Adagrasib Combo Continues to Show Efficacy in KRAS G12C–Mutated NSCLC and PD-L1 ≥50%

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The combination of adagrasib (Krazati) and pembrolizumab (Keytruda) continued to be efficacious when used as first-line treatment in patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC) and a PD-L1 tumor proportion score (TPS of 50% or higher, according to 2-year follow-up findings from the phase 2 portion of the KRYSTAL-7 trial (NCT04613596) presented during the 2025 European Lung Cancer Congress.1

At a data cutoff date of August 23, 2024, the doublet elicited an objective response rate (ORR) of 59% (95% CI, 45.0%-72.4%) in this subset of patients (n = 54). Best overall responses included complete response (2%), partial response (57%), stable disease (22%), progressive disease (4%); no post-baseline imaging assessment was done for 15% of patients. The disease control rate was 81% (95% CI,68.6%-90.7%). Moreover, the median duration of response (DOR) was 26.3 months (95% CI, 26.3-not evaluable [NE]), and the 12-month DOR rate was 83%.

The progression-free survival (PFS) was 27.7 months (95% CI, 8.1-NE); the 12-month PFS rate with the combination was 60% and the 18-month PFS rate was 51%. The median overall survival (OS) was not reached (95% CI, 15.4-NE); the 12- and 18-month OS rates were 70% and 62%, respectively.

“ORR and PFS compared favorably with treatment expectations from a PD-(L)1 inhibitor alone in patients with [a] PD-L1 [TPS of] 50% or higher,” Marina C. Garassino, MD, MBBS, of The University of Chicago, in Illinois, said in a presentation of data. “Treatment-related adverse effects [TRAEs] were consistent with the known safety profiles of adagrasib and pembrolizumab and were effectively managed with established algorithms.”

Keeping Up With KRYSTAL-7: Population, Treatment, and Objectives

The phase 2 study included patients with advanced, unresectable or metastatic NSCLC harboring KRAS G12C mutations who had not previously received systemic therapy for locally advanced or metastatic disease. To participate, they needed to have a known PD-L1 TPS score. Notably, those with treated, neurologically stable, brain metastases were permitted.

Cohorts 1a and 2 received 400 mg of oral adagrasib twice daily paired with 200 mg of intravenous pembrolizumab every 3 weeks. The primary end point of the study was investigator-assessed ORR by RECIST 1.1, and key secondary end points included investigator-assessed DOR and PFS, OS, and safety.

Earlier data from the study showed that at a median follow-up of 10.1 months, the doublet elicited an ORR of 63% and the median PFS was NR in this subgroup.2 At ELCC, investigators reported updated efficacy in the subset of patients with a PD-L1 TPS of at least 50% and updated safety in all participants.1

In the subset of patients with a PD-L1 TPS of 50% or higher, the median age was 66 years (range, 40-80) and 52% were female. Most patients were White (78%), non-Hispanic or Latino (94%), had adenocarcinoma (94%), and had an ECOG performance status of 1 (67%). All patients were current or former smokers. At baseline, patients had adrenal (17%), bone (30%), central nervous system (20%), and liver (20%) metastases.

Safety Insights

Any-grade TRAEs occurred in 95% of patients who received the combination; 8% of events were grade 1, 16% were grade 2, 58% were grade 3, and 11% were grade 4. The most common TRAEs included diarrhea (grade 1, 35%; grade 2, 9%, grade 3, 3%; grade 4, 0%), nausea (33%; 20%; 3%; 0%), vomiting (20%; 12%; <1%; 0%), increased alanine aminotransferase levels (15%; 13%; 11%; <1%), decreased appetite (15%; 9%, <1%; 0%), fatigue (14%; 11%; 4%; 0%), increased aspartate aminotransferase levels (13%; 8%; 13%; 1%), increase lipase (3%; 9%; 11%; 1%). Immune-related AEs occurred in 22% (grade 1, 4%; grade 2, 13%; grade 3, 3%; grade 4, 1%).

TRAEs led to dose reduction or interruption of adagrasib for 48% and 67% of patients, respectively. Most adagrasib dose reductions were because of grade 1 or 2 TRAEs and the most common TRAEs leading to these reductions were increased ALT levels (11%), increased AST levels (7%), nausea (7%), and increased lipase (5%). TRAEs resulted in discontinuation of adagrasib only or pembrolizumab only for 7% and 17% of patients, respectively. Forty-six percent of pembrolizumab discontinuations were because of grade 1 or 2 TRAEs. Seven percent of patients experienced TRAEs that led to discontinuation of both agents.

What’s Next?

“The ongoing phase 3 portion of KRYSTAL-7 is recruiting patients with advanced/metastatic KRAS G12C–mutated NSCLC and PD-L1 of 50% or higher to compare first-line adagrasib plus pembrolizumab vs pembrolizumab monotherapy [NCT04613596],” Garassino concluded.

Disclosures: Dr Garassino disclosed financial interests regarding the following pharmaceutical companies: AbbVie, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, F. Hoffman-La Roche, Gilead Sciences, IO Biotech, Janssen Pharmaceuticals, Lilly, Merck & Co, Mirati Therapeutics, Natera, Novocure, Nuvation Bio, Pfizer, Regeneron, Revolution Medicines, and Takeda Pharmaceuticals. She also disclosed financial interests regarding the following non-pharmaceutical companies: Aptitude Health, ASTRO, IASLC, IDEOlogy Health, Intellisphere Oncology Specialty Group, MJH Life Sciences, and OncoHost. She also disclosed grants received from AIRC, AIFA, Horizon 2020, and Italian MOH, and research fundings from TRANSCAN.

References

1. Garassino MC, Theelen WSME, Jänne PA, et al. First-line adagrasib (ADA) with pembrolizumab (PEMBRO) in patients with advanced/metastatic KRASG12C-mutated non-small cell lung cancer (NSCLC) and PD-L1 ≥ 50% from the phase 2 portion of KRYSTAL-7. Presented at: 2025 European Lung Cancer Congress; March 26-29, 2025; Paris, France. Abstract 5MO.
2. Garassino MC, Theelan WSME, Jotte R, et al. LBA65 KRYSTAL-7: Efficacy and safety of adagrasib with pembrolizumab in patients with treatment-naïve, advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Ann Oncol. 2023;34(suppl 2):S1309-S1310. doi:10.1016/j.annonc.2023.10.066