1. Froelich, Warren

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A three-drug combination has been shown to significantly prolong the lives of patients with advanced BRAF V600 melanoma, according to results of a multi-center phase III study presented during the recent AACR 2020 Virtual Annual Meeting. The novel therapy included two drugs that target mutated BRAF and MEK genes, while the third, an immune checkpoint inhibitor, was designed to unleash the body's immune system to attack and destroy cancer cells.


About 94,000 Americans are diagnosed with melanoma each year, with about 7,000 dying from the disease. About half of all melanoma patients have tumors driven by BRAF V600 mutations.


"The trial was positive which was great news," said Charles Sawyer, MD, Chair of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center in New York. "Triple therapy with immune checkpoint inhibitors and kinase inhibitors is superior to kinase inhibitors alone." Sawyer did not participate in the study but was asked by AACR to discuss the findings.


In recent years, melanoma treatment has progressed with the development of immune checkpoint inhibitors, as well as small molecule inhibitors targeted to BRAF and/or MEK proteins. Previous studies have found that treatment with any one of these drugs alone can dramatically shrink tumors in a small percentage of melanoma patients. But a large majority do not see any benefit, and for others the benefit even with two drugs has been short-lived.


As discussed during the meeting, the current study was built around the hypothesis that combining targeted kinase inhibitors with a checkpoint blockade might create a synergy between the two classes of drugs that could improve efficacy versus targeted therapy alone.


"Collectively, these data lead to the hypothesis that combining BRAF and MEK inhibitors with immune checkpoint inhibitors might overcome clinical limitations of individual classes of therapy and potentially lead to more durable responses," said Grant A. McArthur, MD, PhD, Executive Director of the Victorian Comprehensive Cancer Centre, and Lorenzo Galli Chair of Melanoma and Skin Cancers at the University of Melbourne, Australia, who presented the findings at AACR.


Sawyer noted that this hypothesis mirrors similar remarks about a dozen years ago from James P. Allison, Professor and Chair of the Department of Immunology at the MD Anderson Cancer Center. Allison won the 2018 Nobel Prize in Physiology or Medicine for pioneering cancer treatment that frees the immune system to attack tumors.


"The combination of kinase inhibitors and checkpoint inhibitors could be a fantastic idea because kinase inhibitors would liberate a gold mine of tumor antigens present in tumor cells such that the immune system could now see, if enabled by checkpoint inhibitor," Sawyer said, referring to Allison's earlier hypothesis.


The trial's results appeared to support the hypothesis. Median progression-free survival (PFS) for patients receiving the triplet of drugs-atezolizumab, an immune checkpoint inhibitor; and cobimetinib and vemurafenib, the targeted kinase inhibitors-was 15.1 months compared to 10.6 months with the two targeted drugs plus placebo.


Patients in both arms of the study experienced similar objective response rates, but median duration was longer with the triplet-21 months compared to 12.6 months with the targeted inhibitors plus placebo.


Overall survival was not mature at the time of analysis, but the early results tended to favor the triplet therapy.


"Atezolizumab combined with vemurafenib and cobinmetinib showed a statistically and clinically meaningful improvement in PFS that was investigator-assessed versus placebo plus vemurafenib and cobinmetinib," McArthur concluded.


Antoni Ribas, MD, PhD, Director of the Tumor Immunology Program at Jonsson Comprehensive Cancer Center at UCLA and Chair of the Melanoma Committee at the SWOG Cancer Research Network, added that the results support the notion that patients with BRAF mutations, slated to start a regimen of BRAF and MEK inhibitors, should instead receive the triplet as "the best new therapy."


"This is because the triple therapy markedly improves the duration of responses, suggesting that the addition of immune checkpoint blockade to targeted therapy achieves the goal of turning some of the short-term into long-term responses by enlisting an immune response to melanoma." Also President of AACR, Ribas did not participate in this study but was familiar with the findings.


As described during the meeting, the double-blind trial-called IMspire150-divided 514 previously untreated advanced melanoma patients with BRAF V600 mutations into two roughly equal arms.


The three drugs chosen for the trial were selected to provide a triple-front attack on tumor growth and spread. Cobimetinib is designed to target and inhibit MEK1/2, proteins in a cell signaling pathway that help cell growth and survival. Vemurafenib is designed to put a brake on mutated forms of BRAF, which cause abnormal signaling inside cancer cells leading to tumor growth.


Atezolizumab is an immune checkpoint inhibitor designed to bind to a protein called PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, allowing tumors to avoid detection by the immune system.


One arm received the triplet therapy, while the other received the two targeted inhibitors plus placebo. All patients were treated on days 1 through 28 of a 28-day cycle and were followed for a median of 18.9 months.


A key question revolved around potential debilitating side effects from the regimen. The incidence of treatment-related serious adverse events was similar in both trials-33.5 percent in the triplet arm and 28.8 percent with the placebo arm. Interestingly, 15.7 percent of the patients receiving the two targeted inhibitors and placebo stopped treatment due to adverse effects; some 12.6 percent of patients on triplet therapy stopped treatment. In all, 14 patients died from grade 5 toxicities, seven in the triplet arm and seven in the placebo arm.


The researchers concluded that "combination therapy with atezolizumab plus cobimetinib plus vemurafenib was tolerable and manageable, produced durable responses, and significantly increased PFS versus placebo plus cobimetinib plus vemurafenib.


"Thus, atezolizumab plus cobimetinib plus vemurafenib represents a viable treatment option for BRAFv600 mutation-positive advanced melanoma."


Though the results appeared to support the study's underlying hypothesis, Sawyer nevertheless wondered if the question has been answered or if another option might be considered.


"Another possible explanation, perhaps less scientifically appealing but equally plausible," Sawyer noted, "is a hypothesis of patient-to-patient variability which says the benefit of combination treatment is actually due to some patients responding better to drug A and some better to drug B, but there is no synergy or additivity between the two drugs."


Ribas added this study demonstrated "superiority of triple therapy with BRAF and MEK inhibitors with an anti-PD-L1 antibody over targeted therapy combination alone." However, he noted that many patients already are showing improvements when treated with PD-1 blockade therapy upfront, either alone or in combination with anti-CTLA-4 (cytotoxic T-lymphocyte associated protein 4), another checkpoint inhibitor.


"We don't know if triple therapy is a better choice or not (than other single or combinations of checkpoint drugs)," Ribas said. "With longer follow-up, if this trial demonstrates that triple therapy leads to a tail of the survival curve above 50 percent, it may be the best possible therapy."


Warren Froelich is a contributing writer.