Dr Skoulidis on First-Line Divarasib Plus Pembrolizumab in KRAS G12C+ NSCLC

“All patients who were response evaluable and had at least one post-baseline scan exhibited tumor shrinkage, and there were no patients that exhibited disease progression as their best overall response to treatment.”

Ferdinandos Skoulidis, MD, PhD, MRCP, an associate professor of thoracic/head and neck medical oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed efficacy data from 2 cohorts of the phase 1b/2 KRASCENDO-170 study (NCT05789082) evaluating first-line divarasib plus pembrolizumab (Keytruda) in patients with previously untreated, advanced or metastatic KRAS G12C–mutated non–small cell lung cancer (NSCLC).

Cohort A1 assessed select doses of divarasib plus pembrolizumab in patients with PD-L1–positive tumors, and cohort A2 evaluated the same combination in patients with PD-L1–negative disease, according to Skoulidis.

Among 59 patients in cohort A1, divarasib at 400 mg once daily plus pembrolizumab produced a confirmed objective response rate (ORR) of 72.9% (95% CI, 59.7%-83.6%), including complete responses in 10.2% of patients and partial responses in 62.7%, Skoulidis said. All response-evaluable patients with at least 1 post-baseline scan had tumor shrinkage, and none had disease progression as their best overall response, he noted. The median duration of response was not evaluable ([NE]; 95% CI, 14.5 months-NE), and median progression-free survival (PFS) was 19.3 months (95% CI, 12.4-NE), Skoulidis reported.

In cohort A2, divarasib plus pembrolizumab produced an unconfirmed ORR of 69.6% (95% CI, 47.1%-86.8%) among patients with PD-L1–negative tumors, Skoulidis said, adding that PFS data in this cohort remain immature.

Skoulidis called the results “highly promising, highly encouraging, and…impressive,” emphasizing the efficacy achieved by pairing a targeted therapy with an immune checkpoint inhibitor, including among patients with PD-L1–negative tumors, a population in which checkpoint inhibition alone typically underperforms. The chemotherapy-free combination is now being tested against pembrolizumab plus carboplatin or cisplatin and pemetrexed in the randomized, phase 3 registrational KRASCENDO 2 trial (NCT06793215) in previously untreated, KRAS G12C–mutated NSCLC, he said.