“Patients with advanced or metastatic melanoma have been able to live longer cancer-free lives because of several new therapies approved over the last decade, such as BRAF and MEK inhibitors. However, despite the success of these targeted agents, most patients eventually develop drug resistance and their cancer regrows. A team of researchers at Moffitt Cancer Center have been working to learn more about how melanoma becomes resistant to BRAF inhibitors in order to develop new treatment strategies. They tested whether a drug targeting heat shock protein 90 (HSP90) combined with the BRAF inhibitor vemurafenib could be a safe and potentially effective strategy to treat patients with melanoma. Their study was published online ahead of print in Clinical Cancer Research.”
“In the international phase III BRIM8 trial reported in The Lancet Oncology, Maio et al found inconclusive evidence of benefit of adjuvant vemurafenib treatment in patients with BRAF V600–mutant melanoma.”
“Vemurafenib offered numerical improvement in disease-free survival in a study of patients with completely resected stage IIC to IIIC BRAF V600 mutation–positive melanoma, but the results did not reach statistical significance. The benefit was bigger in those with stage IIC to IIIB disease, but this should be considered exploratory at this point.
” ‘Despite full resection, patients with stage IIC to III melanoma remain at high risk for disease recurrence and death,’ wrote study authors led by Michele Maio, MD, of University Hospital of Siena in Italy. ‘This situation warrants the use of adjuvant approaches to improve clinical outcomes.’ ”
By 2050, the number of deaths due to malignant melanoma in the U.S. could be three times lower than peak levels reached before 1960. Researchers presented the data behind this prediction at the 2017 European Cancer Congress in January.
It is unclear how much of this anticipated decline in deaths can be attributed to the availability of new, effective treatments. However, it is obvious that much-increased awareness of sunlight exposure as the single factor most responsible for the development of skin melanoma has contributed to lower incidence of the disease.
In any case, the armament of treatments available for metastatic melanoma is currently such that this diagnosis has transformed from being almost universally fatal (even just a few years ago) into a being largely treatable. Since 2011, the U.S. Food and Drug Administration (FDA) has approved eight new drugs for melanoma. Continue reading…
In spring of 2014, Peter Fortenbaugh noticed what appeared to be a tick that had bitten his lower calf. “It turned out not to be a tick, but it didn’t really go away,” he says.
The spot began to grow and bulge, and in October, Peter showed it to his primary care doctor, who referred him to a dermatologist to remove it. At the time, Peter recalls, it did not occur to him that the growth could be serious.
“I was actually very concerned about skin cancer because I spent a lot of time out in the sun sailing,” Peter says. “I put on a tremendous amount of sunscreen and protection, but never on my legs…I never connected the dots.”
However, a biopsy of the growth came back positive for melanoma. Peter, who lives in Palo Alto, California, with his wife and three children, immediately reached out to several doctors in the San Francisco Bay Area, and all had the same advice: “Take it out, take a biopsy.” Continue reading…
“The phase 3 COLUMBUS trial, designed to evaluate binimetinib plus encorafenib for the treatment of BRAF–mutant melanoma, met its primary endpoint of improving PFS over vemurafenib, according to the drug’s manufacturer.
“These results also were presented at the Society for Melanoma Research Congress in Boston.
“In part 1 of the trial, researchers randomly assigned 577 patients with locally advanced, unresectable or metastatic melanoma with BRAF V600mutations to receive 45 mg binimetinib (MEK162, Array BioPharma) plus 450 mg of encorafenib (LGX818, Array BioPharma), 300 mg encorafenib monotherapy or 960 mg vemurafenib (Zelboraf, Genentech) monotherapy.”
“The addition of the PD-L1 inhibitor atezolizumab (Tecentriq) to the MEK inhibitor cobimetinib (Cotellic) and the BRAF inhibitor vemurafenib (Zelboraf) induced a high response rate for patients with BRAF-mutant unresectable melanoma, according to findings from a phase Ib study presented at the 2016 Society for Melanoma Research Annual Meeting.
“At the data cutoff of June 15, 2016, 30 patients had received ≥1 dose of atezolizumab. The response rate with the triplet was 83%, which included 3 complete responses (10%) and 21 partial responses. Overall, 29 of the 30 patients were evaluable for response, with just 1 patient experiencing primary progressive disease. At the time of the analysis, median duration of response and progression-free survival were not yet reached.”
“Combination therapy with cobimetinib (Cotellic) and vemurafenib (Zelboraf) reduced the risk of death by 30% compared with vemurafenib alone in patients with BRAF-positive advanced melanoma, according to the final survival analysis of the phase III coBRIM study that has now been published in The Lancet Oncology.
“The targeted combination improved median overall survival (OS) by 4.9 months versus single-agent vemurafenib (HR, 0.70; 95% CI, 0.55-0.90; P = .005). The OS rates for the combination at 1 and 2 years were 74.5% and 48.3%, respectively.
“ ‘Melanoma is one of the few cancers that has increased in incidence over the past 30 years, and until recently, people with advanced forms of the disease have had few treatment options. Five years ago, the survival of people with advanced melanoma was measured in months, and now we have medicines that are helping people live years,’ Josina Reddy, MD, PhD, senior group medical director at Genentech, the company that manufactures the combination, said in an interview with OncLive.”
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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…