NEPTUNE: Phase 3 Study of First-Line Durvalumab Plus Tremelimumab in Patients With Metastatic NSCLC

IntroductionNEPTUNE, a phase 3, open-label study, evaluated first-line durvalumab plus tremelimumab versus chemotherapy in metastatic NSCLC (mNSCLC).MethodsEligible patients with EGFR and ALK wild-type mNSCLC were randomized (1:1) to first-line durvalumab (20 mg/kg every 4 weeks until progression) plus tremelimumab (1 mg/kg every 4 weeks for up to four doses) or standard chemotherapy. Randomization was stratified by tumor programmed death-ligand 1 expression (≥25% versus <25%), tumor histologic type, and smoking history. The amended primary end point was overall survival (OS) in patients with blood tumor mutational burden (bTMB) greater than or equal to 20 mutations per megabase (mut/Mb). Secondary end points included progression-free survival (PFS) in patients with bTMB greater than or equal to 20 mut/Mb and safety and tolerability in all treated patients.ResultsAs of June 24, 2019, 823 patients were randomized (intention-to-treat [ITT]); 512 (62%) were bTMB-evaluable, with 129 of 512 (25%) having bTMB greater than or equal to 20 mut/Mb (durvalumab plus tremelimumab [n = 69]; chemotherapy [n = 60]). Baseline characteristics were balanced in the intention-to-treat. Among patients with bTMB greater than or equal to 20 mut/Mb, OS improvement with durvalumab plus tremelimumab versus chemotherapy did not reach statistical significance (hazard ratio 0.71 [95% confidence interval: 0.49–1.05; p = 0.081]; median OS, 11.7 versus 9.1 months); the hazard ratio for PFS was 0.77 (95% confidence interval, 0.51–1.15; median PFS, 4.2 versus 5.1 months). In the overall safety population, incidence of grade 3 or 4 treatment-related adverse events was 20.7% (durvalumab plus tremelimumab) and 33.6% (chemotherapy).ConclusionsNEPTUNE did not meet its primary end point of improved OS with durvalumab plus tremelimumab versus chemotherapy in patients with mNSCLC and bTMB greater than or equal to 20 mut/Mb. Despite the amended study design, with a resultant small primary analysis population, therapeutic activity was aligned with expectations based on mechanistic biology and previous studies.     

Efficacy and Safety of First-Line Immunotherapy Combinations for Advanced NSCLC: A Systematic Review and Network Meta-Analysis

IntroductionA series of randomized controlled trials have investigated different first-line immunotherapy combinations, but the optimal combination strategy is yet to be established.MethodsWe performed a systematic review and Bayesian network meta-analysis by retrieving relevant literature from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences. We included published and gray sources of randomized clinical trials comparing immunotherapy combinations with other treatments as first-line treatments for patients with advanced NSCLC. This study was registered in the Prospective Register of Systematic Reviews (CRD42020210501) to ensure transparency.ResultsWe analyzed a total of 16 studies involving 8278 patients and including 10 immunotherapy combinations. For patients without programmed death-ligand 1 (PD-L1) selection, pembrolizumab plus chemotherapy was found to be comparable with sintilimab plus chemotherapy in providing the best overall survival (OS) benefit (hazard ratio = 0.96, 95% confidence interval [CI]: 0.72–1.29). Furthermore, atezolizumab plus bevacizumab plus chemotherapy seemed to provide the best progression-free survival (hazard ratio = 0.45, 95% CI: 0.36–0.55) and the best objective response rate (OR = 0.23, 95% CI: 0.12–0.42). Subgroup analysis by PD-L1 suggested that nivolumab plus ipilimumab plus chemotherapy was associated with the best OS in patients with PD-L1 less than 1% and that pembrolizumab plus chemotherapy was associated with the best OS in patients with PD-L1 greater than or equal to 1%. Pembrolizumab and sintilimab were associated with relatively fewer grade greater than or equal to 3 adverse events when compared with other immunotherapies combined with chemotherapy.ConclusionsOur results suggest that antiprogrammed death-1 combinations are associated with potentially higher survival outcomes than anti–PD-L1 combinations with comparable safety profiles. Moreover, pem-chemo and nivo-ipi-chemo seem to be superior first-line immunotherapy combinations for patients with advanced NSCLC with positive and negative PD-L1 expression, respectively. Although atezo-beva-chemo treatment provided the best progression-free survival and objective response rate, the addition of chemotherapy to immunotherapy would increase the toxicity, especially when antiangiogenesis drugs are simultaneously added.     

Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1

IntroductionIn 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.MethodsTreatment-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).ResultsOverall, 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.ConclusionsWith 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.     

