Adagrasib, a covalent inhibitor of KRAS G12C, combined with cetuximab, showed activity in patients with metastatic colorectal cancer in the phase I/II KRYSTAL-1 trial, as presented during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2021 by Jared Weiss, MD, Associate Professor of Medicine, University of North Carolina–Chapel Hill.1
“Adagrasib is tolerable and has a manageable safety profile, both as monotherapy and combined with cetuximab,” Dr. Weiss said.
The combination produced confirmed responses in 39% of patients and disease control in 100%. Adagrasib plus cetuximab is being evaluated in the second-line setting in the phase III KRYSTAL-10 trial.
Jared Weiss, MD
KRAS G12C mutations occur in 3% to 4% of colorectal cancers, act as oncogenic drivers, and are a negative predictor of cetuximab efficacy. Adagrasib irreversibly and selectively binds KRAS G12C in its inactive, guanosine diphosphate—bound state. The drug was optimized for several properties, including a long half-life of about 24 hours, dose-dependent pharmacokinetics, and brain penetration, Dr. Weiss said.
“Maintaining continuous adagrasib exposure above a target threshold enables inhibition of KRAS-dependent signaling for the complete dosing interval and maximizes antitumor activity. Combining adagrasib with cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, may enhance the inhibition of KRAS-dependent signaling or overcome adaptive feedback to improve outcomes,” he explained.
The KRYSTAL-1 trial is a multicohort phase I/II trial evaluating adagrasib in patients with advanced solid tumors harboring KRAS G12C mutations and no available treatment options. Based on the study’s early results, the U.S. Food and Drug Administration granted adagrasib Breakthrough Therapy designation for patients with previously treated KRAS G12C–mutated non–small cell lung cancer.
In the KRYSTAL-1 trial, 78 patients with previously treated colorectal cancer received adagrasib at 600 mg twice daily as a monotherapy (n = 46) or in combination with cetuximab (n = 32). More than half the patients had received three or more prior lines of therapy; mutations in TP53 were found in 69%, and other mutations were identified in 15% to 20% of patients. Median follow-up was 8.9 months for the monotherapy cohort and 7.0 months for the combination group.
The response rate to single-agent adagrasib was 22% (including one unconfirmed partial response), with 87% of patients attaining disease control. The median duration of response was 4.2 months, and at the time of analysis, 40% of patients remained on treatment. Median progression-free survival was 5.6 months; at 6 months, 42% of patients were free from disease progression or death, Dr. Weiss reported.
Treatment beyond disease progression was permitted. Supportive maneuvers, such as radiotherapy or stereotactic radiosurgery for oligometastatic disease progression, were also permitted.
For 28 evaluable patients treated with the combination of adagrasib and cetuximab, the response rate was 43% (including two unconfirmed partial responses), and the disease control rate was 100%. After the data cutoff, one of two patients with unconfirmed responses achieved a confirmed response, and the other developed disease progression, yielding a confirmed response rate of 39%. The remainder had stable disease.
“At the time of analysis, 71% of patients remained on treatment; therefore, the data are … too immature for a meaningful analysis of duration of response or progression-free survival,” Dr. Weiss said.
For either regimen, an exploratory analysis found no apparent association between comutational status and response.
Adagrasib monotherapy and in combination with cetuximab was well tolerated in this study, with a manageable safety profile. Grade 3 or 4 treatment-related adverse events were observed in 30% of patients treated with the single agent (diarrhea in 7%) and in 16% treated with the combination (diarrhea in 3%).
Treatment-related adverse events led to treatment discontinuation in 6% of patients on combination therapy and in none receiving adagrasib as a single agent. No grade 5 toxicities were observed in either treatment arm.
DISCLOSURE: Dr. Weiss reported financial relationships with Nektar, Vesselon, Iovance, Nuvalent, Lyell ImmunoPharma, Achilles Therapeutics, AstraZeneca, EMD Serono, Genentech, G1 Therapeutics, Jounce Therapeutics, AbbVie, Nanobiotix, Azitra, Eli Lilly, Blueprint Medicines, Pfizer, Saatchi Wellness, Jazz Pharmaceuticals, Boehringer Ingelheim, Regeneron, Genmab, SDP Oncology, and BeiGene.
1. Weiss J, Yaeger R, Johnson ML, et al: KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or in combination with cetuximab in patients with colorectal cancer harboring a KRAS G12C mutation. ESMO Congress 2021. Abstract LBA6. Presented September 19, 2021.
“KRAS G12C inhibitors as monotherapy yield a relatively low overall response rate, but when you combine them with an EGFR [epidermal growth factor receptor] inhibitor, the response rate is nearly double,” said Federica Di Nicolantonio, MD, PhD, Professor of Oncology at the University of Turin in...