Adagrasib/Cetuximab Combo Has Activity in KRAS G12C+ Locally Advanced or mCRC

The combination of adagrasib (Krazati) and cetuximab (Erbitux) showed encouraging efficacy and an acceptable safety profile in previously treated patients with KRAS G12C–mutated locally advanced or metastatic colorectal cancer (mCRC), according to pooled results of the phase 1/2 KRYSTAL-1 trial (NCT03785249) that were presented during the 2024 AACR Annual Meeting and simultaneously published in Cancer Discovery.^1,2

Data showed that the confirmed objective response rate (ORR) with the combination per blinded independent central review (BICR) was 34.0% and the disease control rate was 85.1%; the median duration of response (DOR) was 5.8 months.

“Adagrasib and cetuximab demonstrated clinically meaningful activity…in these patients, and the safety profile was consistent with what was previously known,” lead study author Scott Kopetz, MD, PhD, professor of gastrointestinal medical oncology and associate vice president of Translational Integration at The University of Texas MD Anderson Cancer Center, in Houston, said in a press briefing during the meeting. “These data support adagrasib and cetuximab as a new potential standard of care [SOC] for patients with previously treated metastatic KRAS G12C[–mutant] colorectal cancer and will hopefully support a new SOC in the regulatory environment.”

An estimated 3% to 4% of all CRC cases harbor KRAS G12C mutations, which are linked with poor prognostic outcomes.

Adagrasib is an irreversible KRAS G12C inhibitor that is designed to have a 23-hour half-life, dose-dependent pharmacokinetics, and central nervous system penetration. Prior results with the adagrasib monotherapy cohort in KRYSTAL-1 showed that the single agent elicited a 19% ORR and a 5.6-month median PFS.³ When combined with cetuximab in a phase 1 sub-study of KRYSTAL-1, clinical activity was observed.

The National Comprehensive Cancer Network’s Clinical Practice Guidelines in Oncology currently recommend adagrasib plus cetuximab or panitumumab (Vectibix) for use in patients with previously treated KRAS G12C–mutant CRC.

To be eligible for enrollment to the multiple expansion cohort phase 1/2 KRYSTAL-1 trial, patients must have had unresectable or metastatic KRAS G12C–mutated CRC and an ECOG performance status of 0 or 1. In both the phase 1 and 2 portions, patients must have had no available treatment with curative intent or refused/were ineligible for standard treatment. In the phase 2 portion, patients could have received prior fluoropyrimidine, irinotecan, oxaliplatin, and a VEGF/VEGFR inhibitor.

Patients were first treated with 600 mg of adagrasib twice daily plus cetuximab at 400 mg/m² followed by 250 mg/m² weekly or 500 mg/m² every 2 weeks (phase 1; n = 32). In the phase 2 portion, patients received adagrasib at 600 mg twice daily plus cetuximab at 500 mg/m² every 2 weeks.

The primary end points were safety and ORR by BICR per RECIST v1.1 criteria, and secondary end points in the phase 1/2 portions were DOR, PFS, and overall survival (OS), as well as safety in the phase 2 portion alone.

The data presented during the meeting includes findings of the combination from the phase 1 and 2 cohorts of KRYSTAL-1, with a data cutoff date of June 30, 2023, and a median follow-up of 11.9 months.

Regarding baseline characteristics of the 94 total patients, the median age was 57 years (range, 24-75) and slightly more than half of patients were female (53.2%). Most patients were White (71.3%), followed by Black or African American (13.8%), Asian (5.3%), or other (9.6%). Most patients were not Hispanic or Latino (79.8%) and 48.9% had an ECOG performance status of 1.

The median number of prior lines of therapy received was 3 (range, 1-9), with 8.5% of patients receiving 1 prior line of treatment, 36.2% receiving 2 lines, 30.9% receiving 3 lines, and 24.5% receiving 4 lines. All patients previously received fluoropyrimidine; other prior systemic therapies included oxaliplatin (98.9%), an anti-VEGF monoclonal antibody (95.7%), irinotecan (94.7%), trifluridine and tipiracil (TAS-102; Lonsurf; 11.7%), regorafenib (Stivarga; 8.5%), an anti-PD-1/PD-L1 agent (8.5%), or an anti-EGFR agent (3.2%). Most patients had lung metastases per BICR (71.3%); others had liver (63.8%), bone (13.8%), adrenal (2.1%), and brain (1.1%) metastases. A total 73.8% of patients had a concurrent TP53 mutation; 17.5% had a concurrent PIK3CA mutation, 2.5% had an EGFR amplification, and 1.3% had an NTRK fusion.