Patient-Reported Outcomes with Durvalumab With or Without Tremelimumab Versus Standard Chemotherapy as First-Line Treatment of Metastatic Non–Small-Cell Lung Cancer (MYSTIC)

BackgroundThe phase 3 MYSTIC study of durvalumab ± tremelimumab versus chemotherapy in metastatic non–small-cell lung cancer (NSCLC) patients with tumor cell (TC) programmed cell death ligand 1 (PD-L1) expression ≥ 25% did not meet its primary endpoints. We report patient-reported outcomes (PROs).Patients and MethodsTreatment-naïve patients were randomized (1:1:1) to durvalumab, durvalumab + tremelimumab, or chemotherapy. PROs were assessed in patients with PD-L1 TC ≥ 25% using EORTC Quality of Life Questionnaire (QLQ)-C30/LC13. Changes from baseline (12 months) for prespecified PRO endpoints of interest were analyzed by mixed model for repeated measures (MMRM) and time to deterioration (TTD) by stratified log-rank tests.ResultsThere were no between-arm differences in baseline PROs (N = 488). Between-arm differences in MMRM-adjusted mean changes from baseline favored at least one of the durvalumab-containing arms versus chemotherapy (nominal P < .01) for C30 fatigue: durvalumab (−9.5; 99% confidence interval [CI], −17.0 to −2.0), durvalumab + tremelimumab (−11.7; 99% CI, −19.4 to −4.1); and for C30 appetite loss: durvalumab (−11.9; 99% CI, −21.1 to −2.7). TTD was longer with at least one of the durvalumab-containing arms versus chemotherapy (nominal P < .01) for global health status/quality of life: durvalumab (hazard ratio [HR] = 0.7; 95% CI, 0.5-1.0), durvalumab + tremelimumab (HR = 0.7; 95% CI, 0.5-1.0); and for physical functioning: durvalumab (HR = 0.6; 95% CI, 0.4-0.8), durvalumab + tremelimumab (HR = 0.6; 95% CI, 0.5-0.9) (both C30); as well as for the key symptoms of dyspnea: durvalumab (HR = 0.6; 95% CI, 0.5-0.9), durvalumab + tremelimumab (HR = 0.7; 95% CI, 0.5-1.0) (both LC13); fatigue: durvalumab + tremelimumab (HR = 0.6; 95% CI, 0.4-0.8); and appetite loss: durvalumab (HR = 0.5; 95% CI, 0.4-0.7), durvalumab + tremelimumab (HR = 0.7; 95% CI, 0.5-0.9) (both C30).ConclusionDurvalumab ± tremelimumab versus chemotherapy reduced symptom burden and improved TTD of PROs, suggesting it had no detrimental effects on quality of life in metastatic NSCLC patients.     

Brief Report: Durvalumab After Chemoradiotherapy in Unresectable Stage III EGFR-Mutant NSCLC: A Post Hoc Subgroup Analysis From PACIFIC

IntroductionConsolidation durvalumab (the “PACIFIC regimen”) is standard of care for patients with unresectable stage III NSCLC who have not progressed after chemoradiotherapy, on the basis of data from the phase 3 placebo-controlled PACIFIC study (NCT02125461). Nevertheless, the benefit of immunotherapy in patients with stage III EGFR-mutant (EGFRm) NSCLC is not well characterized. Here, we report a post hoc exploratory efficacy and safety analysis from a subgroup of patients with EGFRm NSCLC from the PACIFIC.MethodsPatients with stage III unresectable NSCLC and no progression after more than or equal to two cycles of platinum-based concurrent chemoradiotherapy were randomized (2:1) to receive durvalumab (10 mg/kg intravenously every 2 weeks [wk], for up to 1 y) or placebo; stratified by age, sex, and smoking history. Enrollment was not restricted by oncogenic driver gene mutation status or programmed death-ligand 1 expression. Patients with NSCLC with an EGFR mutation, determined by local testing only, were included in this subgroup analysis. The primary end points were progression-free survival (PFS; assessed by blinded independent central review) and overall survival (OS). Secondary end points included objective response rate and safety. Statistical analyses for the subgroup of patients with EGFRm NSCLC were post hoc and considered exploratory.ResultsOf 713 patients randomized, 35 had locally confirmed EGFRm NSCLC (durvalumab, n = 24; placebo, n = 11). At data cutoff (January 11, 2021), median duration of follow-up for survival was 42.7 months (range: 3.7–74.3 mo) for all randomized patients in the subgroup. Median PFS was 11.2 months (95% confidence interval [CI]: 7.3–20.7) with durvalumab versus 10.9 months (95% CI: 1.9–not evaluable [NE]) with placebo; hazard ratio = 0.91 (95% CI: 0.39–2.13). Median OS was 46.8 months (95% CI: 29.9–NE) with durvalumab versus 43.0 months (95% CI: 14.9–NE) with placebo; hazard ratio = 1.02 (95% CI: 0.39–2.63). The safety profile of durvalumab was generally consistent with the overall population and known profile for durvalumab.ConclusionsPFS and OS outcomes with durvalumab were similar to placebo for patients with EGFRm tumors, with wide CIs. These data should be interpreted with caution owing to small patient numbers and lack of a prospective study that evaluates clinical outcomes by tumor biomarker status. Further research to determine the optimal treatment for unresectable stage III EGFRm NSCLC is warranted.     

