Nivolumab Monotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer.

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

Nivolumab (Anti-PD-1; BMS-936558, ONO-4538) Maintenance as Monotherapy or in Combination With Bevacizumab (BEV) for Non-Small Cell Lung Cancer (NSCLC) Previously Treated With Chemotherapy: Metastatic Non-Small Cell Lung Cancer

MTE09.02 Biomarkers for Targeted Therapies and Immune Checkpoint Inhibitors in Advanced NSCLC

Simple SummaryThe liver is a common metastatic site of non-small cell lung cancer (NSCLC) and is associated with a poor prognosis. Immune checkpoint inhibitors (ICIs), represented by programmed death-1 (PD-1)/ programmed death ligand-1 (PD-L1) inhibitors, have significantly improved efficacy in patients with advanced NSCLC, but the efficacy in patients with NSCLC and liver metastases remains controversial. We aimed to evaluate the efficacy of PD-1/PD-L1 inhibitors in patients with NSCLC and liver metastases in the real-world. In this study, we illustrated that PD-1/PD-L1 inhibitors are effective in NSCLC patients with liver metastases but were inferiorly effective in patients without liver metastases. In addition, PD-L1 expression and CD8+ T cell infiltration may be potential biomarkers for PD-1/PD-L1 inhibitor therapy in NSCLC patients with liver metastases.Background: A controversy exists regarding the efficacy of programmed death-1 (PD-1)/ programmed death ligand-1 (PD-L1) inhibitors for patients with non-small cell lung cancer (NSCLC) and liver metastases. Our study retrospectively evaluated the efficacy of PD-1/PD-L1 inhibitors in NSCLC patients with liver metastases. Methods: This retrospective study included 1627 lung cancer patients who received immunotherapy. Among 648 patients who had advanced NSCLC and received PD-1/PD-L1 inhibitors, 61 had liver metastases and 587 did not have. We analyzed patient characteristics, progression-free survival (PFS) and overall survival (OS). An exploratory analysis of biomarkers including CD4, CD8 and CD68 for efficacy in patients with liver metastases was also performed. Results: In liver metastasis patients receiving PD-1/PD-L1 inhibitors, the objective response rate (ORR) was 29.5%, the disease control rate (DCR) was 72.1%, PFS was 6.4 months and OS was 15.2 months, which were all worse than those of patients without liver metastases (ORR: 35.8%; DCR: 81.8%; PFS: 7.9 months, p = 0.001; OS: 20.6 months, p = 0.008). When compared to non-liver lesions, the ORR (26.2 vs. 39.3%) and DCR (75.4 vs. 88.5%) of liver lesions were lower. During the analysis of PD-L1 expression, 27 PD-L1-positive patients had a longer PFS than 21 patients in the negative group (p = 0.012). Being PD-L1 positive was the independent prognostic indicators for PFS (p = 0.006). Additionally, the PD-L1 and CD8 dual-positive group responded favorably to PD-1/PD-L1 inhibitors. Conclusions: PD-1/PD-L1 inhibitors are effective in liver metastasis–NSCLC patients. However, the efficacy is inferior when compared to those of patients without liver metastases. In NSCLC patients with liver metastases, PD-L1 expression and CD8+ T cell infiltration can predict the response of PD-1/PD-L1-directed immunotherapy.

