First-line adagrasib (ADA) with pembrolizumab (PEMBRO) in patients (pts) with advanced/metastatic KRAS ^G12C -mutated non-small cell lung cancer (NSCLC) from the phase 2 portion of the KRYSTAL-7 study.

Abstract

8500 Background: In the phase 2 KRYSTAL-7 study (NCT04613596), first-line ADA, a KRAS G12C inhibitor, plus PEMBRO demonstrated clinical activity and a manageable safety profile in pts with advanced/metastatic KRAS G12C -mutated NSCLC and PD-L1 ≥50% (Garassino et al. Ann Oncol 2023). Here we report efficacy and safety data, including the first disclosure of survival data, for pts across all PD-L1 tumor expression levels. Methods: Pts with advanced/metastatic KRAS G12C -mutated NSCLC and known PD-L1 tumor proportion score received first-line ADA (400 mg orally BID) plus PEMBRO (200 mg IV Q3W). The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included duration of response (DOR) and progression-free survival (PFS) assessed by investigator, overall survival (OS), and safety. Results: As of August 23, 2024, 149 pts had received ADA plus PEMBRO (median OS follow-up 22.8 mo): median age was 67 years, 48% were female, and 62% had ECOG PS 1. ORR was 44.3% (95% CI 36.2–52.7); median DOR was 26.3 mo (95% CI 14.9–not estimable [NE]); median PFS was 11.0 mo (95% CI 5.8–14.0) with an 18-mo PFS rate of 37.6% (95% CI 29.0–46.1); and median OS was 18.3 mo (95% CI 14.3–NE) with an 18-mo OS rate of 51.8% (95% CI 43.0–59.8). Efficacy outcomes per PD-L1 status are shown in the Table. Treatment-related adverse events (TRAEs) of any grade (G) were reported in 94.6% of pts (G3/4 in 68.4%); three G5 TRAEs were reported (pneumonia [n=2]; pneumonitis [n=1]). The most common hepatic TRAEs (any G) were increases in alanine aminotransferase (39.6%; G3/4 in 11.4%), aspartate aminotransferase (35.6%; G3/4 in 14.1%), and alkaline phosphatase (19.5%; G3/4 in 6.7%). The discontinuation rate due to hepatic TRAEs was 2.0% for ADA, 6.7% for PEMBRO, and 0.7% for both ADA and PEMBRO. Conclusions: In pts with advanced/metastatic KRAS G12C -mutated NSCLC, first-line ADA plus PEMBRO demonstrated promising clinical efficacy and a manageable safety profile, regardless of PD-L1 status. These data represent the largest dataset evaluating a first-line KRAS G12C inhibitor plus PD-(L)1 inhibitor in this population presented to date. The phase 3 portion of KRYSTAL-7, comparing first-line ADA plus PEMBRO vs PEMBRO monotherapy in pts with KRAS G12C -mutated NSCLC and PD-L1 ≥50%, is ongoing and recruiting. Clinical trial information: NCT04613596 . PD-L1 <50%(n=95) PD-L1 ≥50%(n=54) ORR, n (%)95% CI 34 (35.8)26.2–46.3 32 (59.3)45.0–72.4 Median DOR, mo (95% CI) (n=34)18.2 (11.1–NE) (n=32)26.3 (26.3–NE) Median PFS a , mo (95% CI)18-mo rate, % (95% CI) 6.9 (3.9–12.4)29.8 (19.8–40.4) 27.7 (8.1–NE)50.7 (35.5–64.0) Median OS b , mo (95% CI)18-mo rate, % (95% CI) 15.5 (11.1–21.0)45.2 (34.3–55.6) NE (15.4–NE)62.4 (47.5–74.1) a Median PFS follow-up 17.5 mo (PD-L1 <50%) and 22.6 mo (PD-L1 ≥50%); b Median OS follow-up 21.4 mo (PD-L1 <50%) and 24.9 mo (PD-L1 ≥50%).