A Randomized,Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407

IntroductionIn the randomized KEYNOTE-407 study (ClinicalTrials.gov, NCT02775435), pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel (chemotherapy) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus chemotherapy in patients with previously untreated metastatic squamous NSCLC. We report updated efficacy outcomes from the protocol-specified final analysis and, for the first time, progression on next line of treatment.MethodsEligible patients were randomized to chemotherapy plus either pembrolizumab (n = 278) or placebo (n = 281). After positive results from the second interim analysis, patients still receiving placebo could cross over to pembrolizumab monotherapy at the time of confirmed progressive disease. The primary end points were OS and PFS. PFS-2 (time from randomization to progression on next-line treatment/death, whichever occurred first) was an exploratory end point.ResultsAfter median (range) follow-up of 14.3 (0.1–31.3) months, pembrolizumab plus chemotherapy continued to exhibit a clinically meaningful improvement over placebo plus chemotherapy in OS (median, 17.1 mo [95% confidence interval (CI): 14.4‒19.9] versus 11.6 mo [95% CI: 10.1‒13.7]; hazard ratio [HR], 0.71 [95% CI: 0.58‒0.88]) and PFS (median, 8.0 mo [95% CI: 6.3‒8.4] versus 5.1 mo [95% CI: 4.3‒6.0]; HR, 0.57 [95% CI: 0.47‒0.69]). PFS-2 was longer for patients randomized to first-line pembrolizumab plus chemotherapy (HR, 0.59 [95% CI: 0.49‒0.72]). Grade 3 to 5 adverse events occurred in 74.1% and 69.6% of patients receiving pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively.ConclusionsPembrolizumab plus chemotherapy continued to exhibit substantially improved OS and PFS in patients with metastatic squamous NSCLC. The PFS-2 outcomes support pembrolizumab plus chemotherapy as a standard first-line treatment in patients with metastatic squamous NSCLC.     

Clinical Outcomes With Pembrolizumab-Based Therapies in Recurrent/Refractory NSCLC After Chemoradiation and Consolidative Durvalumab

BackgroundOften, patients with NSCLC experience recurrent/refractory (R/R) disease within 2 years of chemoradiation (CRT) and consolidative durvalumab. Despite prior immune checkpoint inhibitor exposure, immunotherapy with or without chemotherapy is typically initiated if a driver-oncogene is absent. However, there remains a paucity of data regarding the efficacy of immunotherapy in this patient population. Here, we present survival outcomes associated with pembrolizumab for R/R NSCLC.Materials and MethodsWe retrospectively assessed adults with NSCLC who received pembrolizumab for R/R disease between January 2016 to January 2023. Primary objective was to estimate OS and PFS in this cohort compared to historical outcomes. Secondary objective was to compare OS and PFS among subgroups.ResultsFifty patients were evaluated. Median follow-up time was 11.3 months (2.9-38.2). OS was 10.6 months (95% CI, 8.8-19.2); 1-year OS rate 49% (95% CI, 36 - 67%). PFS was 6.1 months (95% CI, 4.7-9.0); 1-year PFS rate 25% (95% CI, 15%-42%). Current smokers had significantly better median OS/PFS as compared to former smokers (NA vs. 10.5 and 9.9 vs. 6.0 months, respectively). The addition of chemotherapy demonstrated an OS benefit (median OS 12.9 vs. 6.0 months) but was not statistically significant.ConclusionPatients with R/R NSCLC represent a distinct cohort with inferior survival outcomes when compared to those with de novo stage IV disease treated with pembrolizumab-based regimens. Based on our findings, we recommend oncologists exercise caution when considering checkpoint inhibitor monotherapy in the front-line setting for R/R NSCLC, regardless of PD-L1 expression.     

A Novel Radiogenomics Biomarker for Predicting Treatment Response and Pneumotoxicity From Programmed Cell Death Protein or Ligand-1 Inhibition Immunotherapy in NSCLC

IntroductionPatient selection for checkpoint inhibitor immunotherapy is currently guided by programmed death-ligand 1 (PD-L1) expression obtained from immunohistochemical staining of tumor tissue samples. This approach is susceptible to limitations resulting from the dynamic and heterogeneous nature of cancer cells and the invasiveness of the tissue sampling procedure. To address these challenges, we developed a novel computed tomography (CT) radiomic-based signature for predicting disease response in patients with NSCLC undergoing programmed cell death protein 1 (PD-1) or PD-L1 checkpoint inhibitor immunotherapy.MethodsThis retrospective study comprises a total of 194 patients with suitable CT scans out of 340. Using the radiomic features computed from segmented tumors on a discovery set of 85 contrast-enhanced chest CTs of patients diagnosed with having NSCLC and their CD274 count, RNA expression of the protein-encoding gene for PD-L1, as the response vector, we developed a composite radiomic signature, lung cancer immunotherapy—radiomics prediction vector (LCI-RPV). This was validated in two independent testing cohorts of 66 and 43 patients with NSCLC treated with PD-1 or PD-L1 inhibition immunotherapy, respectively.ResultsLCI-RPV predicted PD-L1 positivity in both NSCLC testing cohorts (area under the curve [AUC] = 0.70, 95% confidence interval [CI]: 0.57–0.84 and AUC = 0.70, 95% CI: 0.46–0.94). In one cohort, it also demonstrated good prediction of cases with high PD-L1 expression exceeding key treatment thresholds (>50%: AUC = 0.72, 95% CI: 0.59–0.85 and >90%: AUC = 0.66, 95% CI: 0.45–0.88), the tumor’s objective response to treatment at 3 months (AUC = 0.68, 95% CI: 0.52–0.85), and pneumonitis occurrence (AUC = 0.64, 95% CI: 0.48–0.80). LCI-RPV achieved statistically significant stratification of the patients into a high- and low-risk survival group (hazard ratio = 2.26, 95% CI: 1.21–4.24, p = 0.011 and hazard ratio = 2.45, 95% CI: 1.07–5.65, p = 0.035).ConclusionsA CT radiomics-based signature developed from response vector CD274 can aid in evaluating patients’ suitability for PD-1 or PD-L1 checkpoint inhibitor immunotherapy in NSCLC.     

