specific codon KRAS The mutations predict an overall survival (OS) benefit for patients with metastatic colorectal cancer (mCRC) treated with trifluridine-tipiracil (FTD/TPI; Lonsurf), based on a genomics-based analysis.
After identifying resistance biomarkers and validating the findings in a real-world data set, the researchers demonstrated that patients with KRAS G12 mutant tumors in the phase III RECOURSE trial did not achieve any clinically relevant OS benefit with the chemotherapy combination, whereas patients with KRAS G13 mutant tumors achieved substantial benefit:
- KRAS G12 mutant: HR 0.96 (95% CI 0.71-1.29)
- KRAS G13 mutant: HR 0.34 (95% CI 0.17-0.67)
“These data show that KRAS G12 mutations are biomarkers for the reduced OS benefit of FTD/TPI treatment, with potential implications for the approximately 28% of mCRC patients under consideration for FTD/TPI treatment,” wrote Emile Voest, MD, PhD, from the Netherlands Cancer Institute in Amsterdam, and colleagues in natural medicine. “In addition, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.”
“Given the KRAS As tests are routinely performed in the molecular study of all CRC patients to guide treatment with EGFR-targeted agents, our findings can be readily adopted in the clinic,” they added.
As previously reported, RESOURCE demonstrated an OS benefit and an acceptable safety profile with oral FTD/TPI in mCRC, and the combination gained approval as a third-line therapy in mCRC.
Although treatment with FTD/TPI has resulted in durable responses in some patients, Voest and co-authors suggested that the median survival improvement of 1.8 months was modest, “highlighting the unmet need for patient selection.”
In conducting their study, the group used whole-genome analysis of 37 mCRC patients treated with FTD/TPI and identified KRAS G12 mutations as a potential resistance biomarker. They validated this using data from 960 mCRC patients treated with FTD/TPI at 36 centers in Italy and the UK, finding that KRAS G12 mutations were significantly associated with poor survival.
Based on these findings, they analyzed the results of RECOURSE, which had assigned 800 mCRC patients who had received intensive treatment to receive FTD/TPI or placebo in a 2:1 ratio.
Just over half of the trial population harbored KRAS mutations and codon-specific mutational status was available for 367 patients. Of these, 76% had KRAS G12 mutations, 16% KRAS G13 mutations, 5.7% had KRAS G12/G13 double mutations, and 1.9% had other mutations.
An analysis of OS in the placebo arm showed that patients with KRAS G12 and KRAS wild-type tumors had similar survival (5.8 and 5.7 months), while those with KRAS The G13 mutations had an OS of about half.
As noted, no OS benefit was observed with FTD/TPI versus placebo in the subgroup with KRAS G12 mutations. When patients with KRAS G12 mutations were excluded, FTD/TPI resulted in a pronounced OS benefit over placebo (adjusted 7.7 vs. 4.9 months; HR 0.57, 95% CI 0.46-0.70). middle OS in the KRAS The G13 mutant subset was 8.7 months on FTD/TPI vs. 2.9 months on placebo.
“Our data shows that KRAS G12 and KRAS G13-mutated mCRC are different clinical entities,” the authors observed. “The former disease is characterized by a better prognosis, but does not show a clinically relevant OS benefit of FTD/TPI treatment… while the latter disease behaves aggressively when treated with placebo, but can be managed more effectively with FTD/TPI treatment.”
“These data caution against bundling KRAS mutations at different codons in biomarker analyzes and clinical trial designs because different biological and biochemical properties may be associated with different clinical outcomes,” they stated.
Voest disclosed endorsements from Roche, Pfizer, GSK, Novartis, Merck, Bristol Myers Squibb, AstraZeneca, Amgen, Bayer, Sanofi, Seagen, Janssen, Eisai, Ipsen, and Lilly, as well as being a founder, strategic advisor, and shareholder of Mosaic Therapeutics, and independent non-executive director and shareholder of Sanofi.
The co-authors revealed multiple industry relationships.
Reference source: van de Haar J, et al “Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer” Nat Med 2023; DOI: 10.1038/s41591-023-02240-8.