Adagrasib Plus Pembrolizumab Shows Promising Efficacy in Certain Patients with Advanced NSCLC

Pasi A. Jänne, MD, PhD

The combination of adagrasib (MRTX849) with pembrolizumab (Keytruda) has shown a favorable safety and efficacy the first-line setting for patients with advanced non-small cell lung cancer (NSCLC) harboring a KRAS ^G12C mutation, according to preliminary results from multiple trials.¹

The preliminary results come from the KRYSTAL-7 (NCT04613596) phase 2 trial and the phase 1b cohort of the KRYSTAL-1 (NCT03785249) study, which demonstrated the feasibility of a concurrent combination of a KRAS ^G12C inhibitor and a PD-1/L1 checkpoint inhibitor in this patient population. Initially, in the KRYSTAL-1 cohort the 7 evaluable patients had an objective response rate (ORR) of 57% with a disease control rate (DCR) of 100%. Moreover, in 4 patients who responded they maintained their response over 9 months and 2 patients maintained a response over 18 months.

These initial results led to the larger phase 2 KRYSTAL-7 trial, but between the 2 trials this represents the largest dataset evaluating a KRAS ^G12C inhibitor in combination with a PD-L1 checkpoint inhibitor as a first-line treatment option for patients with NSCLC.

"Initial results across all cohorts suggest the concurrent combination of adagrasib and pembrolizumab may provide a chemotherapy-free option for treatment-naïve NSCLC with a manageable safety profile and encouraging clinical activity," said Pasi A. Jänne, MD, PhD, from the Dana Farber Cancer Institute, in a press release. "Across all evaluated cohorts, liver-related [treatment-related adverse events; TRAEs] were predominantly low grade and occurred early in treatment, with limited new onset after 3 months."

As of now, there are 75 patients enrolled and evaluable for safety in the KRYSTAL-7 trial, which estimates to have enrolled 250 patients through their primary completion date of October 2023.2 At a median follow up of 3.5 months, with a median duration of treatment at 2 months, no grade 5 treatment-related adverse events (TRAEs) were observed. However, 39% of patients had a grade 1-2 TRAE, 40% with a grade 3 TRAE, and 4% experienced a grade 4 TRAE.

Two patients had to discontinue adagrasib and pembrolizumab due to TRAE while 2 patients only discontinued pembrolizumab, but no patients discontinued adagrasib alone due to TRAEs.

Overall, AEs observed were consistent with AEs seen in the phase 1b portion of the trial. There was a total incidence of Grade 3 liver function tests increases were seen in 9% of patients.

Increases in alanine transaminase (ALT)/ aspartate transaminase (AST) observed were consistent with both agents as a monotherapy, according to the preliminary findings discussed in the press release. Median time from onset of ALT and AST to an increase in ALT and AST was 26 and 37 days, respectively, but just 1 patient experienced new onset treatment-related ALT/AST increases after 3 months of treatment.

Fifty-three patients were clinically evaluable, and one on-study scan showed an ORR of 49% across all PD-L1 subgroups of patients on the combination therapy. In a further subset of patients on response-evaluable patients enrolled 6 months before the data cutoff data, 6 of the 26 patients with clinical responses occurred on a second-study scan with an ORR of 56%.

"We look forward to progressing our clinical development in the first line setting with a goal of providing better options for patients with NSCLC harboring a KRAS ^G12C mutation," said Chuck Baum, president, founder, and head of research and development at Mirati Therapeutics, Inc, in the press release. "This data further underscores the potential of adagrasib as a well-tolerated treatment option for patients. Based on these data, we look forward to initiating a Phase 3 trial."

The preliminary data is set to be presented at the European Society of Medical Oncology Immuno-Oncology (ESMO IO) Congress 2022 with the potential for a further look from the FDA in this patient population.

_References

_{1. Mirati Therapeutics Presents Late-Breaking Results Evaluating Concurrent Adagrasib and Pembrolizumab in First-Line Advanced/Metastatic Non-Small Cell Lung Cancer (NSCLC). News release. December 5, 2022. Accessed: December 6, 2022. https://bit.ly/3uvlQ36}

_{2. Phase 2 Trial of MRTX849 Monotherapy and in Combination With Pembrolizumab for NSCLC With KRAS G12C Mutation KRYSTAL-7. November 3, 2020. Accessed: December 7, 2022. https://bit.ly/3VxGhIB}