First combo trial of mTOR/BRAF inhibition shows potential

 

A combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the BRAF inhibitor vemurafenib appears safe for patients with advanced, BRAF-mutated, solid tumors that had progressed on BRAF and/or MEK therapy, investigators reported.

The combination provided partial responses in a variety of tumor types, and half of the patients achieved stable disease, reported Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center in Houston and his coauthors.

“Activation of alternative parallel signaling pathways such as the PI3K–mTOR pathway have been hypothesized to contribute to primary and acquired resistance to BRAF-targeted therapy,” the authors wrote in JCO Precision Oncology. Preclinical studies have supported this hypothesis, which led to the present study; it is the first to evaluate a combination of a BRAF inhibitor and an mTOR inhibitor.

The open-label, phase 1 trial included 20 patients with BRAF-mutated, advanced cancer that had progressed on BRAF and/or MEK therapy. Solid tumor types included melanoma (n = 7), glioma (n = 5), thyroid cancer (n = 4), appendiceal carcinoma (n = 1), colorectal cancer (n = 1), non–small cell lung cancer (NSCLC; n =1), and cancer of unknown primary (n = 1). More than half of the patients had already been treated with surgery, clinical trial therapy, radiation therapy, or chemotherapy. The median adult age was 64 years; two pediatric patients were aged 10 and 13 years.

Dose-escalation revealed a maximum-tolerated dose of everolimus 5 mg orally once a day and vemurafenib 720 mg orally twice a day. Across doses, the most common grade 3 adverse events were fatigue (20%) and rash (15%), followed distantly by anemia, thrombocytopenia, hyperglycemia, or hypertriglyceridemia, which occurred in one patient each.

 

Responses were evaluated in 18 patients. Of these, 22% had partial responses and 50% achieved stable disease. Partial responses occurred in patients with pleomorphic xanthoastrocytoma, optic nerve glioma, melanoma, and NSCLC.

“Our trial demonstrates that the combination of vemurafenib and everolimus can be tolerated in patients with advanced malignancies,” the authors concluded. “Our trial also demonstrates that the addition of an mTOR inhibitor to everolimus treatment is able to overcome resistance to BRAF and/or MEK inhibition in a subset of patients with BRAF-mutant advanced cancers.”

The authors reported affiliations with Baxter, Bayer, Novartis, Roche, Trovagene, and others.

SOURCE: Subbiah V et al. JCO Prec Oncol. 2018 Sep 13. doi: 10.1200/PO.18.00189.

 

A combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the BRAF inhibitor vemurafenib appears safe for patients with advanced, BRAF-mutated, solid tumors that had progressed on BRAF and/or MEK therapy, investigators reported.

The combination provided partial responses in a variety of tumor types, and half of the patients achieved stable disease, reported Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center in Houston and his coauthors.

“Activation of alternative parallel signaling pathways such as the PI3K–mTOR pathway have been hypothesized to contribute to primary and acquired resistance to BRAF-targeted therapy,” the authors wrote in JCO Precision Oncology. Preclinical studies have supported this hypothesis, which led to the present study; it is the first to evaluate a combination of a BRAF inhibitor and an mTOR inhibitor.

The open-label, phase 1 trial included 20 patients with BRAF-mutated, advanced cancer that had progressed on BRAF and/or MEK therapy. Solid tumor types included melanoma (n = 7), glioma (n = 5), thyroid cancer (n = 4), appendiceal carcinoma (n = 1), colorectal cancer (n = 1), non–small cell lung cancer (NSCLC; n =1), and cancer of unknown primary (n = 1). More than half of the patients had already been treated with surgery, clinical trial therapy, radiation therapy, or chemotherapy. The median adult age was 64 years; two pediatric patients were aged 10 and 13 years.

Dose-escalation revealed a maximum-tolerated dose of everolimus 5 mg orally once a day and vemurafenib 720 mg orally twice a day. Across doses, the most common grade 3 adverse events were fatigue (20%) and rash (15%), followed distantly by anemia, thrombocytopenia, hyperglycemia, or hypertriglyceridemia, which occurred in one patient each.

 

Responses were evaluated in 18 patients. Of these, 22% had partial responses and 50% achieved stable disease. Partial responses occurred in patients with pleomorphic xanthoastrocytoma, optic nerve glioma, melanoma, and NSCLC.

“Our trial demonstrates that the combination of vemurafenib and everolimus can be tolerated in patients with advanced malignancies,” the authors concluded. “Our trial also demonstrates that the addition of an mTOR inhibitor to everolimus treatment is able to overcome resistance to BRAF and/or MEK inhibition in a subset of patients with BRAF-mutant advanced cancers.”

The authors reported affiliations with Baxter, Bayer, Novartis, Roche, Trovagene, and others.

SOURCE: Subbiah V et al. JCO Prec Oncol. 2018 Sep 13. doi: 10.1200/PO.18.00189.

 

A combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the BRAF inhibitor vemurafenib appears safe for patients with advanced, BRAF-mutated, solid tumors that had progressed on BRAF and/or MEK therapy, investigators reported.

The combination provided partial responses in a variety of tumor types, and half of the patients achieved stable disease, reported Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center in Houston and his coauthors.

“Activation of alternative parallel signaling pathways such as the PI3K–mTOR pathway have been hypothesized to contribute to primary and acquired resistance to BRAF-targeted therapy,” the authors wrote in JCO Precision Oncology. Preclinical studies have supported this hypothesis, which led to the present study; it is the first to evaluate a combination of a BRAF inhibitor and an mTOR inhibitor.

The open-label, phase 1 trial included 20 patients with BRAF-mutated, advanced cancer that had progressed on BRAF and/or MEK therapy. Solid tumor types included melanoma (n = 7), glioma (n = 5), thyroid cancer (n = 4), appendiceal carcinoma (n = 1), colorectal cancer (n = 1), non–small cell lung cancer (NSCLC; n =1), and cancer of unknown primary (n = 1). More than half of the patients had already been treated with surgery, clinical trial therapy, radiation therapy, or chemotherapy. The median adult age was 64 years; two pediatric patients were aged 10 and 13 years.

Dose-escalation revealed a maximum-tolerated dose of everolimus 5 mg orally once a day and vemurafenib 720 mg orally twice a day. Across doses, the most common grade 3 adverse events were fatigue (20%) and rash (15%), followed distantly by anemia, thrombocytopenia, hyperglycemia, or hypertriglyceridemia, which occurred in one patient each.

 

Responses were evaluated in 18 patients. Of these, 22% had partial responses and 50% achieved stable disease. Partial responses occurred in patients with pleomorphic xanthoastrocytoma, optic nerve glioma, melanoma, and NSCLC.

“Our trial demonstrates that the combination of vemurafenib and everolimus can be tolerated in patients with advanced malignancies,” the authors concluded. “Our trial also demonstrates that the addition of an mTOR inhibitor to everolimus treatment is able to overcome resistance to BRAF and/or MEK inhibition in a subset of patients with BRAF-mutant advanced cancers.”

The authors reported affiliations with Baxter, Bayer, Novartis, Roche, Trovagene, and others.

SOURCE: Subbiah V et al. JCO Prec Oncol. 2018 Sep 13. doi: 10.1200/PO.18.00189.