Chemotherapy and Survival in Non-Small Cell Lung Cancer: The Old Vexata Questio

Immune checkpoint inhibitors have dramatically reshaped the landscape of non–small-cell lung cancer (NSCLC). In particular, monoclonal antibodies targeting the programmed death-1 (PD-1)/PD ligand 1 (PD-L1) pathway have emerged as powerful new therapeutic tools. In phase I studies, these agents demonstrated promising antitumor activity and durable clinical responses in a subset of patients with NSCLC. On the basis of these early efficacy signals, a series of randomized phase II and III studies were launched to evaluate the activity of PD-1/PD-L1 inhibitors in the second-line setting and beyond in NSCLC. In the CheckMate 017 and 057 studies, for example, the PD-1 inhibitor nivolumab produced significant improvements in overall survival (OS) compared with docetaxel in patients with previously treated, squamous and nonsquamous NSCLC, respectively. Similarly, the PD-1 inhibitor pembrolizumab improved OS compared with docetaxel among patients with previously treated NSCLC whose tumors expressed PD-L1. Together, these studies helped establish PD-1 pathway blockade as a new standard of care for patients with advanced NSCLC who experience progression on or after platinum-based chemotherapy. Recently, the activity and improved tolerability of PD-1/PD-L1 inhibitors in NSCLC have sparked a growing interest in moving these agents to the front-line setting. Currently, the standard of care for management of newly diagnosed patients without targetable oncogenic driver mutations (eg, EGFR, ALK) is platinum-based doublet chemotherapy, which is generally associated with a median progressionfree survival (PFS) of 4 to 6months andmedianOS of 8 to 10months. More recently, maintenance pemetrexed and the addition of monoclonal antibodies directed against vascular endothelial growth factor and epidermal growth factor receptor have resulted in additional, modest improvements in OS, yet long-term outcomes remain poor, underscoring the need for alternative therapeutic approaches. In the two articles accompanying this editorial, we are presented with data from two separate cohorts of the multiarm, phase IB CheckMate 012 study. Each explores a different approach to PD-1 inhibition in patients with treatment-naive NSCLC. First, Gettinger et al report findings from 52 patients with advanced NSCLC treated with first-line nivolumab monotherapy. Importantly, PD-L1 testing was not used to prospectively select patients for study entry, but mandatory pretreatment biopsies were required to evaluate PD-L1 expression retrospectively. Confirmed responses were observed in 23% of patients, including complete responses in four patients (8%). Median PFS on nivolumab was 3.6 months, but the median duration of response was not reached (range, 4.2 to 25.81months). Thus, as with other studies of PD-1/ PD-L1 inhibitors, there was a suggestion of durable clinical responses. Indeed, the median OS in this patient population was noteworthy at 19.4 months. Although the results by Gettinger et al are intriguing, it is noteworthy that the response rate to first-line nivolumab was not too dissimilar from those observed in CheckMate 017 and 057. A key issue, however, is whether this degree of activity will be sufficient to beat platinum-based chemotherapy in randomized trials. In second-line studies (CheckMate 017 and 057), the control arms received single-agent docetaxel, which set a relatively low bar to surpass (historical overall response rate, approximately 7%). By contrast, in the first-line setting, PD-1/PD-L1 inhibitors will need to overtake platinum-based doublet chemotherapy, which has been associated withmuch higher ORRs (25% to 35%). For PD-1/ PD-L1 inhibitors to succeed in this setting, a biomarker enrichment strategy may be necessary. To date, such efforts have centered on assessments of PD-L1 expression. For instance, in the KEYNOTE 001 study, pembrolizumab was associated with an ORR of 24.8% among treatment-naive patients, but the response rate increased to 50% among treatment-naive patients who were PD-L1 positive (proportion score $ 50). In part on the basis of these observations, two randomized phase III studies, CheckMate 026 and KEYNOTE 024, have been launched in PD-L1–positive patients comparing platinum-based chemotherapy versus nivolumab or pembrolizumab, respectively. Both studies have completed accrual, but results are not yet available. In the second article accompanying this editorial, Rizvi et al report a separate first-line cohort from CheckMate 012 that consisted of 56 treatment-naive patients with NSCLC who were treated with nivolumab in combination with three different platinum-based chemotherapy doublets. The authors used a dose de-escalation design, assigning participants to one of four cohorts ranging in size from 12 to 15 patients. Of note, in contrast to the currently approved nivolumab dosing regimen (3 mg/kg every 2 weeks), nivolumab was administered once every 3 weeks in this study (5 to 10mg/kg based on cohort). After completing four cycles of therapy, patients received maintenance nivolumab once every 3 weeks. Overall, no dose-limiting toxicities were observed across study arms, but 14% of patients required discontinuation as

Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non-small-cell lung cancer (NSCLC) receiving nivolumab in this trial. Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle. Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis. Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.

