data from the FRESCO-2 and MOUNTAINEER trial released at the 2022 ESMO Conference provide potential new treatment options for patients with previously treated metastatic colorectal cancer (mCRC). Among them, FRESCO-2 includes a broad patient population, while MOUNTAINEER only includes patients with positive HER2 amplification/overexpression.
MOUNTAINEER Research Reporter John H. Strickler, US
In the Phase III FRESCO-2 trial (LBA25), the median OS in the furquitinib group was 7.4 months compared to 4.8 months in the placebo group (hazard ratio [HR] 0.662; 95% CI 0.549-0.800; p0.001). Median progression-free survival (PFS) was 3.7 months and 1.8 months (HR 0.321; 95% CI 0.267~0.386; p0.001). Fuquintinib is well tolerated, and safety data are consistent with its established monotherapy profile.
Figure 1 The OS and PFS of furoquintinib are significantly better than placebo
This trial met its statistical endpoint, and was praised by Sebastian Stintzing, professor of Charité Universitatsmedizin, Berlin, Germany. The trial evaluated further treatment in patients with mCRC and was not related to the status of biomarker . "This study shows that the use of tyrosine kinase inhibitors is beneficial to mCRC, and OS has almost doubled, and I think this is the most important endpoint in this case, providing an important treatment option for these patients, and the toxic side effects are controllable." According to data from the FRESCO trial, furoquintinib has been approved by regulators in China for third-tier and above mCRC treatment, and will soon be approved by the U.S. FDA. "The biggest question now is whether we can use furoquintinib in combination with other approved drugs, such as standard chemotherapy or TAS-102 (trifluorouridine-tipyramidine) to try to further improve efficacy without increasing toxicity." New data provided by the
Phase II MOUNTAINEER study confirms the data shown in the preliminary analysis of the 2022 ESMO-World Gastrointestinal Cancer Conference, showing the activity and tolerance of tucatinib combined with trastuzumab in patients with previously treated HER2-positive mCRC (LBA27). Data presented at the 2022 ESMO Conference show that another cohort, cohort C (n=30), including patients who have received tucatinib monotherapy, can choose to cross-use tucatinib combined with trastuzumab at week 12 without response (cohorts A and B, previously described, received tucatinib plus trastuzumab). Tucatinib monotherapy and Tucatinib combined with trastuzumab were well tolerated after cross-treatment. The objective response rate (ORR) at week 12 of cohort C was 3.3% (95% CI 0.1-17.2%) and the disease control rate (DCR) was 80.0%. Most patients (28/30; 93.0%) had cross-tubaru treatment with trastuzumab, and the confirmed ORR was 17.9% (95% CI 6.1-36.9%).
Figure 2 MOUNTAINEER Study Design
Figure 3 MOUNTAINEER Study efficacy
Figure 4 MOUNTAINEER Study safety
In the HERACLES-A trial (Clin Colorectal Cancer. 2020;19:256–262.e2), trastuzumab combined with lapatinib has been shown to be active against HER2-positive mCRC, and the MOUNTAINEER trial now provides a new combination therapy for this subgroup of patients, accounting for approximately 5% of all mCRC patients (Ann Oncol. 2018;29:1108–1119). Accurate treatment is key to HER2-positive mCRC patients, with 80% of DCRs after 3 months indicating that these patients are very effective, and this combination seems to be more effective than tucatinib monotherapy. Although this is a Phase II study that recruits a small number of patients, the results are optimistic given the rareness of HER2 positive and provide support for HER2 testing in this case. According to experts, double blockade is a promising treatment and no new safety is proposed in the trial. However, further data are needed to determine which combination is most effective in individual patients, possibly trastuzumab-lapatinib, trastuzumab-tucatinib or trastuzumab and deruxtecan.
References
1, Dasari NA, et al. FRESCO-2: A global phase III multiregional clinical trial (MRCT) evaluating the efficiency and safety of fruquintinib in patients with refractory metastatic colorectal cancer. ESMO Congress 2022, LBA25
Proffered Paper Session 2 – GI, lower dietive, 12.09.2022, h. 10:15 – 11:45, Fécamp Auditorium
2, Strickler J, et al. Additional analysis of MOUNTAINEER: A phase II study of tucatinib and trastuzumab for HER2-positive mCRC. ESMO Congress 2022, LBA27
Mini Oral Session – GI, lower dietive, 12.09.2022, h. 14:45 – 15:55, Grenoble Auditorium
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