writing Engagements: UpToDate; Financial Interests, Institutional, Other, Local PI for Clinical Trials: ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, Bristol Myers Squibb, Clovis Oncology, Novartis, Seagen, Xcovery; Financial Interests, Institutional, Other, Coordinating PI for Clinical Trial: Celgene; Financial Interests, Institutional, Other, Steering Committee Member for clinical trial: Genentech/Roche, Merck; Financial Interests, Personal, Officer, President Elect: International Association for the Study of Lung Cancer (IASLC); Financial Interests, Personal, Leadership Role, Executive Committee: ECOG-ACRIN. N.K. Altorki: Other, Institutional, Research Grant: NCI, DoD, AZ LLC, Janssen. M. Reck: Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Mirati, Merck, MSD, Novartis, Pfizer, Sanofi, Roche; Financial Interests, Personal, Other, Consultancy: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Mirati, Merck, MSD, Novartis, Pfizer, Sanofi, Roche. H. Tanaka: Financial Interests, Personal, Speaker’s Bureau: Chugai Pharmaceutical, AstraZeneca, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, AstraZeneca, MSD, Bristol Myers Squibb, Ono Pharmaceutical. S. McCune: Financial Interests, Institutional, Principal Investigator: Genentech. V. McNally: Financial Interests, Personal, Full or part-time Employment: Genentech/Roche; Financial Interests, Personal, Stocks/Shares: Genentech/Roche. E. Bennett: Financial Interests, Personal, Full or part-time Employment: Roche/Genentech. B. Gitlitz: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Genentech. S. Novello: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Takeda, Roche, AstraZeneca, Boehringer Ingelheim, Beigene, AMG, Eli Lilly, Glaxo Smith Kline; Financial Interests, Personal, Advisory Board: Sanofi, AstraZeneca, Eli Lilly, Glaxo Smith Kline, Novartis, Pfizer, Takeda, Roche. All other authors have declared no conflicts of interest. BackgroundIMpower010 met its primary DFS endpoint in PD-L1 TC ≥1% (SP263) stage II-IIIA NSCLC patients (pts) and all stage II-IIIA NSCLC pts (Felip, Lancet 2021). We report exploratory DFS outcomes by additional PD-L1 subgroups and EGFR/ALK status; we also assessed ctDNA status as a potential biomarker in this setting. IMpower010 met its primary DFS endpoint in PD-L1 TC ≥1% (SP263) stage II-IIIA NSCLC patients (pts) and all stage II-IIIA NSCLC pts (Felip, Lancet 2021). We report exploratory DFS outcomes by additional PD-L1 subgroups and EGFR/ALK status; we also assessed ctDNA status as a potential biomarker in this setting. MethodsEligible pts with resected (R0) stage IB-IIIA NSCLC received up to four 21-day cycles of chemo and were then randomised 1:1 to atezo 1200 mg Q3W (16 cycles) or BSC. Stratification factors included PD-L1 status by SP142. We analysed DFS by PD-L1 expression at different TC levels (SP263; <1%, ≥1%, 1-49%, ≥50%) and by EGFR/ALK status in stage II-IIIA pts. Plasma samples for ctDNA testing were collected after surgery but before adjuvant chemo and analysed using the Natera Signatera RUO assay. Eligible pts with resected (R0) stage IB-IIIA NSCLC received up to four 21-day cycles of chemo and were then randomised 1:1 to atezo 1200 mg Q3W (16 cycles) or BSC. Stratification factors included PD-L1 status by SP142. We analysed DFS by PD-L1 expression at different TC levels (SP263; <1%, ≥1%, 1-49%, ≥50%) and by EGFR/ALK status in stage II-IIIA pts. Plasma samples for ctDNA testing were collected after surgery but before adjuvant chemo and analysed using the Natera Signatera RUO assay. ResultsOf 1005 randomised pts, 979 (97%) were evaluable by SP263; of these, 859 had stage II-IIIA NSCLC. SP263 subgroups were balanced between arms. DFS improvement with atezo vs BSC was seen in all PD-L1+ subgroups (Table). When EGFR/ALK+ pts were excluded, numerical improvements in DFS HRs were seen in all PD-L1 subgroups except TC ≥50%, which remained at 0.43. 