Background

Cytotoxic agents may potentiate immune-checkpoint inhibitors with immunological effects. Camrelizumab plus pemetrexed and platinum is a current standard of care for Chinese patients (pts) with advanced non-squamous NSCLC and negative EGFR/ALK mutation. Here we evaluated first-line camrelizumab plus chemotherapy (chemo) for pts with squamous NSCLC.

Methods

In this double-blind, multicenter, phase 3 trial, previously untreated pts with histologically or cytologically confirmed stage IIIB-IV squamous NSCLC were randomized 1:1 to receive 4–6 cycles of carboplatin (AUC 5) plus paclitaxel (175 mg/m²) with camrelizumab (200 mg) or placebo every 3 weeks, followed by maintenance therapy with camrelizumab or placebo. The primary endpoint was PFS per IRC. Cross-over after disease progression was allowed for pts allocated placebo plus chemo.

Results

Totally, 389 pts (camrelizumab plus chemo, n=193; placebo plus chemo, n=196) were included. As of Nov. 06, 2020, pts treated with camrelizumab plus chemo were associated with significantly prolonged IRC-assessed PFS versus placebo plus chemo (median, 8.5 [95% CI 6.9–10.4] vs 4.9 [95% CI 4.2–5.5] months; HR, 0.37 [95% CI 0.29–0.47], one-sided P<0.0001), with benefit observed in pts with both PD-L1 TPS <1% (HR, 0.49 [95% CI 0.35–0.68]) and ≥1% (HR, 0.34 [95% CI 0.24–0.49]). There was also significant improvement in OS for the camrelizumab plus chemo group (median, NR [18.4–NR] vs 14.5 [95% CI 13.2–16.6] months; HR, 0.55 [95% CI 0.40–0.75], one-sided P<0.0001). Consistently, confirmed ORR (64.8% [95% CI 57.6%–71.5%] vs 36.7% [95% CI 30.0%–43.9%], P<0.0001) and DoR (median, 13.1 [95% CI 9.3–15.7] vs 4.4 [95% CI 4.2–4.9] months) per IRC favored the camrelizumab plus chemo group. Grade ≥3 treatment-related adverse events occurred in 73.6% of pts in the camrelizumab plus chemo group and 71.9% in the placebo plus chemo group, with no unexpected adverse effects.

Conclusions

The addition of camrelizumab to chemotherapy significantly prolonged PFS and OS in the first-line setting with an acceptable safety profile, supporting this combination as an additional first-line treatment option for pts with advanced squamous NSCLC.

Clinical trial identification

ClinicalTrials.gov, NCT03668496

Background

Pembrolizumab (pembro) + carboplatin and paclitaxel/nab-paclitaxel significantly improved OS and PFS vs placebo in patients (pts) with previously untreated stage IV squamous NSCLC in the phase 3 KEYNOTE-407 study (NCT02775435). At protocol-specified final analysis (data cutoff May 9, 2019), HR for OS was 0.71 (95% CI, 0.58–0.88). We report long-term data and outcomes for pts who completed 35 cycles (~2 y) of treatment.

Methods

Eligible pts were randomized 1:1 (stratified by paclitaxel vs nab-paclitaxel; East Asia vs rest of the world; and PD-L1 TPS ≥1% vs <1%) to receive pembro 200 mg + chemo or placebo + chemo Q3W for 4 cycles, then pembro or placebo for up to a total of 35 cycles. Primary endpoints were OS and PFS per RECIST v1.1 by blinded independent central review.

Results

278 pts were randomized to pembro + chemo and 281 to the placebo + chemo group. As of Sep 30, 2020, median time from randomization to data cutoff was 40.1 (range, 33.1–49.4) mo; 117 (41.6%) pts crossed over from the placebo + chemo group to receive pembro monotherapy. Median OS in the pembro + chemo group was 17.2 vs 11.6 mo for placebo + chemo; HR 0.71 (95% CI, 0.59−0.86). 3-year OS rate was 29.7% vs 18.2%, respectively. Median PFS2 was 13.8 vs 9.1 mo, respectively; HR 0.59 (95% CI, 0.49−0.71; Table). Grade 3−5 AEs occurred in 74.8% of pts in the pembro + chemo group and 70.0% in the placebo + chemo group. Among 55 pts who completed 35 cycles of pembro, ORR was 92.7% (5 CR, 46 PR) and 4 pts (7.3%) had SD. 51 pts (92.7%) were alive, and 1-year OS and PFS after completion of 35 cycles were 96.0% and 82.6%. 7 pts had initiated a second course of pembro at data cutoff.

Conclusions

With ~3 y of follow-up, pembro + chemo continued to demonstrate durable benefit vs chemo alone without additional toxicity. Most pts who completed 35 cycles had objective responses and were alive at data cutoff. These data continue to support pembro + chemo as first-line treatment in pts with metastatic squamous NSCLC.