BackgroundPembrolizumab plus platinum‐based chemotherapy has demonstrated improved clinical outcomes over chemotherapy alone in patients with previously untreated advanced/metastatic non–small cell lung cancer (NSCLC), regardless of tumor programmed death ligand 1 (PD‐L1) expression. This study pooled data from 3 randomized controlled trials to evaluate outcomes with pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced/metastatic NSCLC negative for PD‐L1 (ie, a tumor proportion score < 1%).MethodsIndividual patient data were pooled from KEYNOTE‐021 cohort G (nonsquamous; NCT02039674), KEYNOTE‐189 (nonsquamous; NCT02578680 and NCT03950674), and KEYNOTE‐407 (squamous; NCT02775435). Treatment comprised pembrolizumab plus chemotherapy (pemetrexed and platinum for nonsquamous histology and carboplatin and paclitaxel/nab‐paclitaxel for squamous histology) or chemotherapy alone. Responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 by blinded, independent, central review. No α was assigned to this descriptive, exploratory analysis.ResultsFour hundred forty‐four of the 1328 patients (33.4%) who were enrolled across the 3 trials had PD‐L1‒negative tumors (256 on pembrolizumab plus chemotherapy [nonsquamous, n = 155; squamous, n = 94; other, n = 7] and 188 on chemotherapy alone [nonsquamous, n = 83; squamous, n = 99; other, n = 6]). The median time from randomization to the data cutoff was 28.0 months (range, 14.7‐55.4 months). Pembrolizumab plus chemotherapy improved overall survival (OS; hazard ratio [HR], 0.63; 95% CI, 0.50‐0.79) and progression‐free survival (HR, 0.68; 95% CI, 0.56‐0.83) over chemotherapy. Sixteen patients in the pembrolizumab plus chemotherapy arm completed 2 years of treatment; the objective response rate was 87.5% (95% CI, 61.7%‐98.4%), and the 3‐year OS rate was 100%. Adverse events (AEs) were experienced by 99.2% of the patients who received pembrolizumab plus chemotherapy and by 98.9% of the patients who received chemotherapy alone, with grade 3 or higher AEs occurring in 71.4% and 72.0%, respectively; immune‐mediated AEs and infusion reactions were experienced by 29.0% and 12.4%, respectively.ConclusionsPembrolizumab plus chemotherapy demonstrated response and survival improvements with manageable safety in comparison with chemotherapy alone in PD‐L1‒negative advanced/metastatic NSCLC, and it is a standard‐of‐care first‐line therapy for patients with advanced NSCLC, regardless of PD‐L1 expression.Lay SummarySome tumors produce a protein called programmed death ligand 1 (PD‐L1), which interacts with the body's immune system and prevents an immune response against cancer.Antibody therapies such as pembrolizumab block interactions between tumor PD‐L1 and the immune system and enable an immune response. Used alone, pembrolizumab provides benefit for patients with non–small cell lung cancer (NSCLC) tumors that produce PD‐L1. However, when it is combined with chemotherapy, which can stimulate anticancer immune responses, pembrolizumab provides a benefit, regardless of tumor PD‐L1 production.This article shows that among patients with NSCLC whose tumors produce no PD‐L1, outcomes are better with pembrolizumab plus chemotherapy in comparison with chemotherapy alone.

Programmed death-ligand 1 testing in patients with non-small cell lung cancer: Ready for prime time?

