FDA Approves Adagrasib With Cetuximab in KRAS G12C-Mutated CRC

• The combination of adagrasib (Krazati) with cetuximab (Erbitux) is now an FDA-approved treatment option for patients with previously treated locally advanced or metastatic colorectal cancer (CRC) with a KRAS G12C mutation.
• Adagrasib is a highly selective and potent oral small-molecule inhibitor of KRAS G12C.
• In the KRYSTAL-1 study (NCT03785249), the combination elicited encouraging clinical activity and had manageable safety profiles in this patient population.

The FDA has approved the combination of adagrasib with cetuximab for the treatment of patients with locally advanced or metastatic CRC harboring a KRAS G12C mutation who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.¹

This approval is supported by findings from the KRYSTAL-1 study where the combination showed encouraging clinical activity and manageable safety profiles for adagrasib and cetuximab in patients with metastatic CRC harboring a KRAS G12C mutation. The safety profiles of each drug were consistent with previous reports and the known safety profiles of each drug individually.

Most recently, results of the phase 1/2 KRYSTAL-1 trial presented during the 2024 American Association for Cancer Research Annual Meeting and simultaneously published in Cancer Discovery showed that the confirmed objective response rate (ORR) with the combination per blinded independent central review (BICR) was 34.0%.^2,3 These data come from patients in the phase 1 and 2 cohorts of KRYSTAL-1 treated with the combination, with a data cutoff date of June 30, 2023, and a median follow-up of 11.9 months. Moreover, the disease control rate was 85.1%, and the median duration of response (DOR) was 5.8 months.

The pooled phase 1 and 2 cohorts of the study showed that of the 94 total patients, the median age was 57 years (range, 24-75), 53.2% were female, and most patients were White (71.3%), followed by Black or African American (13.8%), Asian (5.3%), or other (9.6%). The majority of patients were not Hispanic or Latino (79.8%), and 48.9% had an ECOG performance status of 1.

Patients received a median number of 3 prior lines of therapy (range, 1-9), 8.5% received 1 prior line of treatment, 36.2% received 2 lines, 30.9% received 3 lines, and 24.5% received 4 lines. A concurrent TP53 mutation was seen in 73.8% of patients, a concurrent PIK3CA mutation in 17.5%, EGFR amplification in 2.5%, and an NTRK fusion in 1.3%.

Additional results from the study showed that the median progression-free survival (PFS) was 6.9 months (95% CI, 5.7-7.4) and the 6-month PFS rate was 57.7%, and the median overall survival (OS) was 15.9 months (95% CI, 11.8-18.8) with a 6-month OS rate of 87.8%.

For safety, 100% of patients experienced any-grade treatment-related adverse effects (TRAEs), most of which were grade 2 (63.8%). TRAEs which were most commonly seen included 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%).

In 2022, the combination of adagrasib and cetuximab was also granted a breakthrough therapy designation by the FDA for patients with KRAS G12C-mutated advanced CRC whose cancer progressed following prior treatment with chemotherapy and an anti-VEGF therapy. Then in February 2024, the FDA accepted a supplemental new drug application for priority review regarding the combination. Both regulatory decisions were based on findings from KRYSTAL-1.

About the KRYSTAL-1 Trial

Enrollment in the trial was open to patients with 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.

First, patients were treated with 600 mg of adagrasib twice per day 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 of the study, adagrasib was given at a dose of 600 mg twice daily plus cetuximab at 500 mg/m² every 2 weeks.

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

Previous findings were published in the New England Journal of Medicine.⁴ Here, adagrasib given with or without cetuximab led to antitumor activity in the heavily pretreated study population. Of the 28 evaluable patients, the ORR was 46% (95% CI, 28%-66%), and the median DOR was 7.6 months(95% CI, 5.7-not estimable). The median PFS with adagrasib was 6.9 months (95% CI, 5.4-8.1).

No synergistic adverse effects were observed with the combination, and of the patients treated with adagrasib alone, grade 3 or 4 TRAEs were seen in 34% of patients vs 16% of patients who received adagrasib plus cetuximab. Moreover, no grade 5 TRAEs were seen.

REFERENCES:

1. FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer. News release. FDA. June 21, 2024. Accessed June 21, 2024. https://tinyurl.com/3dezap8f

2. 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 KRAS G12C mutation. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT013.

3. Yaeger R, Uboha NV, Pelster MS, et al. Efficacy and safety of adagrasib plus cetuximab in patients with KRAS G12C-mutated metastatic colorectal cancer. Cancer Discov. Published April 8, 2024. doi:10.1158/2159-8290.CD-24-0217

4. Yaeger R, Weiss J, Pelster MS, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med. Published December 21, 2022. doi: 10.1056/NEJMoa2212419