Osimertinib Plus Durvalumab in Patients With EGFR-Mutated,Advanced NSCLC: A Phase 1b,Open-Label,Multicenter Trial

IntroductionEGFR tyrosine kinase inhibitors (TKIs) are recommended for EGFR-mutated NSCLC treatment. EGFR activation up-regulates programmed death-ligand 1 expression and other immunosuppressive factors in NSCLC, causing immune microenvironment remodeling. Osimertinib (an EGFR TKI) plus durvalumab (programmed death-ligand 1 blockade) was evaluated in the TATTON study (NCT02143466).MethodsThis open-label, phase 1b study enrolled patients with advanced EGFR-mutated NSCLC. In part A, patients who had progressed on a previous EGFR TKI received osimertinib (80 mg once daily) plus durvalumab 3 or 10 mg/kg every 2 weeks. In part B, patients received first-line osimertinib plus durvalumab 10 mg/kg every 2 weeks. However, part B enrollment was terminated early owing to an increased incidence of interstitial lung disease (ILD)-related adverse events (AEs). Safety (primary objective) and preliminary anti-tumor activity determined by objective response rate (ORR), best overall response, duration of response (DOR), and progression-free survival were evaluated.ResultsBefore enrollment termination, 23 and 11 patients received treatment across parts A and B, respectively. The most common AEs across parts A and B were as follows: diarrhea (50%), nausea (41%), and decreased appetite (35%). A total of 12 patients (35%) reported ILD-related AEs (lung disorder, ILD or pneumonitis). In part A, ORR was 43% (95% confidence interval [CI]: 23–66); median DOR was 20.4 months. In part B, ORR was 82% (95% CI: 48–98), median DOR was 7.1 months, and median progression-free survival was 9.0 months (95% CI: 3.5–12.3).ConclusionsThis study highlighted a potential risk of ILD-related AEs when combining osimertinib with durvalumab. Further research looking to combine EGFR TKIs with immune checkpoint inhibitors should be approached with caution.     

Classification of Tumor Immune Microenvironment According to Programmed Death-Ligand 1 Expression and Immune Infiltration Predicts Response to Immunotherapy Plus Chemotherapy in Advanced Patients With NSCLC

IntroductionAccording to mechanisms of adaptive immune resistance, tumor immune microenvironment (TIME) is classified into four types: (1) programmed death-ligand 1 (PD-L1)–negative and tumor-infiltrating lymphocyte (TIL)–negative (type I); (2) PD-L1–positive and TIL-positive (type II); (3) PD-L1–negative and TIL-positive (type III); and (4) PD-L1–positive and TIL-negative (type IV). However, the relationship between the TIME classification model and immunotherapy efficacy has not been validated by any large-scale randomized controlled clinical trial among patients with advanced NSCLC.MethodsOn the basis of RNA-sequencing and immunohistochemistry data from the ORIENT-11 study, we optimized the TIME classification model and evaluated its predictive value for the efficacy of immunotherapy plus chemotherapy.ResultsPD-L1 mRNA expression and immune score calculated by the ESTIMATE method were the strongest predictors for the efficacy of immunotherapy plus chemotherapy. Therefore, they were determined as the optimized definition of the TIME classification system. When compared between combination therapy and chemotherapy alone, only the type II subpopulation with high immune score and high PD-L1 mRNA expression was significantly associated with improved progression-free survival (PFS) (hazard ratio = 0.12, 95% confidence interval: 0.06–0.25, p < 0.001) and overall survival (hazard ratio = 0.27, 95% confidence interval: 0.13–0.55, p < 0.001). In the combination group, the type II subpopulation had a much longer survival time, not even reaching the median PFS or overall survival, but the other three subpopulations were susceptible to having similar PFS. In the chemotherapy group, there was no marked association between survival outcomes and TIME subtypes.ConclusionsOnly patients with both high PD-L1 expression and high immune infiltration could benefit from chemotherapy plus immunotherapy in first-line treatment of advanced NSCLC. For patients lacking either PD-L1 expression or immune infiltration, chemotherapy alone might be a better treatment option to avoid unnecessary toxicities and financial burdens.     

