FDA review data confirms differences in tumor response rates by KRAS mutation
Improved overall patient survival… Phase 3 progress with G12D selective inhibitor combination
While Revolution Medicine's new drug for pancreatic cancer, daraxonelasib, was approved in the United States for its improved survival time, differences in tumor response by genetic mutation emerged as a new issue. Recently released U.S. Food and Drug Administration (FDA) review data showed relatively low response rates for some mutations, drawing attention to the treatment effectiveness for each patient group and the possibility of competition with follow-up drugs.
Revolution Medicine stock price fell 6.3% on the 8th (local time). American pharmaceutical media outlet Pierce Pharma reported on the 9th that the results of the KRAS G12D mutation patient group in the review data released by the FDA the previous day reflected investors' concerns that future competing drugs could affect Daraxonelasib's market position. However, according to the same report, analysts at Relink Partners and Jefferies evaluated the market reaction as excessive based on the survival effect.
Daraxonelasib is an oral targeted treatment that inhibits RAS protein, which is involved in cancer cell proliferation. On August 26, the FDA approved the product under the product name ‘Rasonque’ for use in adult patients with metastatic pancreatic adenocarcinoma who have previously received systemic treatment at least once or who are not suitable for systemic treatment using multiple drugs together. Approval was not limited to patients with specific RAS mutations.
The phase 3 clinical trial ‘RASolute 302’, which is the basis for approval, was conducted on 500 patients with metastatic pancreatic cancer whose disease had progressed after previous treatment. In the initial analysis, the median overall survival time was 13.2 months in the Daraxone Lasib group and 6.7 months in the chemotherapy group. Additional follow-up analysis as of June 15 included in the FDA review report also showed favorable results for the new drug group at 12.4 months and 6.8 months, respectively. The FDA assessed that the results of the additional analysis were generally consistent with the initial analysis.
What attracted attention this time was an exploratory analysis that looked at patients divided by genetic mutation. Among mutations in KRAS, a RAS family gene, G12D accounted for the largest proportion, approximately 43% of all clinical participants. In this patient group, the objective response rate, which is the percentage of patients whose tumors shrank beyond a certain standard, was 24% in the Daraxone Lasib group and 10% in the chemotherapy group. In G12V, they were 50% and 15%, and in G12R, they were 7% and 14%, respectively.
However, a distinction must be made between response rate, which measures tumor shrinkage, and overall survival, which evaluates how long the patient survived. In an exploratory analysis by mutation submitted by the company at the request of the FDA, the risk ratio of death for G12D patients was 0.49, and the risk of death in the Daraxone Lasib group was 51% lower than that in the chemotherapy group. The hazard ratio for death for G12V was 0.32, with a 68% lower risk of death. Although both patient groups showed survival results favorable to the new drug group, the difference in effect between variants cannot be considered confirmed based on subgroup estimates alone.
The G12R results require more careful interpretation. The risk ratio estimate for death was 0.61, which was in favor of the new drug group, but the 95% confidence interval was wide at 0.29 to 1.30 and included 1, meaning there was no difference between the two groups. In all clinical trials, there were only 61 G12R patients. Therefore, it is difficult to express that the improvement in survival has been confirmed in this patient group or to conclude that there is no treatment effect based on the low response rate alone.
Revolution Medicine is also directly involved in the G12D competition that the market is concerned about. Prior to the release of review data, on the 5th, the company announced the start of patient administration of 'RASolute 309', a phase 3 clinical trial that uses daraxonerasib in combination with its own G12D selective inhibitor candidate 'Zoldonrasib'. It is a strategy to improve treatment performance by adding drugs that target specific mutations to drugs that broadly inhibit multiple RAS mutations.
While existing monotherapy studies targeted patients whose disease progressed after previous treatment, RASolute 309 is conducted in the first-line treatment of metastatic G12D mutant pancreatic cancer. The subject of comparison is gemcitabine and nabpaclitaxel chemotherapy. The study confirms the effectiveness of the combination therapy and evaluates its safety, focusing on progression-free survival and overall survival. Whether combination therapy increases survival time compared to standard chemotherapy and the burden of side effects are expected to determine its role in future treatment.