600 pts were ctDNA evaluable; of these, 534 had stage II-IIIA NSCLC. ctDNA+ prevalence increased with disease stage (IB, 9%; II, 14%; IIIA, 29%). ctDNA+ vs ctDNA− stage II-IIIA pts had worse prognosis; improved DFS with atezo vs BSC was seen in both ctDNA+ and ctDNA− stage II-IIIA pts, with greater benefit in PD-L1 TC ≥1% vs <1% pts. Of 1005 randomised pts, 979 (97%) were evaluable by SP263; of these, 859 had stage II-IIIA NSCLC. SP263 subgroups were balanced between arms. DFS improvement with atezo vs BSC was seen in all PD-L1+ subgroups (Table). When EGFR/ALK+ pts were excluded, numerical improvements in DFS HRs were seen in all PD-L1 subgroups except TC ≥50%, which remained at 0.43. 600 pts were ctDNA evaluable; of these, 534 had stage II-IIIA NSCLC. ctDNA+ prevalence increased with disease stage (IB, 9%; II, 14%; IIIA, 29%). ctDNA+ vs ctDNA− stage II-IIIA pts had worse prognosis; improved DFS with atezo vs BSC was seen in both ctDNA+ and ctDNA− stage II-IIIA pts, with greater benefit in PD-L1 TC ≥1% vs <1% pts. ConclusionsTable: 2OStage II-IIIA ptsSP263 BEPTC <1%TC ≥1%TC 1-49%TC ≥50%AtezoBSCAtezoBSCAtezoBSCAtezoBSCn181202248228133114115114mDFS, mo36.137.0NR35.332.831.4NR35.7HRa 95% CI0.970.72, 1.310.660.49, 0.870.870.60, 1.260.430.27, 0.68SP263 BEP excluding EGFR/ALK+n15415821319710794106103mDFS, mo37.137.0NR36.0NR36.0NR37.3HRa 95% CI0.920.65, 1.300.620.45, 0.860.820.54, 1.250.430.26, 0.71ctDNA BEPctDNA−ctDNA+TC <1%bTC ≥1%bTC <1%bTC ≥1%bAtezoBSCAtezoBSCAtezoBSCAtezoBSCn941061249815223637mDFS, moNRNRNR37.35.18.021.87.2HRa 95% CI0.950.60, 1.500.570.36, 0.900.880.40, 1.910.540.31, 0.93BEP, biomarker-evaluable population; NR, not reached. a Unstratified HR. b By SP263. Open table in a new tab BEP, biomarker-evaluable population; NR, not reached. a Unstratified HR. b By SP263. Clinical trial identificationNCT02486718. NCT02486718. Editorial acknowledgementMedical writing assistance for this abstract was provided by Kia C. E. Walcott, PhD of Health Interactions and funded by F. Hoffmann-La Roche, Ltd. Medical writing assistance for this abstract was provided by Kia C. E. Walcott, PhD of Health Interactions and funded by F. Hoffmann-La Roche, Ltd. Legal entity responsible for the studyF. Hoffmann-La Roche, Ltd. F. Hoffmann-La Roche, Ltd. FundingF. Hoffmann-La Roche, Ltd. F. Hoffmann-La Roche, Ltd.

Dans l’essai de phase 3 randomisé CM 9LA, l’association en 1L NIVO + IPI avec 2 cycles de CT a amélioré de manière significative la survie globale (OS), la survie sans progression (PFS) et le taux de réponse objective (ORR) par rapport à la CT seule (4 cycles). Le bénéfice clinique a été observé quels que soient le niveau d’expression PD-L1 et l’histologie. Nous rapportons ici les données du suivi minimum à 2 ans. Les patients (pts) adultes présentant un CBNPC de stade IV/récurrent, un ECOG PS ≤ 1, et aucune altération sensibilisante connue de l’EGFR/ALK ont été stratifiés en fonction de PD-L1 (< 1 % versus ≥ 1 %), du sexe et de l’histologie et ont été randomisés 1:1 entre NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + CT (2 cycles; n = 361) ou CT seule (4 cycles; n = 358). Les pts atteints de CBNPC non épidermoïde dans le bras CT seule pouvaient recevoir une maintenance par pemetrexed. Le critère d’évaluation principal était l’OS. Les critères d’évaluation secondaires incluaient la PFS et l’ORR (évaluation BICR), et l’efficacité selon les sous-groupes PD-L1. La tolérance était un critère exploratoire. Après un suivi minimum de 24,4 mois pour l’OS (DBL: 18 février 2021), le bénéfice en survie reste plus favorable chez les pts traités par NIVO + IPI + CT versus la CT, avec une médiane d’OS de 15,8 mois versus 11,0 mois respectivement (HR, 0,72 [IC 95 %, 0,61–0,86]) ; les taux d’OS à 2 ans étaient de 38 % vs 26 %. La médiane de PFS entre était de 6,7 mois pour NIVO + IPI + CT versus 5,3 mois pour la CT (HR, 0,67 [IC 95 %, 0,56–0,79]) ; respectivement 8 % et 37 % des pts dont la maladie a progressé ont reçu une immunothérapie ultérieure. L’ORR était de 38 % avec NIVO + IPI + CT versus 25 % avec la CT. Un bénéfice clinique similaire a été observé avec NIVO + IPI + CT versus la CT chez tous les pts randomisés et dans la majorité des sous-groupes, y compris selon le niveau d’expression de PD-L1 (Tableau 1) ou l’histologie. Des effets indésirables liés au traitement de tout grade et de grade 3–4 ont été rapportés chez 92 % et 48 % des patients du groupe NIVO + IPI + CT contre 88 % et 38 % dans le groupe CT, respectivement (Tableau 1). Avec un suivi minimum de 2 ans, l’association NIVO + IPI + CT en 1L a démontré une survie durable et un bénéfice par rapport à la CT chez les pts atteints de CBNPC avancé; aucun nouveau signal de sécurité n’a été identifié. Abstract présenté à l’ASCO 2021

