Pembrolizumab Plus Adagrasib Demonstrates Preliminary Efficacy in KRAS G12C–Mutated NSCLC

Marina Garassino, MD

Concurrent adagrasib (Krazati) and pembrolizumab (Keytruda) generated early signals of efficacy in patients with treatment-naïve, advanced non–small cell lung cancer (NSCLC) harboring KRAS G12C mutations, particularly in those who had a PD-L1 tumor proportion score (TPS) of at least 50%, according to findings from the phase 2 KRYSTAL-7 trial (NCT04613596) presented at the 2023 ESMO Congress.^1,2

“With longer follow-up, concurrent adagrasib and [pembrolizumab] demonstrated encouraging preliminary activity in patients with PD-L1 greater than 50% and a manageable safety profile,” Marina Garassino, MD, professor of hematology and oncology at the University of Chicago in Illinois and one of the study’s investigators, said of the mid-stage data.

In patients with a PD-L1 TPS of at least 50%, adagrasib and pembrolizumab generated an overall response rate (ORR) of 63% (32/51; 95% CI, 48-76) and a disease control rate (DCR) of 84% (43/51; 95% CI, 12.6-not evaluable [NE]). The ORR seen with the combination compares favorably with the ORR of pembrolizumab, which ranges from 39% to 45% when used as a single agent.¹

Safety Considerations

The safety profile of the combination of adagrasib and pembrolizumab was consistent with the known safety profiles of either agent as a monotherapy. Among the 148 patients, treatment-related adverse events (TRAEs) led to permanent adagrasib discontinuation in 6% of patients (n = 9), and 11% (n = 16) of patients discontinued pembrolizumab because of TRAEs. Only 4% (n = 6) of patients discontinued both drugs because of TRAEs. Dose reductions due to TRAEs occurred in 46% (n = 66) of patients, and 59% (n = 88) temporarily discontinued treatment because of TRAEs.

Nausea and diarrhea were the most common TRAEs, occurring at any grade in 51 and 44 patients, respectively. Immune-related TRAEs of any grade occurred in 18% (n = 26) of patients, and immune-related TRAEs grade 3 or higher occurred in 5% (n = 8) of patients. There were 2 grade 5 TRAEs of pneumonitis and pneumonia.

Hepatic Safety

“Sotorasib has already shown a severe hepatotoxicity when combined in the first-line with immune checkpoint inhibitors in treatment of [patients with treatment-naïve NSCLC] and also when it was administered sequentially following a prior immune checkpoint inhibitor, in particular, within 30 days,” Garassino said in her presentation.

However, adagrasib does not share the same hepatotoxicity concerns, potentially because of its steady-state pharmacokinetics (PK) and low peak-to-trough ratio. The administration of adagrasib sequentially or in combination with pembrolizumab is not limited by hepatotoxicity.

In the KRYSTAL-7 trial, treatment-related hepatic events occurred in less than 10% of patients. Alanine transaminase (ALT) and aspartate transaminase (AST) increases were observed in 38 and 32 patients, respectively, but no patient discontinued both adagrasib and pembrolizumab because of an increase in ALT/AST or hepatic TRAEs.

Moreover, hepatic TRAEs, particularly ALT/AST increases, were resolved favorably. The median time to first resolution of increase ALT/AST was 22 days, and resolution occurred in about 80% of cases.

KRYSTAL-7 Trial

KRYSTAL-7’s phase 2 primary end point is ORR to establish the efficacy of adagrasib monotherapy and in combination with pembrolizumab administered to patients with advanced or metastatic NSCLC. The phase 2 secondary end points are safety, tolerability, duration of response (DoR), progression-free survival (PFS), and PK.

The trial consists of 3 cohorts. Cohort 1a includes patients with a PD-L1 TPS of less than 1% who received adagrasib 400 mg twice daily in combination with pembrolizumab. Cohort 1b had a PD-L1 TPS of less than 1% and received adagrasib monotherapy 600 mg twice daily. Cohort 2 had a PD-L1 TPS of at least 1% and received adagrasib 400 mg twice daily with pembrolizumab.

The median follow-up was 8.7 months for all patients and 10.1 months for patients with PD-L1 TPS of at least 50%. The median time to response was 1.4 months, and the median PFS was not reached (95% CI, 8.2-NE).

Patients were eligible for phase 2 if they had a histologically confirmed diagnosis of unresectable or metastatic NSCLC with a KRAS G12C mutation and any PD-L1 TPS.²

Future of KRYSTAL-7

“These findings support the initiation of a phase 3 trial evaluating concurrent adagrasib and [pembrolizumab] vs [pembrolizumab] in treatment naïve KRAS G12C,” Garassino said in her presentation.

The phase 3 KRYSTAL-7 trial plans to begin enrollment at the end of this year.³ The phase 3 primary end point is PFS, and the secondary end points are safety, tolerability, PK, health-related quality-of-life, overall survival, and DoR.

References

1. Garassino MC, Theelan WSME, Jotte R, et al. 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. Presented at: European Society for Medical Oncology Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA65.
2. Mirati presents late-breaking results evaluating the combination of adagrasib and pembrolizumab in first-line non–small cell lung cancer (NSCLC). News release. Mirati. October 17, 2023. Accessed October 20, 2023. https://tinyurl.com/msuznadj
3. Phase 2 trial of MRTX849 monotherapy and in combination with pembrolizumab and a phase 3 trial of adagrasib in combination in patients with a KRAS G12C mutation KRYSTAL-7. ClinicalTrials.gov. Updated October 10, 2023. Accessed October 20, 2023.https://www.clinicaltrials.gov/study/NCT04613596