BRAF v600E-mutant cancers treated with vemurafenib alone or in combination with everolimus, sorafenib, or crizotinib or with paclitaxel and carboplatin (VEM-PLUS) study

by Selleckchem | Sep 16 2023

Combined BRAF + MEK inhibition is FDA approved for BRAF V600E-mutant solid tumors except for colorectal cancer. However, beyond MAPK mediated resistance several other mechanisms of resistance such as activation of CRAF, ARAF, MET, P13K/AKT/mTOR pathway exist among other complex pathways. In the VEM-PLUS study, we performed a pooled analysis of four phase one studies evaluating the safety and efficacy of vemurafenib monotherapy and vemurafenib combined with targeted therapies (sorafenib, crizotinib, or everolimus) or carboplatin plus paclitaxel in advanced solid tumors harboring BRAF V600 mutations. When vemurafenib monotherapy was compared with the combination regimens, no significant differences in OS or PFS durations were noted, except for inferior OS in the vemurafenib and paclitaxel and carboplatin trial (P = 0.011; HR, 2.4; 95% CI, 1.22-4.7) and in crossover patients (P = 0.0025; HR, 2.089; 95% CI, 1.2-3.4). Patients naïve to prior BRAF inhibitors had statistically significantly improved OS at 12.6 months compared to 10.4 months in the BRAF therapy refractory group (P = 0.024; HR, 1.69; 95% CI 1.07-2.68). The median PFS was statistically significant between both groups, with 7 months in the BRAF therapy naïve group compared to 4.7 months in the BRAF therapy refractory group (P = 0.016; HR, 1.80; 95% CI 1.11-2.91). The confirmed ORR in the vemurafenib monotherapy trial (28%) was higher than that in the combination trials. Our findings suggest that, compared with vemurafenib monotherapy, combinations of vemurafenib with cytotoxic chemotherapy or with RAF- or mTOR-targeting agents do not significantly extend the OS or PFS of patients who have solid tumors with BRAF V600E mutations. Gaining a better understanding of the molecular mechanisms of BRAF inhibitor resistance, balancing toxicity and efficacy with novel trial designs are warranted.

Comments:

The passage you provided describes the results of the VEM-PLUS study, which aimed to evaluate the safety and efficacy of vemurafenib (a BRAF inhibitor) alone or in combination with other targeted therapies in patients with advanced solid tumors harboring BRAF V600 mutations.

The study found that when comparing vemurafenib monotherapy with combination regimens, there were no significant differences in overall survival (OS) or progression-free survival (PFS), except for inferior OS in the vemurafenib and paclitaxel plus carboplatin trial. Additionally, patients who were naive to prior BRAF inhibitors had statistically significant improved OS and PFS compared to those who were refractory to BRAF therapy.

The median PFS was longer in the BRAF therapy-naive group (7 months) compared to the BRAF therapy-refractory group (4.7 months), and the overall response rate (ORR) was higher in the vemurafenib monotherapy trial (28%) than in the combination trials.

These findings suggest that combinations of vemurafenib with cytotoxic chemotherapy or RAF- or mTOR-targeting agents do not significantly improve OS or PFS compared to vemurafenib monotherapy in patients with solid tumors harboring BRAF V600E mutations. The study highlights the importance of gaining a better understanding of the molecular mechanisms of BRAF inhibitor resistance and the need for novel trial designs that balance toxicity and efficacy.

It's important to note that this information is based on the provided passage, and additional studies or clinical trials may have been conducted since then. Therefore, it is always recommended to consult the latest research and consult with a healthcare professional for personalized medical advice.