Adagrasib Added to Pembrolizumab Safely, Effectively Treats Advanced NSCLC in Phase 2 KRYSTAL-7 Trial

Pembrolizumab monotherapy is a standard of care for patients with treatment-naïve advanced non–small cell lung cancer (NSCLC), but there is currently an unmet need for optimized combinations that increase response rates and durability.

Marina Garassino, MD, PhD

Image credit: University of Chicago

The results of the KRYSTAL-7 phase 2 trial found adding adagrasib to pembrolizumab in patients with advanced, unresectable, or metastatic NSCLC with KRASG12C mutation showed “encouraging preliminary activity” especially in patients with high PD-L1 expression (Tumor Proportion Score [TPS] ≥ 50%), explained Marina Chiara Garassino, MD, professor of medicine at the University of Chicago.

Garassino presented safety and efficacy results for KRYSTAL-7 during ESMO Congress 2023, held virtually and in Madrid, Spain, October 20-24, 2023. The study was assessing whether a KRASG12C inhibitor could be combined with an immune checkpoint inhibitor, and specifically if adagrasib could safely and effectively be combined with pembrolizumab.

Adagrasib was chosen for some of its favorable properties, she explained, such as its long half-life and dose-dependent pharmacokinetics, its central nervous system penetration, and its non-covalent binding affinity and minimized cysteine reactivity. The mechanism of action binding to GDP-bound KRASG12C and locking it in an off state is believed to be the reason “there is less off-target toxicity and less liver toxicity,” Garassino explained.

The study included 2 cohorts: Cohort 1a had patients with PD-L1 expression of less than 1%, while Cohort 2 had patients with PD-L1 expression of 1% or greater. All of the patients were treatment naïve and had the KRASG12C mutation. She reported on safety for all 148 patients treated, as well as efficacy in the 51 patients in Cohort 2 who had high PD-L1 expression (PD-L1 TPS ≥ 50%). The median follow-up for all patients was 8.7 months and for those with high PD-L1 expression was 10.1 months.

In the patients with high PD-L1 expression, the confirmed objective response rate (ORR) was 63% (95% CI, 48%-76%) and the disease control rate was 84% (95% CI, 71%-93%). The response to treatment was very quick, according to Garassino, with a median time to response of 1.4 months. The median duration of response was not reached (95% CI, 12.6-NE). Median progression-free survival was also not reached (95% CI, 8.2-NE) at the median follow-up of 10.1 months.

The most common treatment-related adverse events (TRAEs) were nausea and diarrhea (any grade 51% and 44%, respectively). There were 2 grade 5 TRAEs: pneumonitis and pneumonia. TRAEs led to dose reduction of adagrasib in 46% of patients, temporary dose interruption in 59% of patients, and permanent discontinuation in 6%. TRAEs led to permanent discontinuation of pembrolizumab in 11% of patients, while 4% discontinued both drugs.

Looking specifically at liver TRAEs, 16% of patients had grade ≥ 3 treatment-related alanine aminotransferase (ALT) and raised aspartate aminotransferase (AST) increase. This is notable because for sotorasib, 27% to 37% of patients had severe grade ≥ 3 treatment-related ALT/AST increase when the KRAS inhibitor was given in sequence or concurrently with a PD-L1 inhibitor, explained Fiona Blackhall, MD, PhD, of University of Manchester, during a discussion after the trial results presentation.

“There appears to be a reduced risk of hepatotoxicity and [it’s] possible to administer this combination, for sure, but the risk is still present,” Blackhall said. She added that there is a debate of whether the risk of hepatotoxicity is a class effect or drug effect, and she believes it is a class effect. “So, there are implications for guidelines and management moving forwards, but also potentially for other KRAS inhibitors in development.”