Combination superior to standard care for metastatic colorectal cancer
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Key takeaways:
- Sotorasib plus panitumumab extended PFS compared with standard care.
- Grade 3 or higher adverse events occurred less frequently with the combination.
MADRID — Sotorasib plus panitumumab prolonged PFS compared with standard of care for patients with chemorefractory KRAS G12C-mutated metastatic colorectal cancer, study results presented at ESMO Congress showed.
The combination also conferred benefit with regard to response rate, response duration and disease control, according to the findings, published simultaneously in The New England Journal of Medicine.
“In my opinion, [this trial establishes this regimen] as the new standard third-line therapy for KRAS G12C mutated metastatic colorectal cancer,” researcher Marwan Fakih, MD, medical oncologist and professor in the department of medical oncology and therapeutics research at City of Hope, told Healio. “The combination has also been shown previously to be safe when combined with FOLFIRI and has been associated with robust activity in this population. That data provides further rationale to moving sotorasib [and] panitumumab in combination with systemic chemotherapy in earlier lines of treatment.”
KRAS G12C mutations are present in 3% to 4% of metastatic colorectal cancers. Monotherapy with KRAS G12C inhibitors has demonstrated only modest benefit, according to study background.
Fakih and colleagues conducted the randomized phase 3 CodeBreaK 300 study to assess whether combining sotorasib (Lumakras, Amgen) — a KRAS G12C inhibitor — and panitumumab (Vectibix, Amgen), a fully human monoclonal anti-EGFR antibody, could improve outcomes.
The multicenter, open-label trial included 160 patients with chemorefractory metastatic colorectal cancer who had not received prior treatment with a KRAS G12C inhibitor.
Researchers randomly assigned 53 patients to sotorasib 960 mg daily plus panitumumab 6 mg/kg IV; 53 patients to sotorasib 240 mg daily plus panitumumab 6 mg/kg IV; and 54 patients to investigator’s choice of trifluridine–tipiracil (Lonsurf; Taiho Oncology, Servier) or regorafenib (Stivarga, Bayer).
PFS by blinded independent central review served as the primary endpoint. Key secondary endpoints included OS, objective response and disease control rate.
Median follow-up was 7.8 months (range, 0.1-13.9).
The study met its primary endpoint, as both sotorasib-panitumumab combinations conferred significant PFS improvement compared with standard of care (sotorasib 960 mg, HR = 0.49; 95% CI, 0.3-0.8; sotorasib 240 mg, HR = 0.58; 95% CI, 0.36-0.93).
“These results are highly meaningful and are more than double the PFS noted with other approved agents, such trifluridine/tipiracil and regorafenib,” Fakih said. “Keep in mind that in unselected patient populations with metastatic colorectal cancer, the median PFS on second-line treatments is approximately 6 months. To see a median PFS of 5.6 months in a poor-prognosis population with KRAS G12C is welcome news to our patients.”
OS data remained immature at data cutoff.
“The study was not powered for an OS endpoint and, hence, we should not be expecting to meet that endpoint,” Fakih told Healio. “Saying that, one can see that the OS are starting to separate in favor of sotorasib-panitumumab on the high-dose sotorasib arm. I do believe that the separation will become more meaningful as we continue to follow those patients.”
Researchers reported longer median PFS in both sotorasib-panitumumab groups (sotorasib 960 mg, 5.6 months; sotorasib 240 mg, 3.9 months; standard care, 2.2 months).
Results also showed higher ORRs (sotorasib 960 mg, 26.4%; sotorasib 240 mg, 5.7%; standard care, 0%) and a higher disease control rate (sotorasib 960 mg, 71.7%; sotorasib 240 mg, 67.9%; standard care, 46.3%) with the combination.
Median duration of response was 4.4 months in the sotorasib 960 group and not reached in in the sotorasib 240 mg group.
“Sotorasib plus panitumumab has an acceptable safety profile,” Fakih said. “Most of the side effects were related to panitumumab and were consistent with what we see with single agent panitimumab, such as rash and hypomagnesemia. Severe constitutional symptoms such as fatigue, gastrointestinal toxicities and bone marrow toxicities were rare.”
Grade 3 or higher treatment-related adverse events occurred among 35.8% of patients in the sotorasib 960 mg group, 30.2% of those in the sotorasib 240 mg group and 43.1% of those in the standard care group.
Grade 3 or higher treatment-related events reported among patients in the sotorasib 960 mg group included dermatitis acneiform (11.3%), hypomagnesemia (5.7%) and rash (5.7%). Grade 3 or higher treatment-related adverse events observed in the sotorasib 240 mg group included hypomagnesemia (7.5%) and diarrhea (5.7%).
In the standard care group, grade 3 or higher treatment-related adverse events included neutropenia (23.5%), anemia (5.9%) and hypertension (5.9%).
No fatal treatment-related adverse events occurred.
Perspective
Back to TopMiriam Koopman, MD, PhD
CodeBreaK 300 is the first randomized phase 3 study investigating the effect of combined KRAS G12C inhibition plus anti-EGFR therapy in pretreated metastatic colorectal cancer.
We have seen promising results with high percentages of tumor shrinkage from baseline, and a significant benefit in PFS among heavily pretreated patients.
The comparable results of the control arm of CodeBreaK 300 with previously published phase 3 studies with trifluridine–tipiracil and regorafenib support the validity of the results.
However, with trifluridine–tipiracil and bevacizumab (Avastin, Genentech) being the current late-line standard, we need comparison of sotorasib plus panitumumab vs. trifluridine–tipiracil plus bevacizumab for patients with KRAS G12C-mutated tumors.
The results on OS and quality of life will determine the use of sotorasib plus panitumumab in the standard-of-care last line for patients with KRAS G12C-mutated disease. If positive, this combination should only be used in patients meeting the eligibility criteria of CodeBreaK 300, and with only 3% of patients with performance status of 2, we need more data on this subset of patients.
Other studies in the first and second lines with RAS inhibitor plus anti-EGFR plus chemotherapy are ongoing. Moving to earlier lines of treatment with the combination of chemotherapy may add more benefit to our patients.
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Pietrantonio F, et al. Abstract LBA10. Presented at: European Society for Medical Oncology Congress; Oct. 20-24, 2023; Madrid.
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