Introduction: Prior to the introduction of immunotherapies, treatment options were limited for patients (pts) with NSCLC who progressed after first-line platinum doublet chemotherapy. The majority of pts with advanced disease died within 1 y of diagnosis, and 5-y survival for metastatic NSCLC was ~1%. Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, showed encouraging activity in pts with heavily pretreated advanced NSCLC in a phase 1 dose-escalation cohort expansion trial (CA209-003; NCT00730639). Based on improved overall survival (OS) versus docetaxel in 2 phase 3 studies in previously treated advanced NSCLC (CheckMate 017 and 057), nivolumab was approved in this population. Reports of long-term efficacy and safety with immune checkpoint inhibitors are limited. Here we report updated results from CA209-003 based on ~5 y of follow-up, representing the longest survival follow-up for an immune checkpoint inhibitor in advanced NSCLC to date. Methods: Pts with heavily pretreated (1-5 prior systemic regimens) advanced NSCLC received nivolumab (1, 3, or 10 mg/kg) every 2 wk in 8-wk cycles for up to 96 wk. The primary objective was safety and tolerability; secondary objectives included objective response rate and duration of response. OS from the time of first dose was an exploratory objective. The minimum follow-up for the current analysis was 58.25 mo. Results: At database lock, the Kaplan-Meier-estimated 5-y OS rate in all pts (N = 129) was 16% (95% confidence interval [CI]: 10, 23). OS rates at 5 y were similar in pts with squamous (SQ; n = 54; 16% [95% CI: 8, 28]) and non-SQ (n = 74; 15% [95% CI: 8, 25]) NSCLC (excludes 1 pt with unknown histology). Of the 16 pts who survived ≥5 y (median age: 61.5 y [range: 44, 80]), 9 pts were male and 12 were current smokers at baseline (2 former smokers; 2 unknown). In 10 evaluable pts, PD-1 ligand 1 (PD-L1) expression was ≥1% in 7 pts (≥50% in 5) and &amp;lt;1% in 3 pts. Nine of the 16 pts completed the maximum number of nivolumab cycles per protocol; the remainder discontinued due to adverse events (n = 4), disease progression (n = 2), and initiation of a new treatment regimen (n = 1). Twelve of the 16 pts achieved a partial response, and 2 pts each had stable disease (SD) and progressive disease (PD) as best overall response (BOR) to nivolumab. At 5 y, per investigator, 12 pts had received no further therapy after stopping nivolumab treatment and were without evidence of PD. Further details of the disease and treatment course in select pts will be presented. Conclusions: Nivolumab resulted in durable OS in a notable proportion of pts with pretreated advanced NSCLC, as demonstrated by a 5-y OS rate of 16%. Long-term survivors had diverse baseline and on-treatment characteristics including histology, PD-L1 expression level (including pts with &amp;lt;1% PD-L1), and BOR to nivolumab (including pts with SD/PD). Citation Format: Julie Brahmer, Leora Horn, David Jackman, David Spigel, Scott Antonia, Matthew Hellmann, John Powderly, Rebecca Heist, Lecia Sequist, David C. Smith, Philip Leming, William J. Geese, Dennis Yoon, Ang Li, Scott Gettinger. Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC): Clinical characteristics of long-term survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT077. doi:10.1158/1538-7445.AM2017-CT077

FP03.05 TLR9 Agonist CMP-001 Plus Atezolizumab +/- Radiation Therapy in Patients With PD-1 Blockade Resistant Advanced NSCLC

AK112, a novel PD-1/VEGF bispecific antibody, in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC): an open-label, multicenter, phase II trial

Although tumor mutation burden (TMB) has been explored as a potential biomarker of immunotherapy efficacy in solid tumors, there still is a lack of consensus about the optimal TMB threshold that best discriminates improved outcomes of immune checkpoint inhibitor therapy among patients with non-small cell lung cancer (NSCLC). To determine the association between increasing TMB levels and immunotherapy efficacy across clinically relevant programmed death ligand-1 (PD-L1) levels in patients with NSCLC. This multicenter cohort study included patients with advanced NSCLC treated with immunotherapy who received programmed cell death-1 (PD-1) or PD-L1 inhibition in the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center (MSKCC), and in the Stand Up To Cancer (SU2C)/Mark Foundation data sets. Clinicopathological and genomic data were collected from patients between September 2013 and September 2020. Data analysis was performed from November 2021 to February 2022. Treatment with PD-1/PD-L1 inhibition without chemotherapy. Association of TMB levels with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). In the entire cohort of 1552 patients with advanced NSCLC who received PD-1/PD-L1 blockade, the median (range) age was 66 (22-92) years, 830 (53.5%) were women, and 1347 (86.8%) had cancer with nonsquamous histologic profile. A regression tree modeling ORR as a function of TMB identified 2 TMB groupings in the discovery cohort (MSKCC), defined as low TMB (≤19.0 mutations per megabase) and high TMB (>19.0 mutations per megabase), which were associated with increasing improvements in ORR, PFS, and OS in the discovery cohort and in 2 independent cohorts (DFCI and SU2C/Mark Foundation). These TMB levels also were associated with significant improvements in outcomes of immunotherapy in each PD-L1 tumor proportion score subgroup of less than 1%, 1% to 49%, and 50% or higher. The ORR to PD-1/PD-L1 inhibition was as high as 57% in patients with high TMB and PD-L1 expression 50% or higher and as low as 8.7% in patients with low TMB and PD-L1 expression less than 1%. Multiplexed immunofluorescence and transcriptomic profiling revealed that high TMB levels were associated with increased CD8-positive, PD-L1-positive T-cell infiltration, increased PD-L1 expression on tumor and immune cells, and upregulation of innate and adaptive immune response signatures. These findings suggest that increasing TMB levels are associated with immune cell infiltration and an inflammatory T-cell-mediated response, resulting in increased sensitivity to PD-1/PD-L1 blockade in NSCLC across PD-L1 expression subgroups.

