Melanoma: New Drugs and New Challenges (Part 2 of 2)


Editor’s note: This is part 2 of a 2-part post on the latest research in melanoma. To learn about research into drug combinations for melanoma that may work better than single drugs, check out Melanoma: New Drugs and New Challenges (Part 1 of 2).

As always, the more new treatments become available in melanoma, the more new challenges arise. With eight new drugs approved for melanoma in the last five years, oncologists may sometimes face the difficult choice of what drugs to choose for a patient’s first-line treatment. Immune checkpoint drugs sometimes cause serious side effects, but progress is being made on how to treat these and also how to treat patients with pre-existing autoimmune conditions. New approaches are needed in efforts to prevent recurrence of melanomas diagnosed at earlier stages of disease progression. These and other challenges are discussed below. Continue reading…


Melanoma: New Drugs and New Challenges (Part 1 of 2)


New targeted and immunotherapy drugs have changed the diagnosis of metastatic melanoma from a death sentence into a disease that can potentially be managed and even cured. Nevertheless, these new drugs do not work in all patients, or they may stop working after a transient response. This post (part one of two) will describe ongoing efforts to find drug combinations with higher efficacy than single drugs and decipher the mechanisms underlying drug resistance. Continue reading…


Oxnard Explains Role of BRAF in NSCLC

Excerpt:

“Geoffrey R. Oxnard, MD, specializes in researching molecular mutations in non–small cell lung cancer (NSCLC) with a particular emphasis on prognostic and predictive biomarkers. Oxnard, who is an assistant professor of Medicine at Harvard Medical School and a thoracic oncologist at the Dana-Farber Cancer Institute, spoke with Targeted Oncology about the potential for BRAF-targeting therapies in NSCLC.

“TARGETED ONCOLOGY: What is the potential for utilizing currently available BRAF/MEK-targeted therapies in treating patients with NSCLC?

“Oxnard: Combination BRAF/MEK inhibitor therapy is a very compelling approach because combinations of BRAF and MEK inhibitors have clearly been shown to improve response rates and overall survival in melanomas harboring BRAF V600E mutations when compared with single-agent BRAF inhibition.”

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Combining BRAF Inhibition, Anti-PD-1 No Help in BRAF-Mutant Melanoma

Excerpt:

“Patients with BRAF-mutant melanoma obtained no survival benefit from combined treatment of anti-BRAF therapy and an immune checkpoint inhibitor, a retrospective analysis showed.

“Median progression-free survival (PFS) was 6.0 to 6.5 months in BRAF-inhibitor naive patients who received a PD-1/PD-L1 inhibitor alone or with a BRAF inhibitor. Patients with prior exposure to a BRAF inhibitor had a median PFS of 8.0 months with anti–PD-1 therapy and 4.5 months with combined treatment. Median overall survival was 10.5 to 12 months with a PD-1/PD-L1 inhibitor alone or in combination with a BRAF inhibitor, regardless of prior BRAF inhibitor exposure status.

“ ‘BRAF inhibitor-refractory patients derived no additional benefit with anti-PD therapy in combination with BRAF inhibition,’ Wen-Jen Hwu, MD, of MD Anderson Cancer Center in Houston, and colleagues concluded in a poster presentation at the 2016 ASCO Annual Meeting in Chicago. ‘Clinical findings are similar with either anti-PD alone or in combination with BRAF inhibition in terms of objective response rate (ORR), disease control rate (DCR), and overall survival (OS).’ ”

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Distinct Features Associated With Benefit for BRAF/MEK Inhibition

Excerpt:

“With the development of novel targeted and immunotherapeutic agents that are more efficacious than traditional chemotherapy, treatment paradigms in melanoma have undergone major changes. Current recommendations for first-line systemic therapy for patients with advanced or metastatic melanoma consider BRAF mutation status, tumor growth rate, and the presence or absence of cancer-related symptoms.

“Immunotherapies with agents that block CTLA-4 or PD-1/PD-L1 checkpoints have been associated with durable responses in a subset of patients, and are often considered for patients with low-volume, asymptomatic metastatic melanoma. Targeted therapies, on the other side, are preferred for patients with BRAF-mutant tumors who have symptomatic disease and benefit from the rapid response associated with these agents.”