Clinical trial identification

ClinicalTrials.gov, NCT02775435

Editorial acknowledgement

Writing support was provided by Kathleen Estes, PhD, of ICON plc (North Wales, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Background

In CheckMate 9LA (NCT03215706), 1L NIVO + IPI + chemo (2 cycles) significantly improved overall survival (OS) vs chemo (4 cycles) in patients (pts) with aNSCLC regardless of tumor histology or PD-L1 expression. TMB is potentially associated with the clinical efficacy of immune checkpoint inhibitors. We evaluated efficacy by tissue and blood TMB (tTMB/bTMB) in CheckMate 9LA.

Methods

tTMB was evaluated using the FoundationOne CDx^TM assay from tissue samples collected prior to enrollment. Plasma samples collected at baseline were used for isolation of circulating cell-free tumor DNA and evaluation of bTMB using the Guardant OMNI platform. TMB was not a stratification factor for randomization. Analyses of OS, progression-free survival (PFS), and objective response rate (ORR) were based on prespecified TMB thresholds (tTMB, 10 mut/Mb; bTMB, 16 and 20 mut/Mb). Analyses were based on the March 9, 2020 database lock (DBL; minimum OS follow-up, 12.7 mo).

Results

Of 711 randomized pts with available TMB data at DBL, 64% had evaluable tTMB and 73% had evaluable bTMB. Baseline characteristics were generally well balanced between all randomized, TMB-evaluable and non-evaluable, as well as TMB-high and TMB-low subgroups (both bTMB and tTMB). Overall, clinical benefit (OS, PFS, ORR) was observed with NIVO + IPI + chemo vs chemo in both TMB-high and TMB-low subgroups (Table). The OS benefit with NIVO + IPI + chemo vs chemo was similar between tTMB ≥ 10 and < 10 mut/Mb, and between bTMB ≥ 16 and < 16 mut/Mb subgroups; a numerically higher OS benefit was seen in bTMB ≥ 20 vs < 20 mut/Mb subgroups. For PFS and ORR, the magnitude of benefit was higher in TMB-high versus TMB-low subgroups for both tTMB and bTMB.

Conclusions

Higher TMB appeared to be associated with improved PFS and ORR benefits of NIVO + IPI + chemo over chemo. OS benefit was generally similar between high and low TMB.

Clinical trial identification

NCT03215706

Editorial acknowledgement

Writing and editorial assistance were provided by Nick Patterson, of Caudex, London, UK, funded by Bristol Myers Squibb.

Background

KRAS, the most frequently mutated oncogene in cancer, is a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRAS^G12C mutations occur in approximately 14% of NSCLC (adenocarcinoma). Adagrasib, an investigational agent, is a potent, covalent inhibitor of KRAS^G12C that irreversibly and selectively binds to KRAS^G12C, locking it in its inactive state and was optimized for favorable PK properties, including oral bioavailability, long half-life (~24 h), and extensive tissue distribution.

Methods

KRYSTAL-1 (NCT03785249) is a multi-cohort Phase 1/2 study evaluating adagrasib in pts with advanced or metastatic solid tumors, including NSCLC, harboring a KRAS^G12C mutation previously treated with chemotherapy and an anti-PD-(L)1. Exploratory endpoints include correlative analysis of co-occurring genetic alterations in tumor tissue at baseline and evaluation of the modulation of PD markers, including transcriptomics, in pretreatment and on-study biopsies.

Results

As of 30 August 2020, 79 pts with pretreated NSCLC were treated with adagrasib 600 mg BID (Phase 1/1b and Phase 2). Most commonly reported (>20%) TRAEs included: nausea (54%), diarrhea (48%), vomiting (34%), fatigue (28%), and increased ALT (23%). Among the 51 pts evaluable for clinical activity, 45% (23/51) had a partial response (PR) and 26 pts had stable disease (SD). In a subpopulation of pts with STK11-comutations, ORR was 64% (9/14).

Preliminary PD and mechanistic biomarker analyses on pre- and post-treatment tumor NSCLC biopsies (n=3) demonstrate downregulation of KRAS/MAPK pathway genes including DUSP6 and SPRY4. In pts with tumors harboring STK11-comutations, there was minimal expression of immune transcripts (eg, CD4 and CD8) at baseline and these transcripts were increased after treatment with adagrasib suggesting a potential immune response to therapy.

Conclusions

Adagrasib is tolerable and has demonstrated clinical activity in pts with previously treated KRAS^G12C-mutant NSCLC. Additional PD and mechanistic data will be presented.

Clinical trial identification

NCT03785249

Editorial acknowledgement

Editorial support was provided by Robin Serody of Axiom Healthcare Strategies.