Nivolumab plus ipilimumab versus pembrolizumab as chemotherapy‐free, first‐line treatment for PD‐L1‐positive non‐small cell lung cancer

Abstract

Background Nivolumab plus ipilimumab (N‐I) or pembrolizumab (PEM) is associated with survival improvement as chemotherapy‐free, first‐line treatment for patients with advanced non‐small cell lung carcinoma (NSCLC) and positive programmed cell death ligand 1 (PD‐L1). However, no direct comparison data exist between these two regimens to inform clinical decisions. Therefore, we performed indirect comparison for N‐I versus PEM using frequentist methods. Results Three randomized trials (KEYNOTE‐024, KEYNOTE‐042, and CheckMate 227) involving 2372 patients were included. For patients with tumor PD‐L1 level of ≥1%, pooled meta‐analyses showed that both N‐I and PEM improved overall survival (OS) relative to chemotherapy (N‐I: hazard ratio [HR] 0.82, 95% CI 0.69‐0.97; PEM: HR 0.81, 95% CI 0.71‐0.93); whereas only N‐I significantly improved progression‐free survival (PFS) (N‐I: HR 0.79, 95% CI 0.65‐0.96; PEM: HR 1.07, 95% CI 0.94‐1.21). Neither N‐I nor PEM was associated with improved objective response rate (ORR) compared with chemotherapy (N‐I: relative risk [RR] 1.20, 95% CI 0.98‐1.46; PEM: RR 1.03, 95% CI 0.86‐1.23). Indirect comparisons showed that N‐I was associated with longer PFS than PEM (HR 0.77, 95% CI 0.62‐0.95). However, N‐I was not superior to PEM in terms of OS (HR 0.98, 95% CI 0.77‐1.24) and ORR (RR 1.17, 95% CI 0.89‐1.52). N‐I showed a less favorable toxicity profile relative to PEM (all grade adverse events: RR 1.28, 95% CI 1.17‐1.40). Conclusions N‐I and PEM provide comparable OS benefit for PD‐L1‐positive NSCLC. N‐I further improves PFS relative to PEM but at meaningful cost of toxicities.

Cost-Minimization Analysis of Pembrolizumab Monotherapy Versus Nivolumab in Combination with Ipilimumab as First-Line Treatment for Metastatic PD-L1-Positive Non-small Cell Lung Cancer: A US Payer Perspective

“…PFS and OS HRs were estimated using inversevariance weighting, and treatment-related AEs (TRAEs) were compared using the Mantel-Haenszel method. The study found no significant differences in OS, with an HR of 0.98 (95% CI 0.77-1.24) for nivolumab plus ipilimumab versus pembrolizumab, consistent with the findings by Halmos et al [10,11]. The PFS HR of nivolumab plus ipilimumab versus pembrolizumab was estimated to be 0.77 (95% CI 0.62-0.95) by Zhou et al indicating a larger and statistically significant difference in treatment effects on PFS between the two regimens compared with what was detected by Halmos et al [10,11].…”

“…The study found no significant differences in OS, with an HR of 0.98 (95% CI 0.77-1.24) for nivolumab plus ipilimumab versus pembrolizumab, consistent with the findings by Halmos et al [10,11]. The PFS HR of nivolumab plus ipilimumab versus pembrolizumab was estimated to be 0.77 (95% CI 0.62-0.95) by Zhou et al indicating a larger and statistically significant difference in treatment effects on PFS between the two regimens compared with what was detected by Halmos et al [10,11]. We speculate the different finding in PFS might be due to the following reasons: the MAIC conducted by Halmos et al reduced cross-trial differences by adjusting the IPD of KEYNOTE-024 and -042 to match the baseline characteristics of patients in CheckMate 227 Part 1a, making its HR estimates more robust than the HRs estimated by Zhou et al [10,11].…”

“…Adverse event (AE) comparisons were not included in the study by Halmos et al due to potential biases in AE collection, reporting, and follow-up between trials [10]. Another identified ITC comparing the two regimens was a network meta-analysis (NMA) conducted by Zhou et al [11]. Published summary results of KEYNOTE-042 and CheckMate 227 Part 1a were used as inputs in the ITC for the comparison between pembrolizumab and nivolumab plus ipilimumab.…”

If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for KRAS-Mutant Lung Cancer

“…In the last decade, better biochemical insights into KRAS structural biology finally allowed researchers to develop direct KRAS(G12C) inhibitors like the preclinical compounds SML-8-73-1, compound 12 ("Shokat compound"), ARS-853 and ARS-1620, as well as the clinical compounds AMG-510 (Amgen), MRTX-849 (Mirati Immune checkpoint inhibitors (ICIs) block the PDL1-PD1 receptor interaction and thus can reinvigorate antitumor immune responses in some patients with so-called "hot" tumors. ICIs alone or in combination with chemotherapy have become standard-of-care treatment for NSCLC patients whose tumors express PDL1 and lack EGFR mutations or EML4/ALK rearrangements [94][95][96][97][98][99]. These immunologically "hot" tumors are characterized by the accumulation of proinflammatory cytokines, high PD-L1 expression and intratumoral accumulation of CD8+ tumor-infiltrating lymphocytes (TILs), which are required for ICIs to be effective [100].…”

“…Immune checkpoint inhibitors (ICIs) block the PDL1–PD1 receptor interaction and thus can reinvigorate antitumor immune responses in some patients with so-called “hot” tumors. ICIs alone or in combination with chemotherapy have become standard-of-care treatment for NSCLC patients whose tumors express PDL1 and lack EGFR mutations or EML4/ALK rearrangements [ 94 , 95 , 96 , 97 , 98 , 99 ]. These immunologically “hot” tumors are characterized by the accumulation of proinflammatory cytokines, high PD-L1 expression and intratumoral accumulation of CD8+ tumor-infiltrating lymphocytes (TILs), which are required for ICIs to be effective [ 100 ].…”