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Do you have questions about this story? Let us know in a comment below. If you’re wondering whether this story applies to your own cancer case or a loved one’s, we invite you to use our Ask Cancer Commons service.


Targeted Therapy Combinations Still Key in Metastatic Melanoma

“Combinations of targeted therapies continue to advance toward full regulatory approval for patients with metastatic or unresected melanoma, given the substantial benefits seen with these agents. At this time, the FDA is considering two applications for separate combinations of BRAF and MEK inhibiting agents for patients with unresectable or metastatic BRAFV600 mutation-positive melanoma.

“ ‘The future of the treatment of melanoma is clearly going to be in combinations, both for targeted therapy and for immunotherapy,’ said Jeffrey S. Weber, MD, PhD, who recently joined the NYU Langone Medical Center. ‘Already, there is an FDA-approved combination therapy that is targeted; that is dabrafenib and trametinib. There are new combinations coming up, mainly concerning CDK 4/6 and MEK inhibitors in NRAS-mutated but BRAF wild-type melanoma, which is an unmet medical need.’ “


Pembrolizumab Increases Progression-Free Survival vs Chemotherapy in Ipilimumab-Refractory Advanced Melanoma

“In a randomized phase II KEYNOTE-002 trial reported in The Lancet Oncology, Ribas et al found that treatment with the anti–PD-1 antibody pembrolizumab (Keytruda) prolonged progression-free survival vs investigator-choice chemotherapy in patients with advanced melanoma progressing on ipilimumab (Yervoy) and, if BRAF V600 mutant–positive, a BRAF or MEK inhibitor.

“The open-label trial included 540 patients from 12 countries with progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF V600 mutant–positive, previous treatment with a BRAF or MEK inhibitor or both. Patients were randomly assigned 1:1:1 between November 2012 and November 2013 to receive pembrolizumab 2 mg/kg (n = 180) or 10 mg/kg (n = 181) every 3 weeks or investigator-choice chemotherapy (n = 179, including 42 to paclitaxel plus carboplatin, 28 to paclitaxel, 13 to carboplatin, 45 to dacarbazine, and 43 to temozolomide)…

“The investigators concluded: ‘These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma.’ “


Cobimetinib and Vemurafenib Combination Treatment Is Highly Active in BRAF+ Melanoma

“Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced follow-up data from two studies of the investigational MEK inhibitor cobimetinib in combination with Zelboraf® (vemurafenib). Updated data from the pivotal coBRIM Phase III study showed the combination helped people with previously untreated BRAF V600 mutation-positive advanced melanoma live a median of one year (12.3 months) without their disease worsening or death (progression-free survival; PFS) compared to 7.2 months with Zelboraf alone (hazard ratio [HR]=0.58, 95 percent confidence interval [CI] 0.46-0.72).1

“ ‘The combination of cobimetinib and Zelboraf extended the time people lived without their disease getting worse to a year,’ said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. ‘These results are exciting because they underscore the importance of combining medicines that target the signals, which cause about half of all melanomas to grow.’ “


AstraZeneca-Novartis Three-Drug Melanoma Treatment Found Safe

“A first-of-its-kind combination of three drugs to treat a deadly form of skin cancer can be taken safely, passing the first hurdle to regulatory approval for a potentially long-lasting treatment.

“The treatment was tested in an early-stage trial that was a collaboration between AstraZeneca Plc and Novartis AG. Researchers combined two drugs, dabrafenib and trametinib — a so-called doublet therapy that has been proven effective in targeting melanomas with mutations in the BRAF gene — with an immune system-based treatment that may prevent the disease from relapsing.

“Dabrafenib, sold as Tafinlar, and trametinib, sold as Mekinist, were developed by GlaxoSmithKline Plc and acquired by Novartis in March. The immune therapy drug, MEDI4736, is being developed by AstraZeneca.

“Melanoma is a rare but deadly form of skin cancer for which a number of drugs have been approved in recent years. Among them are BRAF inhibitors like dabrafenib, which target mutations found in about half of all melanoma patients, as well as immune therapies like Bristol-Myers Squibb Co.’s Yervoy, which unleash the body’s own immune system. Because the immune system can be trained, those therapies may be more durable than other forms of treatment.”