Antitumor Activity Demonstrated With Cobimetinib/Vemurafenib Combo in Patients With BRAF Mutations

Antitumor activity was seen with combination of cobimetinib plus vemurafenib of in patients with BRAF mutations otherwise ineligible for treatment with other FDA-approved therapies.

Cobimetinib (Cotellic) in combination with vemurafenib (Zelboraf) demonstrated antitumor activity in patients with solid tumors who harbor a variety of BRAF mutations, according to findings from a cohort of the Targeted Agent and Profiling Utilization Registry (TAPUR; NCT02693535) trial which were presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

BRAF mutations occur commonly in melanoma and at low frequency in many other solid tumors,” Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics – the Phase I Program, medical director of the Institute for Personalized Cancer Therapy, and The Nellie B. Connally Chair in Breast Cancer at The University of Texas MD Anderson Cancer Center in Houston, said during a presentation of the data. “The objective response rate [ORR] of 57% [95% CI, 37%-76%] confirms that BRAF is a driver and cobimetinib and vemurafenib may be effective with a variety of different tumor types,” she added. “The toxicity report in this study is consistent with known side effects of this drug combination.”

Among 28 patients, the combination regimen demonstrated a disease control rate (DCR) of 68% (1-sided 90% CI, 54%-100%), including 2 complete responses, 1 each in BRAF V600E–mutant breast and ovarian cancer; 14 partial responses, comprised of 13 tumors with V600E mutations and 1 with a N581I mutation; and 3 occurrences of stable disease lasting at least 16 weeks, including 2 with V600E mutations and 1 with a T599V600 insertion mutation.

“I do want to highlight that on the waterfall plot, 2 patients who had clinical progression but no post-treatment tumor measurements were listed as having a 20% increase,” Meric-Bernstam said. “Further, a patient who had a treatment-related death was also listed as having a 20% increase. You can see several patients had deep regressions including tumors such as breast cancer, [gastrointestinal stromal tumor (GIST)], and neuroendocrine carcinoma.”

Of the 16 patients who had a complete or partial response, the duration of response (DOR) was 20.5 weeks (range, 8.0-189.9) with most responses occurring early, Meric-Bernstam said.

Among the 31 patients treated, median progression-free survival (PFS) was 5.8 months and median overall survival (OS) was 15.2 months.

Grade 3 adverse events (AEs) included rash in 4; 2 events each of anemia, hypokalemia, alkaline phosphatase, and aspartate aminotransferase increase; and 1 event each of alanine aminotransferase increase, creatine phosphokinase increase, diarrhea, gamma-glutamyl transferase (GGT) increase, hypophosphatemia, lymphocyte count decreased, multiple squamous cell carcinomas of the skin, platelet count decreased, and treatment-related secondary malignancy. Grade 4 GGT occurred in 1 patient.

Serious AEs consisted of 1 event of grade 1 fever; 1 each of grade 2 abdominal pain, constipation, and fatigue; 2 grade 3 acute kidney injury; 1 each of grade 3 bilirubin increase, diarrhea, nausea, rash, syncope, and upper gastrointestinal hemorrhage; and 2 grade 5 acute kidney injury.

“The TAPUR study provides additional supportive information in terms of targeting BRAF V600E mutations across cancers. And although the full safety data was not collected as part of the study, we’re pretty comfortable in terms of the safety profile of these drugs,” Philippe L. Bedard, MD, FRCPC, of University Health Network, said in a discussion of the presentation.

In the phase 2 basket trial, investigators are assessing the antitumor activity of commercially available targeted agents in patients with advanced cancers with genomic alterations. In her presentation, Meric-Bernstam discussed outcomes with the combination of cobimetinib plus vemurafenib in patients with a variety of tumors with BRAF mutations.

“The clinical activity of BRAF inhibitors were initially demonstrated in melanoma, but since that time, we’ve seen that there’s efficacy signal in several tumor types including lung cancer, anaplastic thyroid cancer, and cholangiocarcinoma,” Meric-Bernstam said. “Resistance to BRAF inhibitors can arise both due to MAP kinase reactivation and through MAP kinase independent signaling in melanoma. Combining BRAF and MEK inhibitors improves progression-free survival compared to BRAF inhibition alone.”

The nonrandomized TAPUR study includes 17 current treatments across more than 85 genomic targets in any advanced and/or metastatic solid tumors if there is no FDA-approved indication for that disease.

Thirty-one patients received 60 mg oral cobimetinib daily for a 21-days-on, 7-days-off schedule plus 960 mg oral vemurafenib every 12 hours daily. The regimen was administered until disease progression, unacceptable toxicity, or patient withdrawal.

DCR served as the study’s primary end point. Secondary end points included ORR, PFS, OS, DOR, and occurrence of grade 3 or greater AEs or serious AEs possibly related to study treatment.

Patients were included in the trial if they had advanced solid tumors; an ECOG performance score of 0 to 2; adequate organ function; measurable disease in accordance with RECIST v1.1; genomic testing performed in a CLIA-certified, CAP-accredited laboratory; and a BRAF V600E/D/K/R mutation or other BRAF mutation approved by the trial’s Molecular Tumor Board. Those with MAP2K1/2, MEK1/2, or NRAS mutations and those with prior treatment on a BRAF or MEK inhibitor were ineligible for the study.

Primary tumor origins included ovary (n = 6), neuroendocrine carcinoma (n = 5), breast (n = 4), pancreas (n = 3), cholangiocarcinoma (n = 2), and non-small cell lung cancer (n = 2), as well as angiosarcoma, colon, GIST, hepatocellular carcinoma, malignant neoplasm with site unspecified, melanoma, malignant phyllode tumor of the breast, prostate, and soft tissue sarcoma (n = 1 each).

Median age was 63 years (range, 31-79). The majority of patients were women (65%) and White (87%) and had an ECOG performance score of 0 to 1 (87%), 3 or more lines of prior systemic therapy (52%), and BRAF V600E mutations.

“I do want to highlight that our understanding of BRAF mutation sites have evolved over the last several years. We now think of BRAF mutations as being in 3 classes,” Meric-Bernstam explained. “I highlight this because now we think these mutations, based on preclinical data, would not be sensitive to vemurafenib, but maybe sensitive to MEK signaling inhibition.”

Reference
Meric-Bernstam D, Rothe M, Garrett-Mayer E, et al. Cobimetinib plus vemurafenib (C+V) in patients (Pts) with solid tumors with BRAF V600E/d/k/R mutation: Results from the targeted agent and profiling utilization registry (TAPUR) study. J Clin Oncol. 2022;40(suppl 16):3008. doi:10.1200/JCO.2022.40.16_suppl.3008