Further findings showed that the median PFS was 6.9 months (95% CI, 5.7-7.4) and the 6-month PFS rate was 57.7%. The median OS was 15.9 months (95% CI, 11.8-18.8) and the 6-month OS rate was 87.8%.

Regarding safety, all patients experienced any-grade treatment-related adverse effects (TRAEs) and most were grade 2 (63.8%). The most frequent TRAEs were nausea (any-grade, 60.6%; grade 3, 2.1%), vomiting (51.5%; 0%), diarrhea (48.9%; 1.1%), dermatitis acneiform (47.9%; 2.1%), fatigue (42.6%; 1.1%), dry skin (34.0%; 0%), hypomagnesemia (28.7%; 2.1%; grade 4, 1.1%), headache (26.6%; 3.2%), and rash (22.3%; 2.1%).

Dose reductions of adagrasib only due to TRAEs occurred in 29.8% of patients, and TRAEs led to dose reductions of cetuximab for 6.4% of patients. Adagrasib- and cetuximab-related dose interruptions were required in 36.2% and 35.1% of patients, respectively. Eight patients (8.5%) discontinued cetuximab due to TRAEs, and no patients had to discontinue adagrasib.

Kopetz noted that future research efforts will determine how and when this combination can best be used in this patient population, adding that the phase 3 KRYSTAL-10 trial (NCT04793958), which is randomizing patients with second-line KRAS G12C–mutant metastatic CRC to receive adagrasib/cetuximab or mFOLFOX6/FOLFIRI, has completed enrollment.

“More broadly, thinking about how we incorporate this [combination] in other lines and settings will be another area to explore,” Kopetz concluded.

In February 2024, the FDA accepted a supplemental new drug application for priority review regarding the approval of adagrasib plus cetuximab for this population, based on the KRYSTAL-1 findings.⁴ The agency has set an action date of June 21, 2024.

Editor’s Note: Dr Kopetz reported the following disclosures: ownership interests in Lutris Pharma, Iylon Precision Oncology, LLC, Frontier Medicines, Xilis Inc., and Navire Pharma; consulting roles with Genentech/Roche, EMD Serono Inc., Merck, Holy Stone Healthcare, Novartis, Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca/MedImmune, Bayer Health, Redx Pharma, Ipsen, HalioDx, Lutris Pharma, Jacobio Pharmaceuticals Group Co. Ltd., Pfizer, Repare Therapeutics, NeoGenomics Laboratories/Inivata, GSK, Jazz Pharmaceuticals, Iylon Precision Oncology, LLC, Xilis Inc., AbbVie, AMAL Therapeutics, Gilead Sciences, Mirati Therapeutics, Flame Biosciences, Servier Pharmaceuticals, Carina Biotech, Bicara Therapeutics, Endeavor BioMedicines, Numab Therapeutics AG, Johnson & Johnson/Janssen Pharmaceuticals, Genomic Health, Frontier Medicines, Replimune, Taiho Pharmaceutical, Cardiff Oncology, Ono Pharmaceutical, Co. Ltd., Bristol Myers Squibb/Medarex, Amgen, Tempus, Foundation Medicine, Harbinger Health, Takeda Pharmaceuticals, Cureteq AG, Zentalis Pharmaceuticals, Blackstone Therapeutics, Accademia Nazionale di Medicina, and Tachyon Therapeutics, Inc; and funding from Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono Inc., AstraZeneca/MedImmune, Novartis, Eli Lilly and Company, and Daiichi Sankyo.

References

1. Kopetz S, Uboha NV, Klempner SJ, et al. KRYSTAL-1: pooled phase 1/2 efficacy and safety of adagrasib (MRTX849) in combination with cetuximab in patients with metastatic colorectal cancer (CRC) harboring a KRASG12C mutation. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT013.
2. Yaeger R, Uboha NV, Pelster MS, et al. Efficacy and safety of adagrasib plus cetuximab in patients with KRASG12C-mutated metastatic colorectal cancer. Cancer Discov. Published April 8, 2024. doi:10.1158/2159-8290.CD-24-0217
3. Yaegar R, Weiss J, Pelster M, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Eng J Med. 2023;388(1):44-54. doi:10.1056/NEJMoa2212419
4. US Food and Drug Administration (FDA) accepts supplemental new drug application for Krazati (adagrasib) in combination with cetuximab as a targeted treatment option for patients with previously treated KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC) for priority review. News release. Bristol Meyers Squibb. February 20, 2024. Accessed April 8, 2024. https://news.bms.com/news/details/2024/U.S.-Food-and-Drug-Administration-FDA-Accepts-Supplemental-New-Drug-Application-for-KRAZATI-adagrasib-in-Combination-with-Cetuximab-as-a-Targeted-Treatment-Option