Frontline Adagrasib Plus Pembrolizumab Elicits Encouraging Clinical Activity in KRAS G12C+ Advanced NSCLC


Concurrent adagrasib and pembrolizumab produced preliminary activity when administered as first-line treatment in patients with non–small cell lung cancer harboring a KRAS G12C mutation, irrespective of PD-L1 status, according to data from the KRYSTAL-1 phase 1b and the KRYSTAL-7 phase 2 cohorts.

Pasi A. Jänne, MD, PhD

Pasi A. Jänne, MD, PhD

Concurrent adagrasib (MRTX849) and pembrolizumab (Keytruda) produced preliminary activity when administered as first-line treatment in patients with non–small cell lung cancer harboring a KRAS G12C mutation, irrespective of PD-L1 status, according to data from the KRYSTAL-1 (NCT03785249) phase 1b and the KRYSTAL-7 (NCT04613596) phase 2 cohorts.1

Data presented at the 2022 ESMO Immuno-Oncology Annual Congress showed that at a median follow-up of 3.5 months, the doublet elicited an objective response rate (ORR) of 49% (95% CI, 35%-63%) among the 53 clinically evaluable patients on KRYSTAL-7 who received at least 1 on-study scan. Of those who responded to treatment, 2% experienced a complete response and 47% experienced a partial response. Forty percent of patients achieved stable disease, and 11% experienced disease progression. The disease control rate (DCR) reported in this population was 89% (95% CI, 77%-96%).

Clinical activity with the regimen was observed across all PD-L1 subgroups. Specifically, responses were experienced by 59% of those with a PD-L1 tumor proportion score (TPS) of 50% or higher (n = 13/36), 48% of those with a score of 1% to 49% (n = 10/28), and 30% of those with a score of less than 1% (n = 3/11).

Moreover, at a median follow-up of 19.3 months, adagrasib plus pembrolizumab induced an ORR of 57% in evaluable patients enrolled to the phase 1b cohort of KRYSTAL-1, with a DCR of 100%. Responses occurred in both patients with a PD-L1 TPS of at least 50%, 1 of the 4 patients with a PD-L1 TPS of 1% to 49%, and in the 1 patient who had a PD-L1 TPS of less than 1%. All 4 responders experienced a durable response that persisted for longer than 9 months; 2 of these patients were still receiving the regimen for longer than 18 months.

“Initial results across all cohort 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,” Pasi A. Jänne, MD, PhD, lead study author, senior physician, and director of the Lowe Center for Thoracic Oncology, the Belfer Center for Applied Cancer Science, and the Chen-Huang Center for EGFR Mutant Lung Cancers at the Dana-Farber Cancer Institute, Boston, MA, stated in a press release.2

Approximately 14% of patients with NSCLC (adenocarcinoma) have tumors that harbor a KRAS G12C mutation.3 Adagrasib, a KRAS G12C inhibitor, was designed to have a half-life of 23 hours, a dose-dependent pharmacokinetic (PK) profile, and the ability to penetrate the central nervous system (CNS).4,5

Prior data have demonstrated the activity of the agent in those with KRAS G12C–mutated solid tumors, including those with NSCLC and CNS metastases.5-9 In preclinical models, investigators have observed a boost in immune response when adagrasib was paired with a PD-1 inhibitor.10 Increased innate and adaptive immune responses have also been reported in patients who have received the KRAS G12C inhibitor.

The KRYSTAL-1 phase 1b and KRYSTAL-7 phase 2 cohorts included patients with KRAS G12C–mutated advanced, unresectable, or metastatic NSCLC who had not previously received systemic treatment for locally advanced or metastatic disease. Those with stable brain metastases were permitted.

In both studies, participants were given adagrasib at a twice-daily dose of 400 mg plus pembrolizumab at 200 mg every 3 weeks.

The primary end point of KRYSTAL-1 was safety, and secondary end points included ORR by RECIST v1.1 criteria, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). The KRYSTAL-7 phase 2 population included cohort 1a, those who had a PD-L1 TPS of less than 1%, and cohort 2, those with a PD-L1 TPS of 1% or higher. ORR by RECIST v1.1 criteria serves as the primary end point for KRYSTAL-7. Secondary end points comprise DOR, PFS, OS, safety, and PK.

Among the 75 patients enrolled to KRYSTAL-7, the median age was 66 years (range, 40-84); 51% of patients were female, 89% were White. Regarding ECOG performance status, 35% had a status of 0 and the remaining 65% had a status of 1. The majority (99%) were current or former smokers. Most patients had bone metastases at baseline (40%); 20% had liver metastases, 13% had adrenal metastases, and 12% had CNS metastases.

