Adagrasib in combination with cetuximab did not significantly improve OS or PFS in KRAS G12C–mutated metastatic colorectal cancer.
Adagrasib (Krazati) plus cetuximab (Erbitux) did not meet either of the dual primary end points of overall survival (OS) or progression-free survival (PFS) vs chemotherapy in patients with KRAS G12C–mutated metastatic colorectal cancer (CRC) who experienced disease progression on first-line fluoropyrimidine-based therapy, according to results from the final analysis of the phase 3 KRYSTAL-10 trial (NCT02872116) presented during the
At a minimum follow-up of 26.4 months, the median OS was 21.6 months (95% CI, 18.4-25.5) with adagrasib plus cetuximab (n = 231) vs 21.7 months (95% CI, 18.0-24.8) with chemotherapy (n = 230; HR, 0.83; 95% CI, 0.67-1.03; P = .0938). The 12-, 30-, and 36-month OS rates in the adagrasib arm were 73.4%, 38.0%, and 27.1%, respectively. These respective rates were 70.1%, 27.3%, and 22.5% in the chemotherapy arm.
At a minimum follow-up of 16.4 months, the median PFS was 7.5 months (95% CI, 6.3-9.2) in the investigational arm vs 8.1 months in the chemotherapy arm (95% CI, 7.3-9.2; HR, 0.89; 95% CI, 0.71-1.13; P = .3241). The 12-month PFS rates were 30.2% and 24.4%, respectively; the respective 18-month PFS rates were 20.0% and 15.4%.
“The combination of adagrasib plus cetuximab did not result in a statistically significant in PFS or OS vs chemotherapy in patients with metastatic CRC [with] a KRAS G12C mutation in the second-line setting,” Josep Tabernero, MD, PhD, said during the presentation.
Tabernero is the head of the Medical Oncology Department at the Vall d’Hebron Barcelona Hospital Campus, the director of the Vall d’Hebron Institute of Oncology (VHIO), and the codirector of VHIO’s Gastrointestinal and Endocrine Tumours Group and the Research Unit for Molecular Therapy of Cancer, in Spain.
KRYSTAL-10 was a global, randomized, open-label trial that enrolled 461 patients with histologically confirmed metastatic CRC with a confirmed KRAS G12C mutation.1,2 Patients were also required to have experienced disease progression on a first-line fluoropyrimidine-based oxaliplatin- or irinotecan-containing regimen and an ECOG performance status of 0 or 1.
Patients were randomly assigned 1:1 to receive adagrasib at 600 mg twice daily plus cetuximab at 500 mg/m2 every 2 weeks or investigator's choice of FOLFIRI or modified FOLFOX, with or without a VEGF/VEGFR inhibitor.1 Patients were stratified by region (US/Canada vs other) and time to progression after starting first-line treatment (< 6 vs ≥ 6 months).
OS and PFS by blinded independent central review served as dual primary end points. Overall response rate (ORR), duration of response (DOR), 1-year OS rate, and safety represented key secondary end points.
Baseline characteristics were generally balanced between arms. The median age was 60 (range, 27-95) and 60 years (range, 24-91) in the investigational and control arms, respectively. Most patients in both arms had an ECOG performance status of 0 (51% vs 53%), primarily left-sided tumors (63% vs 58%), received 1 prior line of therapy (89% vs 85%), and received prior fluoropyrimidine (99% vs 99%).
The ORR favored the adagrasib combination at 47% (95% CI, 40%-53%) vs 16% (95% CI, 11%-21%) with chemotherapy, including complete response rates of 7% vs less than 1%. The difference in response rates was 31% (95% CI, 23%-39%). The median DOR was 9.2 months (95% CI, 7.4-11.1) in the adagrasib arm vs 9.4 months (95% CI, 5.6-11.8) in the chemotherapy arm.
Patient disposition data showed that a higher proportion of patients in the chemotherapy arm went on to receive a subsequent KRAS G12C inhibitor compared with those in the adagrasib plus cetuximab arm (30% vs 4%). Patients in the adagrasib and chemotherapy arms discontinued treatment due to disease progression (71% vs 57%), adverse effects (AEs; 5% vs 4%), global deterioration of health (5% vs 9%), death (2% vs 2%), and other reasons (4% vs 7%).
Any-grade treatment-related treatment-emergent AEs (TEAEs) occurred in 98% of patients treated with adagrasib plus cetuximab and 96% of those who received chemotherapy; grade 3 to 5 treatment-related TEAEs were reported in 46% and 55% of patients, respectively. Serious treatment-related TEAEs occurred in 9% and 12% of patients, respectively and treatment-related TEAEs leading to treatment discontinuation occurred in 3% and 2% of patients, respectively. One treatment-related death, due to sepsis, occurred in the chemotherapy arm.
The most common any-grade treatment-related TEAEs with adagrasib plus cetuximab included diarrhea (64%), nausea (45%), dermatitis acneiform (42%), vomiting (31%), rash (30%), dry skin (26%), increased aspartate aminotransferase levels (22%), and increased alanine aminotransferase levels (21%). In the chemotherapy arm, hematologic toxicities were more frequent, including decreased neutrophil count (any grade, 36%; grade 3-5, 20%) and neutropenia (23%; 16%).
“The safety [profile] of adagrasib plus cetuximab was manageable and there were no new [safety] signals observed,” Taberneo said. “While KRYSTAL-10 did not meet its primary end points, these results support the clinical activity of the combination of adagrasib plus cetuximab previously treated patients with KRAS G12C-mutated metastatic CRC.”
Disclosures: Taberneo holds consultancy or advisory roles with Accent Therapeutics, Alentis Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Carina Biotech, Cartography Biosciences, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche, Genentech, Ipsen Innovation SAS, Johnson & Johnson/Janssen, Kayak Therapeutics, Larkspur Biosciences, Lilly, Marengo Therapeutics, Menarini, Merus, MSD, Novartis, One-carbon Therapeutics, Ono Pharma USA, Peptomyc, Pfizer, Pierre Fabre, Quantro Therapeutics, Scandion Oncology, Scorpion Therapeutics, Servier, Sotio Biotech, Syntelios AG, Taiho, Takeda Oncology, Theriva Biologics, and Tolremo Therapeutics. He also holds stock ownership in Adualys Therapeutics AG, Alentis Therapeutics, Oniria Therapeutics, 1TRIALSP, and Pangaea Oncology.