BackgroundPembrolizumab is a standard-of-care first-line treatment for advanced/metastatic NSCLC, either as monotherapy (for patients with PD-L1 tumor proportion score [TPS] ≥1%) or combined with platinum chemotherapy. An improved OS benefit has been demonstrated for both pembrolizumab monotherapy and pembrolizumab plus chemotherapy in patients with higher tumor PD-L1 expression, and for pembrolizumab monotherapy in patients with higher tissue tumor mutation burden (tTMB). Mutations in KRAS occur relatively frequently in patients with nonsquamous NSCLC but infrequently in those with squamous NSCLC; most mutations are in codon 12. Notably, the pembrolizumab OS treatment effect was not diminished in patients with KRAS G12C mutations in phase 3 studies evaluating pembrolizumab monotherapy and pembrolizumab in combination with chemotherapy.1 2 Herein we describe prevalence of KRAS mutations among patients with advanced nonsquamous NSCLC from two phase 3 clinical studies evaluating first-line pembrolizumab (KEYNOTE-042 and KEYNOTE-189) and the relationship of such mutations with select patient characteristics.MethodsKEYNOTE-042 (NCT02220894) evaluated pembrolizumab versus platinum-based chemotherapy for advanced PD-L1–positive NSCLC (any histology) without EGFR/ALK alterations. KEYNOTE-189 (NCT02578680) evaluated pembrolizumab plus platinum-based chemotherapy versus platinum-based chemotherapy alone for metastatic nonsquamous NSCLC without EGFR/ALK alterations irrespective of tumor PD-L1 expression. Whole-exome sequencing of tumor tissue and matched normal DNA (blood) was performed for patients with nonsquamous histology. PD-L1 TPS was evaluated using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA, USA). Prevalence of KRAS mutations and their relationships with TMB, PD-L1 TPS, and smoking status were analyzed descriptively.Results590 patients with nonsquamous NSCLC were included in these analyses (KEYNOTE-042, n=301; KEYNOTE-189, n=289). Overall, 42.9% of patients had tTMB ≥175 mut/exome, 81.4% were current/former smokers and, 40.3%, 42.7%, and 16.9% had PD-L1 TPS ≥50%, 1–49% and <1% respectively. KRAS G12C, G12D, and G12V mutations occurred in 11.0%, 4.1%, and 5.4% of patients, respectively. Prevalence of KRAS mutations by patient characteristics is summarized in the table (table 1). KRAS G12C mutations occurred almost exclusively in current/former smokers. KRAS G12C was enriched in tumors with tTMB ≥175 mut/exome and tumors with PD-L1 TPS ≥50%. Prevalence was highest in tumors with both tTMB ≥175 mut/exome and PD-L1 TPS ≥50%.Abstract 364 Table 1KRAS Mutation PrevalenceConclusionsKRAS G12C mutations occurred with moderate frequency in patients with nonsquamous NSCLC, with most occurring in current/former smokers. KRAS G12C mutations occurred at higher frequency in patient subgroups defined by higher tTMB and PD-L1 TPS.AcknowledgementsMedical writing assistance was provided by Christabel Wilson, MSc, of ICON plc (North Wales, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationKEYNOTE-042, ClinicalTrials.gov, NCT02220894; KEYNOTE-189, ClinicalTrials.gov, NCT02578680ReferencesGadgeel S, Rodriguez-Abreu D, Felip E, et al. KRAS mutational status and efficacy in KEYNOTE-189: pembrolizumab (pembro) plus chemotherapy (chemo) vs placebo plus chemo as first-line therapy for metastatic non-squamous NSCLC. Ann Oncol 2019;30(suppl 11):xi64-xi5.Herbst RS, Lopes G, Kowalski DM, et al. Association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in KEYNOTE-042. Ann Oncol 2019;30(suppl 11):xi63-xi4.Ethics ApprovalFor both trials, the protocol and all amendments were approved by the appropriate ethics committee at each center, the study was conducted in accordance with the standards of Good Clinical Practice. Patients provided written informed consent before enrollment.

In CheckMate 227 Part 1 (NCT02477826), 1L NIVO+IPI significantly improved overall survival (OS) vs chemo in patients with aNSCLC and tumor PD-L1 ≥1% (primary analysis) or <1% (descriptive analysis). We report data with 3-year minimum follow-up.