Additional data from this cohort showed that the median time to response to adagrasib plus pembrolizumab was 1.4 months. Of the 26 responders, 6 experienced a response after more than 2 months of treatment. Sixty-six percent of the 53 evaluable patients are still receiving the regimen, including in 24 patients with response.

Moreover, the doublet induced an ORR of 56% in a subset of response-evaluable patients who enrolled at least 6 months before the data cutoff date of August 30, 2022 (n = 14/25). Six of the 26 clinical responses happened at the time of the second on-study scan or later.

Regarding safety, 83% of the 75 patients in the KRYSTAL-7 cohort experienced an any-grade treatment-related adverse effect (TRAE); 15% had grade 1 TRAEs, 24% had grade 2 TRAEs, 40% had grade 3 TRAEs, and 4% had grade 4 TRAEs. No grade 5 TRAEs occurred.

The most common TRAEs experienced with the combination were nausea, diarrhea, vomiting, increased alanine (ALT) and aspartate (AST) aminotransferase, fatigue, decreased appetite, and increased amylase. The median time to onset for ALT and AST increase was 26 days and 37 days, respectively; only 1 patient reported new onset treatment-associated ALT/AST increase following 3 months.

Thirty-one percent and 41% of patients, respectively, experienced TRAEs that resulted in a dose reduction or interruption of adagrasib. Three percent of patients experienced TRAEs that led to discontinuation of both agents; 3% of patients experienced TRAEs that resulted in discontinuation of pembrolizumab alone.

“Based on these findings, phase 3 trials are planned in first-line NSCLC, evaluating concurrent adagrasib at 400 mg twice daily plus pembrolizumab vs standard of care by PD-L1 status,” Jänne, who is also a professor of medicine at Harvard Medical School, Boston, MA, concluded.


  1. Jänne PA, Smit EF, de Marinis F, et al. Preliminary safety and efficacy of adagrasib with pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Presented at: 2022 ESMO Immuno-Oncology Annual Meeting; December 7-9, 2022; Geneva, Switzerland. Presentation LBA4
  2. Mirati Therapeutics presents late-breaking results evaluating concurrent adagrasib and pembrolizumab in first-line advanced/metastatic non-small cell lung cancer (NSCLC). News release. Mirati Therapeutics, Inc. December 5, 2022. Accessed December 7, 2022.
  3. Nassar AH, Adib E, Kwiatkowski DJ. Distribution of KRASG12C somatic mutations across race, sex, and cancer type. N Engl J Med. 2021;384(2):185-187. doi:10.1056/NEJMc2030638
  4. Hallin J, Engstrom LD, Hargis L, et al. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 2020;10(1):54-71. doi:10.1158/2159-8290.CD-19-1167
  5. Ou S-HI, Jänne PA, Leal TA, et al. First-in-phase I/IB dose-finding study of adagrasib (MRTX849) in patients with advanced KRASG12Csolid tumors (KRYSTAL-1). J Clin Oncol. 2022;40(23):2530-2538. doi:10.1200/JCO.21.02752
  6. Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non-small-cell lung cancer harboring a KRASG12Cmutation. N Engl J Med. 2022;387(2):120-131. doi:10.1056/NEJMoa2204619
  7. Sabari JK, Spira AI, Heist RS, et al. Activity of adagrasib (MRTX849) in patients with KRASG12C-mutated NSCLC and active, untreated CNS metastases in the KRYSTAL-1 trial. J Clin Oncol. 2022;40(suppl 17):LBA9009. doi:10.1200/JCO.2022.40.17_suppl.LBA9009
  8. Klempner SJ, Weiss J, Pelster M, et al. LBA24 KRYSTAL-1: updated efficacy and safety of adagrasib (MRTX849) with or without cetuximab in patients with advanced colorectal cancer (CRC) harboring a KRASG12C mutation. Ann Oncol. 2022;33(suppl 7):S1391. doi:10.1016/j.annonc.2022.08.020
  9. Bekaii-Saab TS, Spira AI, Yaeger R, et al. KRYSTAL-1: updated activity and safety of adagrasib (MRTX849) in patients (pts) with unresectable or metastatic pancreatic cancer (PDAC) and other gastrointestinal (GI) tumors harboring a KRASG12C mutation. J Clin Oncol. 2022;40(suppl 4):519. doi:10.1200/JCO.2022.40.4_suppl.519
  10. Briere DM, Li S, Calinisan A, et al. The KRASG12C inhibitor MRTX849 reconditions the tumor immune microenvironment and sensitizes tumors to checkpoint inhibitor therapy. Mol Cancer Ther. 2021;20(6):975-985. doi:10.1158/1535-7163.MCT-20-0462
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