Cemiplimab Plus Chemotherapy Versus Chemotherapy Alone in Advanced NSCLC: 2-Year Follow-Up From the Phase 3 EMPOWER-Lung 3 Part 2 Trial

IntroductionEMPOWER-Lung 3 part 2 (NCT03409614), a double-blind, placebo-controlled phase 3 study, investigated cemiplimab (antiprogrammed cell death protein 1) plus chemotherapy versus placebo plus chemotherapy in patients with advanced NSCLC without EGFR, ALK, or ROS1 aberrations, with either squamous or nonsquamous histology, irrespective of programmed death-ligand 1 levels. At primary analysis, after 16.4 months of follow-up, cemiplimab plus chemotherapy improved median overall survival (OS) versus chemotherapy alone (21.9 versus 13.0 mo, hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.53–0.93, p = 0.014). Here, we report protocol-specified final OS and 2-year follow-up results.MethodsPatients (N = 466) were randomized 2:1 to receive histology-specific platinum-doublet chemotherapy, with 350 mg cemiplimab (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks. Primary end point was OS; secondary end points included progression-free survival and objective response rates.ResultsAfter 28.4 months of median follow-up, median OS was 21.1 months (95% CI: 15.9–23.5) for cemiplimab plus chemotherapy versus 12.9 months (95% CI: 10.6–15.7) for chemotherapy alone (HR = 0.65, 95% CI: 0.51–0.82, p = 0.0003); median progression-free survival was 8.2 months (95% CI: 6.4–9.0) versus 5.5 months (95% CI: 4.3–6.2) (HR = 0.55, 95% CI: 0.44–0.68, p < 0.0001), and objective response rates were 43.6% versus 22.1%, respectively. Safety was generally consistent with previously reported data. Incidence of treatment-emergent adverse events of grade 3 or higher was 48.7% with cemiplimab plus chemotherapy and 32.7% with chemotherapy alone.ConclusionsAt protocol-specified final OS analysis with 28.4 months of follow-up, the EMPOWER-Lung 3 study continued to reveal benefit of cemiplimab plus chemotherapy versus chemotherapy alone in patients with advanced squamous or nonsquamous NSCLC, across programmed death-ligand 1 levels.     

Checkpoint Inhibitors in Metastatic EGFR-Mutated Non–Small Cell Lung Cancer—A Meta-Analysis

IntroductionWe performed a meta-analysis to assess the role of immune checkpoint inhibitors as second-line therapy in EGFR-mutant advanced NSCLC.MethodsRandomized trials comparing immune checkpoint inhibitors against chemotherapy were identified. We retrieved the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS) of the intention-to-treat population and EGFR mutation–defined subgroups. We used the fixed-effects inverse variance–weighted method to pool estimates of treatment efficacy. Statistical tests were two sided.ResultsIn the three included studies that compared immune checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68, 95% CI: 0.61–0.77, p < 0.0001) and in the EGFR wild-type subgroup (n = 1362, HR = 0.66, 95% CI: 0.58–0.76, p < 0.0001) but not in the EGFR-mutant subgroup (n = 186, HR = 1.05, 95% CI: 0.70–1.55, p < 0.81; treatment-mutation interaction p = 0.03).ConclusionIn EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do not improve OS over that with docetaxel. Mechanisms of acquired resistance to first-line tyrosine kinase inhibitor therapy should be elucidated to guide selection of second-line treatment for these patients.     

Phase 3 Trial Comparing Nanoparticle Albumin-Bound Paclitaxel With Docetaxel for Previously Treated Advanced NSCLC

IntroductionWe aimed to evaluate the efficacy and safety of nanoparticle albumin-bound (nab-) paclitaxel for previously treated patients with advanced NSCLC.MethodsIn this randomized, open-label, noninferiority phase 3 trial, we enrolled patients with advanced NSCLC previously treated with cytotoxic chemotherapy. Patients were randomly allocated (1:1) to receive docetaxel (60 mg/m²) on day 1 or nab-paclitaxel (100 mg/m²) on days 1, 8, and 15 of a 21-day cycle. The primary end point was overall survival (OS) analyzed on an intention-to-treat basis.ResultsBetween May 22, 2015, and March 12, 2018, a total of 503 patients were randomly allocated to the treatment. Median OS was 16.2 months (95% confidence interval [CI]: 14.4–19.0) for the 252 patients allocated to nab-paclitaxel and 13.6 months (95% CI: 10.9–16.5) for the 251 patients allocated to docetaxel (hazard ratio = 0.85, 95.2% CI: 0.68–1.07). Median progression-free survival was 4.2 months (95% CI: 3.9–5.0) for the nab-paclitaxel group versus 3.4 months (95% CI: 2.9–4.1) for the docetaxel group (hazard ratio = 0.76, 95% CI: 0.63–0.92, p = 0.0042). The objective response rate was 29.9% (95% CI: 24.0–36.2) for the nab-paclitaxel group and 15.4% (95% CI: 10.9–20.7) for the docetaxel group (p = 0.0002). Adverse events of grade greater than or equal to 3 included febrile neutropenia (5 of 245 patients [2%] in the nab-paclitaxel group versus 55 of 249 patients [22%] in the docetaxel group) and peripheral sensory neuropathy (24 [10%] versus 2 [1%], respectively).ConclusionsNab-paclitaxel was noninferior to docetaxel in terms of OS. It should, thus, be considered a standard treatment option for previously treated patients with advanced NSCLC.     

