First-line adagrasib (ADA) with pembrolizumab (PEMBRO) in patients (pts) with advanced/metastatic KRAS <sup>G12C</sup> -mutated non-small cell lung cancer (NSCLC) from the phase 2 portion of the KRYSTAL-7 study.
Pasi A. Jänne, Willemijn S.M.E. Theelen, Marina Chiara Garassino, Alexander I. Spira, Janessa Laskin, Filippo de Marinis, Firas Badin, Lisenka Boom, Carlos Aguado, Izabela Chmielewska, Enriqueta Felip, Gyula Ostoros, Lauren Jimenez‐Kurlander, Cassie M. Lane, Archie Sachdeva, Laura J. Eccles, Shun Lu
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%).