Background:Nonsmall cell lung cancer (NSCLC)-patients treated with standard chemotherapy experienced progression rapidly. A novel therapy based on programed death 1 (PD-1)/programed death ligand 1 (PD-L1) inhibitors showed an increasing potential in several malignancies including advanced NSCLC.Objectives:This article is a meta-analysis aiming to systematically evaluate the efficacy and safety profiles of PD-1/PD-L1 agents in patients with NSCLC.Data sources:Data were collected from eligible studies searched from PubMed, ScienceDirect, and Web of Science.Synthesis methods:Pooled hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) was estimated to assess the efficacy of PD-1/PD-L1 inhibitors versus docetaxel, pooled odds ratio (OR) was calculated for objective response rate (ORR). The overall frequency was estimated for 1-year OS, 1-year progression-free survival, and ORR. A subgroup analysis among NSCLC patients tested with different epidermal growth factor receptor (EGFR) status was also performed to figure out the relationship between EGFR status and efficacy of PD-1/PD-L1 therapies. OR for occurrence of any grade and grade 3 to 5 treatment-related adverse effect was calculated for evaluating the safety of PD-1/PD-L1 therapies.Results:Nine studies were included in this analysis. The pooled HRs for OS and PFS were 0.68 (95% confidence interval [CI] 0.61–0.75) and 0.83 (95% CI 0.75–0.91), respectively, the pooled OR for ORR was 1.83 (95% CI 1.41–2.36), indicating a significant improvement in OS, PFS, and ORR. In the results of subgroup analysis, the HR for OS in NSCLC patients was 1.05 (95% CI 0.69–1.59) in patients with mutant EGFR and 0.66 (95% CI 0.57–0.77) in patients with wild-type EGFR status. OR for occurrence was 0.36 (95% CI 0.28–0.46) in any grade treatment-related adverse effect and 0.18 (95% CI 0.14–0.22) in grade 3 to 5 treatment-related adverse effect, suggesting a superior safety profile of PD-1/PD-L1 inhibitors.Conclusion:The PD-1/PD-L1 therapy significantly prolonged the OS and improved the ORR, simultaneously lowering the treatment-related adverse effect events versus docetaxel.

Programmed cell death ligand 1 (PD-L1) is more readily expressed in ROS proto-oncogene 1 (ROS1) rearranged non-small cell lung cancer (NSCLC) compared to NSCLC cases lacking driver gene mutations. Prior research has established a link between PD-L1 expression and reduced effectiveness of EGFR or ALK inhibitors in EGFR or ALK-positive NSCLC. Nonetheless, the relationship between initial PD-L1 levels and the clinical impact of first-line crizotinib therapy in ROS1-rearranged NSCLC is still uncertain. From January 2016 to December 2021, a total of 246 patients with ROS1 positive tumors were collected. Out of these, 82 patients with advanced ROS1-rearranged NSCLC, who were treated with crizotinib as their initial therapy, were selected for the study. The study aimed primarily to evaluate the objective response rate (ORR) and progression-free survival (PFS), and secondarily to assess disease control rate (DCR) and overall survival (OS). Of the 82 advanced ROS1-rearranged NSCLC patients, 38 exhibited PD-L1 positivity, subdivided into 11 with high and 27 with low expression levels, while the remaining 44 showed no PD-L1 expression. The ORR for all included patients was 80.5%. No statistically significant variance in ORR was observed among ROS1-rearranged NSCLC patients across differing PD-L1 expression statuses. However, there was a statistically significant difference in DCR between PD-L1 negative group (100%) and high expression group (90.9%) (p=0.04). The median PFS spanned 26.4 months for the PD-L1 negative group, 16.6 for the low expression group, and 13.7 for the high expression group (p=0.001). Additionally, a notable statistical disparity was also observed in median PFS between the PD-L1 negative and positive groups (p=0.02). For the entire study population, the median OS was 53.0 months (95% CI 43.8 - 62.2). In the PD-L1-negative group, the median OS reached 57.2 months, compared to 53.0 months in the PD-L1-positive group, a difference lacking statistical significance (p=0.43). Our results suggest that for ROS1-positive NSCLC patients receiving crizotinib as first-line therapy, PD-L1 expression may serve as a negative prognostic marker for PFS rather than OS.