First-Line Nivolumab Plus Ipilimumab With Chemotherapy Versus Chemotherapy Alone for Metastatic NSCLC in CheckMate 9LA: 3-Year Clinical Update and Outcomes in Patients With Brain Metastases or Select Somatic Mutations

IntroductionIn the phase 3 CheckMate 9LA study, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy alone. We report updated efficacy and safety (≥3 y of follow-up), clinical outcomes in patients with baseline brain metastases, and exploratory somatic mutation analyses.MethodsAdults with stage IV or recurrent NSCLC, no known sensitizing EGFR or ALK alterations, and Eastern Cooperative Oncology Group performance status less than or equal to 1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy alone (four cycles). Assessments included OS, progression-free survival (PFS), and objective response rate. Exploratory analyses included systemic and intracranial efficacy in patients with or without baseline brain metastases, in addition to OS and PFS by KRAS, TP53, STK11, and KEAP1 somatic mutation status in patients with nonsquamous NSCLC.ResultsWith a minimum follow-up of 36.1 months, nivolumab plus ipilimumab with chemotherapy continued to prolong OS versus chemotherapy alone in the intent-to-treat population (median [hazard ratio; 95% confidence interval] OS: 15.8 versus 11.0 mo [0.74; 0.62–0.87]; 3-y OS: 27% versus 19%). Efficacy outcomes were improved in patients with pretreated baseline brain metastases (median [hazard ratio; 95% confidence interval] OS: 19.3 versus 6.8 mo [0.45; 0.29–0.70]; systemic PFS: 9.7 versus 4.1 mo [0.44; 0.28–0.69]; intracranial PFS: 11.4 versus 4.6 mo [0.42; 0.26–0.68]). A trend of OS benefit was observed in patients treated with nivolumab plus ipilimumab with chemotherapy versus chemotherapy alone, despite KRAS, TP53, and STK11 tumor mutations. Extended follow-up revealed no new safety signals.ConclusionsWith a 3-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy continued to have long-term, durable efficacy versus chemotherapy alone; a manageable safety profile; and survival benefit in patients with or without baseline brain metastases or select somatic mutations, further supporting the regimen as first-line treatment for patients with metastatic NSCLC.     

First-line Pembrolizumab Versus Pembrolizumab Plus Chemotherapy Versus Chemotherapy Alone in Non–small-cell Lung Cancer: A Systematic Review and Network Meta-analysis

BackgroundThis study aimed to comprehensively review the available evidence regarding the efficacy of first-line pembrolizumab for advanced/metastatic non–small-cell lung cancer (NSCLC), and to compare pembrolizumab monotherapy versus pembrolizumab plus chemotherapy versus chemotherapy alone.Materials and MethodsA search of the PubMed, EMBASE, and Cochrane Library databases was performed in July 2018, and abstracts from the American Society of Clinical Oncology meetings (2015-2018) were reviewed. Summaries of the results were pooled using a random-effect model to determine the pooled hazard ratio (HR) for progression-free survival (PFS), overall survival (OS), and their 95% confidence intervals (CIs). A network meta-analysis was used to indirectly compare pembrolizumab monotherapy with pembrolizumab plus chemotherapy.ResultsA total of 4 relevant phase III trials comprising 2754 patients were identified. Pembrolizumab (with or without chemotherapy) led to significant improvements in OS and PFS, irrespective of the programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS). In particular, for the subgroup with PD-L1 TPS ≥ 50%, the HR of PFS was 0.49 (95% CI, 0.32-0.76; P = .001), and that of OS was 0.57 (95% CI, 0.45-0.73; P < .001). In terms of PFS, pembrolizumab plus chemotherapy was superior to pembrolizumab monotherapy with an HR of PFS 0.52 (95% CI, 0.27-0.99; P = .048) for the subgroup with PD-L1 TPS ≥ 50%.ConclusionsFor patients with NSCLC with PD-L1 TPS ≥ 50%, pembrolizumab plus chemotherapy has a better PFS than pembrolizumab monotherapy in this meta-analysis. To confirm this finding, a prospective phase III trial that directly compares the treatments is warranted.     

