Cemiplimab plus chemotherapy produced variable outcomes by genomic profile in patients with nonsquamous NSCLC.
Varying outcomes were observed following treatment with cemiplimab-rwlc (Libtayo) plus chemotherapy in molecularly defined subsets of patients with nonsquamous non–small cell lung cancer (NSCLC), according to findings from an analysis of the phase 3 EMPOWER-Lung 3 trial (NCT03409614) presented during the
Patients with nonsquamous NSCLC with STK11 mutations and any PD-L1 status who received cemiplimab plus chemotherapy (n = 32) experienced a median overall survival (OS) of 9.6 months (95% CI, 6.7-36.3) compared with 10.8 months (95% CI, 5-19.1) among patients who received chemotherapy alone (n = 13; HR, 0.67; 95% CI, 0.31-1.45). Those with STK11 wild-type disease in the cemiplimab (n = 118) and placebo (n = 28) arms had a median OS of 18.1 months (95% CI, 13.9-24.8) and 7.6 months (95% CI, 5.5-16.1), respectively (HR, 0.49; 95% CI, 0.31-0.78).
In those with STK11-mutated disease and a PD-L1 expression level of at least 1%, the median OS values in the cemiplimab (n = 15) and placebo (n = 11) cohorts were 36.3 months (95% CI, 6.7-not evaluable [NE]) and 13 months (95% CI, 5-19.1), respectively (HR, 0.39; 95% CI, 0.13-1.13). Those with STK11 wild-type disease experienced a median OS of 24 months (95% CI, 18.1-35.5) in the cemiplimab arm (n = 84) compared with 9.2 months (95% CI, 3.8-17.4) in the placebo arm (n = 21; HR, 0.37; 95% CI, 0.21-0.64).
Patients with a PD-L1 expression level of 1% to 49% with STK11-mutated disease who received the combination (n = 8) experienced a median OS of 54.2 months (95% CI, 6-NE) compared with 13 months (95% CI, 0.8-19.1) with chemotherapy alone (n = 10; HR, 0.2; 95% CI, 0.04-1). The median OS values for patients with STK11 wild-type disease in the cemiplimab (n = 38) and placebo (n = 10) arms were 19.4 months (95% CI, 14-31.9) and 12 months (95% CI, 1.7-18.2), respectively (HR, 0.43; 95% CI, 0.19-0.96).
“Comprehensive genomic analyses revealed differential outcomes with cemiplimab plus chemotherapy in molecularly defined subsets of NSCLC, including benefit in those with historically limited [immune checkpoint inhibitor therapy] response,” Fred R. Hirsch, MD, PhD, and coauthors, wrote in a poster presentation of the data.
Hirsch is a professor of medicine, hematology, and medical oncology, and of pathology, molecular, and cell-based medicine, the Ning Zhao Chair and Professor of Medicine (Hematology and Medical Oncology) and Pathology, and the executive director of the Center for Thoracic Oncology at the Icahn School of Medicine at Mount Sinai in New York, New York. He is also the codirector of the Center of Excellence for Thoracic Oncology and associate director of biomarker discovery at the Mount Sinai Tisch Cancer Center.
In November 2022, the
EMPOWER-Lung 3 enrolled treatment-naive patients with stage IIIB/IIIC and IV nonsquamous and squamous advanced NSCLC.1 Other key eligibility criteria included the absence of EGFR, ALK, or ROS1 aberrations, and an ECOG performance status of 0 or 1. Patients with any level of PD-L1 expression were permitted. Stratification occurred based on PD-L1 expression levels (< 1% vs 1%-49% vs ≥ 50%) and histology (nonsquamous vs squamous).
Eligible patients were randomly assigned 2:1 to receive cemiplimab at 350 mg every 3 weeks or a matching placebo. Patients in both arms received investigator’s choice of platinum-doublet chemotherapy every 3 weeks for 4 cycles. In the genomic analysis, baseline tumor samples or plasma was assessed via fixed gene panel next-generation sequencing using the Foundation One Tracker or Liquid CDx assays.
The primary end point was OS. Key secondary end points included progression-free survival and overall response rate (ORR).
At baseline, 78% (n = 362) of patients in the intention-to-treat population had available genomic data. Patients with available data and nonsquamous disease (n = 191) were treated with cemiplimab plus chemotherapy (n = 150) or chemotherapy alone (n = 41). In the PD-L1 all-comer population, disease mutations consisted of TP53 (63%), KRAS (33%), STK11 (24%), and KEAP1 (13%).
Additional findings from the genomic analysis revealed that patients with STK11/KRAS comutations who received the combination (n = 12) experienced an ORR of 33.3%. Patients with KRAS mutations/STK11 wild-type (n = 38), STK11 mutations/KRAS wild-type (n = 20), and STK11/KRAS wild-type (n = 80) disease achieved respective ORRs of 36.8%, 35%, and 42.5%.
Patients with STK11/TP53 comutations who received the combination (n = 23) had an ORR of 34.8%. Patients with TP53 mutations/STK11 wild-type (n = 72), STK11 mutations/TP53 wild-type (n = 9), and TP53/STK11 wild-type (n = 46) disease achieved ORRs of 45.8%, 33.3%, and 32.6%, respectively.
Among patients with KEAP1/STK11 comuations who received cemiplimab plus chemotherapy (n = 13), the ORR was 15.4%. Patients with KEAP1 mutations/STK11 wild-type (n = 7), STK11 mutations/KEAP1 wild-type (n = 19), and KEAP1/STK11 wild-type (n = 111) disease experienced respective ORRs of 0%, 47.4%, and 43.2%.
In the KEAP1/KRAS–comutated subgroup (n = 12), the ORR was 16.7%. Those with KRAS mutations/KEAP1 wild-type (n = 38), KEAP1 mutations/KRAS wild-type (n = 8), and KRAS/KEAP1 wild-type (n = 92) disease had respective ORRs of 42.1%, 0%, and 44.6%.
“These comprehensive genomic analyses [highlighted] the differential effects of driver mutations on clinical outcomes following first-line anti–PD-L1 and chemotherapy combination [treatment] for patients with advanced NSCLC by PD-L1 expression levels,” Hirsch and his coauthors wrote. “Cemiplimab combined with chemotherapy may provide clinical benefits in molecular subgroups, such as STK11-mutant NSCLC, which have historically shown [a] limited response to anti–PD-(L)1 therapies.”
Disclosures: Hirsch did not list any financial disclosures in the presentation.
