KRAS Mutations in Metastatic CRC Predict Survival Benefit of Chemo Combo

Codon-specific KRAS mutations are predictive of an overall survival (OS) benefit for metastatic colorectal cancer (mCRC) patients treated with trifluridine-tipiracil (FTD/TPI; Lonsurf), according to a genomics-based analysis.

After identifying biomarkers of resistance and validating the findings in a real-world dataset, researchers showed that patients with KRAS G12-mutant tumors in the phase III RECOURSE trial achieved no clinically relevant OS benefit from the chemotherapy combination, while patients with KRAS G13-mutant tumors achieved a 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 reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI," wrote Emile Voest, MD, PhD, of The Netherlands Cancer Institute in Amsterdam, and colleagues in Nature Medicine. "Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies."

"Given that KRAS testing is routinely performed in the molecular workup of all patients with CRC to guide treatment with EGFR-targeting agents, our findings can be readily adopted in the clinic," they added.

As previously reported, RECOURSE demonstrated an OS benefit and an acceptable safety profile with oral FTD/TPI in mCRC, with the combination going on to win approval as a third-line therapy in mCRC.

While treatment with FTD/TPI has resulted in durable responses in some patients, Voest and co-authors suggested the 1.8-month median survival improvement was modest, "highlighting the unmet need for patient selection."

To conduct their study, the group used whole-genome analysis of 37 patients with mCRC treated with FTD/TPI, and identified KRAS G12 mutations as a potential biomarker of resistance. They validated this using data from 960 patients with mCRC treated with FTD/TPI in 36 centers across Italy and the U.K., finding that KRAS G12 mutations were significantly associated with poor survival.

Based on these findings, they analyzed results from RECOURSE, which had assigned 800 heavily pretreated patients with mCRC to receive either 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 G13 mutations had an OS about half that.

As noted, no OS benefit was observed with FTD/TPI versus placebo in the subset 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). Median OS in the KRAS G13-mutant subset was 8.7 months with FTD/TPI versus 2.9 months with placebo.

"Our data demonstrate that KRAS G12 and KRAS G13 mutated mCRC are different clinical entities," the authors observed. "The former disease is characterized by better prognosis but shows no clinically relevant OS benefit of FTD/TPI treatment ... whereas the latter disease behaves aggressively when treated with placebo but can be more effectively managed with FTD/TPI treatment."

"These data caution against lumping together KRAS mutations at different codons in biomarker analyses and clinical trial designs because different biological and biochemical properties may be associated with different clinical outcomes," they stated.

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