Phase II Trial of Combination Nab-paclitaxel and Gemcitabine in Non–squamous Non–small Cell Lung Cancer After Progression on Platinum and Pemetrexed

BackgroundBetter therapies are needed to improve survival in metastatic non–small cell lung cancer (NSCLC). Given the synergy of combination nab-paclitaxel and gemcitabine in metastatic pancreatic cancer and their individual activity in advanced NSCLC, we sought to determine whether the same combination would confer a therapeutic benefit in the second-line therapy of recurrent or metastatic non–squamous (NSQ) NSCLC.Materials and MethodsThis single-arm phase II trial of nab-paclitaxel and gemcitabine was performed from June 2015 to April 2020 at an academic referral cancer center. Patients with advanced NSQ-NSCLC whose disease progressed on first-line pemetrexed plus platinum +/- immunotherapy were enrolled. Patients received intravenous nab-paclitaxel 100 mg/m² and gemcitabine 1000 mg/m² on days 1 and 8 of each 21-day cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Safety and tolerability were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.ResultsThirty-seven patients (15 men [41%] and 22 women [59%]; median age, 66 years [range, 41-81 years]) were accrued. ORR was 13.5% (95% CI, 2.5-24.5%). DCR was 59.5% (95% CI, 43.5-75.5%). Median PFS was 2.6 months (95% CI, 1.4-3.8 months). Median OS was 6.2 months (95% CI, 4.2-8.2 months). 1-year OS was 24% (95% CI, 10-38%). Safety and tolerability were similar to other second-line chemotherapies, although there was an 11% incidence of grade 2-3 pneumonitis.ConclusionCombination nab-paclitaxel and gemcitabine after platinum and pemetrexed for NSQ-NSCLC was not associated with greater efficacy than would be expected for single-agent chemotherapy in this setting. The higher-than-expected risk of pneumonitis was also concerning.Trial RegistrationClinicalTrials.gov Identifier: NCT02303977Micro-AbstractIn this phase II trial, 37 patients with metastatic non–squamous non–small cell lung cancer were treated with nab-paclitaxel/gemcitabine in second-line. ORR = 13.5% (95% CI, 2.5%-24.5%). Median PFS = 2.6 months (95% CI, 1.4-3.8 months). Median OS = 6.2 months (95% CI, 4.2-8.2 months). Nab-paclitaxel and gemcitabine was not associated with greater efficacy than would be expected for single-agent chemotherapy in this setting.     

A randomized trial of TLR-2 agonist CADI-05 targeting desmocollin-3 for advanced non-small-cell lung cancer

BackgroundRandomized controlled trial to evaluate synergy between taxane plus platinum chemotherapy and CADI-05, a Toll like receptor-2 agonist targeting desmocollin-3 as a first-line therapy in advanced non-small-cell lung cancer (NSCLC).Patients and methodsPatients with advanced NSCLC (stage IIIB or IV) were randomized to cisplatin-paclitaxel (chemotherapy group, N= 112) or cisplatin-paclitaxel plus CADI-05 (chemoimmunotherapy group, N = 109). CADI-05 was administered a week before chemotherapy and on days 8 and 15 of each cycle and every month subsequently for 12 months or disease progression. Overall survival was compared using a log-rank test. Computed tomography was carried out at baseline, end of two cycles and four cycles. Response rate was evaluated using Response Evaluation Criteria in Solid Tumors criteria by an independent radiologist.ResultsAs per intention-to-treat analysis, no survival benefit was observed between two groups [208 versus 196 days; hazard ratio, 0.86; 95% confidence interval (CI) 0.63–1.19; P = 0.3804]. In a subgroup analysis, improvement in median survival by 127 days was observed in squamous NSCC with chemoimmunotherapy (hazard ratio, 0.55; 95% CI 0.32–0.95; P = 0.046). In patients receiving planned four cycles of chemotherapy, there was improved median overall survival by 66 days (299 versus 233 days; hazard ratio, 0.64; 95% CI 0.41 to 0.98; P = 0.04) in the chemoimmunotherapy group compared with the chemotherapy group. This was associated with the improved survival by 17.48% at the end of 1 year, in the chemoimmunotherapy group. Systemic adverse events were identical in both the groups.ConclusionThere was no survival benefit with the addition of CADI-05 to the combination of cisplatin-paclitaxel in patients with advanced NSCLC; however, the squamous cell subset did demonstrate a survival advantage.     

The Impact of Durvalumab on Local-Regional Control in Stage III NSCLCs Treated With Chemoradiation and on KEAP1-NFE2L2-Mutant Tumors

IntroductionKEAP1-NFE2L2-mutant NSCLCs are chemoradiation resistant and at high risk for local-regional failure (LRF) after concurrent chemoradiation (cCRT). To elucidate the impact of durvalumab on local-regional control, we evaluated LRF in patients with NSCLC treated with cCRT with and without durvalumab.MethodsPatients with stage III NSCLC treated with cCRT or cCRT and durvalumab who underwent tumor genomic profiling were evaluated. The incidence of LRF and outcomes of patients with and without KEAP1-NFE2L2-mutant tumors were evaluated.ResultsWe analyzed 120 consecutive patients (cCRT alone, n = 54; cCRT and durvalumab, n = 66). Patients treated with cCRT alone had significantly more LRF events compared with those treated with cCRT and durvalumab, with 12-month LRF incidence of 39% (95% confidence interval [CI]: 24%–54%) and 18% (95% CI: 8%–28%), respectively (p = 0.002). Among patients treated with cCRT alone and cCRT and durvalumab, 20 patients (37%) and 18 patients (27%), respectively, had KEAP1-NFE2L2-mutant tumors. In patients treated with cCRT alone, those with KEAP1-NFE2L2-mutant tumors had worse local-regional control (p = 0.015), and on multivariate analysis, KEAP1-NFE2L2 mutation predicted for LRF (hazard ratio = 3.9, 95% CI: 1.6–9.8, p = 0.003). Nevertheless, patients with and without KEAP1-NFE2L2-mutant tumors had similar LRF outcomes (p = 0.541) when treated with cCRT and durvalumab, and mutational status did not predict for LRF (p = 0.545). Among those with KEAP1-NFE2L2-mutant tumors, cCRT and durvalumab significantly reduced the incidence of LRF compared with cCRT alone: 12-month LRF incidence of 62% (95% CI: 40%–84%) versus 25% (95% CI: 4%–46%), respectively (p = 0.021).ConclusionsDurvalumab after cCRT significantly improves local-regional control and reduces LRF in chemoradiation-resistant KEAP1-NFE2L2-mutant NSCLC tumors.     

Four-Year Survival With Durvalumab After Chemoradiotherapy in Stage III NSCLC—an Update From the PACIFIC Trial

IntroductionIn the Phase 3, placebo-controlled PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression after concurrent chemoradiotherapy, consolidative durvalumab was associated with significant improvements in the primary end points of overall survival (OS) (hazard ratio [HR] = 0.68; 95% confidence interval [CI]: 0.53–0.87; p = 0.00251; data cutoff, March 22, 2018) and progression-free survival (PFS) (blinded independent central review; Response Evaluation Criteria in Solid Tumors version 1.1) (HR = 0.52; 95% CI: 0.42–65; p < 0.0001; February 13, 2017) with manageable safety. Here, we report updated analyses of OS and PFS, approximately 4 years after the last patient was randomized.MethodsPatients with WHO performance status of 0 or 1 (and any tumor programmed death-ligand 1 status) were randomized (2:1) to intravenous durvalumab (10 mg/kg) or placebo, administered every 2 weeks (≤12 months), stratified by age, sex, and smoking history. OS and PFS were analyzed using a stratified log-rank test in the intent-to-treat population. Medians and 4-year OS and PFS rates were estimated by the Kaplan–Meier method.ResultsOverall, 709 of 713 randomized patients received durvalumab (n/N=473/476) or placebo (n/N=236/237). As of March 20, 2020 (median follow-up = 34.2 months; range: 0.2–64.9), updated OS (HR = 0.71; 95% CI: 0.57–0.88) and PFS (HR = 0.55; 95% CI: 0.44–0.67) remained consistent with the primary analyses. The median OS for durvalumab was reached (47.5 mo; placebo, 29.1 months). Estimated 4-year OS rates were 49.6% versus 36.3% for durvalumab versus placebo, and 4-year PFS rates were 35.3% versus 19.5% respectively.ConclusionThese updated exploratory analyses demonstrate durable PFS and sustained OS benefit with durvalumab after chemoradiotherapy. An estimated 49.6% of patients randomized to durvalumab remain alive at 4 years (placebo, 36.3%), and 35.3% remain alive and progression-free (placebo, 19.5%).     

Comparison of Chemotherapy Plus Pembrolizumab vs. Chemotherapy Alone in EGFR-Mutant Non–small-Cell Lung Cancer Patients

IntroductionPlatinum doublet chemotherapy is the standard of care in patients with non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation who had disease progression after tyrosine kinase inhibitor (TKI). We aimed to assess immune checkpoint inhibitors efficacy in EGFR-mutant advanced NSCLC.Materials and MethodsWe retrospectively reviewed the data of sensitive EGFR-mutant NSCLC patients who progressed after EGFR-TKIs and received platinum doublet chemotherapy plus immunotherapy between 2015 and 2021. Efficacy outcomes, including overall response rate, progression-free survival, and overall survival, were assessed and compared with those of patients who had received platinum-based doublet chemotherapy.ResultsOf the total 869 patients, 82 treated with pembrolizumab and chemotherapy and 82 with only chemotherapy were selected. The median progression-free survival in patients administered pembrolizumab was significantly longer than those not administered pembrolizumab (6.7 months; 95% confidence interval [CI] 5.0-8.5 vs. 4.2 months; 95% CI 3.3-5.0, hazard ratio [HR] 0.64, 95% CI 0.46-0.89, P = .0076). Improved median overall survival was also observed in patients receiving pembrolizumab plus chemotherapy (26.7 [95% CI 22.6-30.8] vs. 13.4 months [95% CI 10.4-16.4], HR, 0.49 [95% CI 0.31-0.75], P = .0052). In addition, the overall response rate was higher in patients treated with than patients treated without pembrolizumab (34.1% and 20.7%, respectively).ConclusionThe combination of pembrolizumab with chemotherapy is associated with improved efficacy and survival in patients with EGFR-mutant NSCLC after TKI resistance, but these findings need to be confirmed in further prospective studies.