It has been over a year since I last wrote about new developments in treatment of melanoma, and it is time for an update. There is certainly some good news for melanoma patients!
Neoadjuvant (before surgery) treatments for resectable melanoma
Stage III—and more rarely, stage IV—melanoma tumors that have not spread widely can be sometimes treated surgically. Last year a small clinical trial showed that, in BRAF-mutant melanoma, treatment with the BRAF/MEK inhibitors dabrafenib and trametinib (D/T) before and after surgery provides a significant improvement over just post-surgery treatment, by preventing later recurrence.
Later in 2018, researchers reported that using the immune checkpoint drugsnivolumab and ipilimumab prior to surgery led to tumor reduction in 73% of patients treated in a clinical trial. After surgery, they remained disease-free for 2 years (the reported time of observation). Treatment with nivolumab alone was not nearly as active in this randomized trial, with only 25% of patients responding to neoadjuvant nivolumab; still, 75% were disease-free within the 2-year observation period.
An interesting trial tested a single dose of the drug pembrolizumab given three weeks prior to surgery. Of 27 patients who received this single infusion, eight (29%) had a complete or major pathological response, meaning that their tumors were reduced by 90% or more. These eight patients continued on pembrolizumab after surgery and were disease-free for over 2 years. Continue reading…
“The combination of encorafenib and binimetinib resulted in longer overall survival (OS) compared with vemurafenib in patients with BRAF V600–mutant melanoma, according to results of the COLUMBUS trial. Combined with an earlier report showing improved progression-free survival (PFS), this suggests the regimen should become an important option in this setting.
“Small-molecule BRAF inhibitors, originally introduced as monotherapy, offered improvements in outcomes for these melanoma patients. ‘However, response durations were short and BRAF inhibitor treatment was associated with the development of squamous cell skin cancer and other skin toxicities related to paradoxical MAPK pathway activation,’ wrote study authors led by Reinhard Dummer, MD, of University Hospital Zurich in Switzerland. Combinations of BRAF and MEK inhibition have improved the situation further, but better treatment options are still needed.”
“In patients with advanced BRAF V600–mutant melanoma, combining the BRAF inhibitor encorafenib (Braftovi) with the MEK inhibitor binimetinib (Mektovi) improved overall survival compared to vemurafenib (Zelboraf) or encorafenib as monotherapy, with a favorable toxicity profile, according to updated results from the phase III COLUMBUS trial.
“Combined BRAF/MEK inhibitor therapy is standard of care in advanced BRAF V600–mutant melanoma, but approved combinations have unique toxicities that may impact the ability to deliver optimal treatment (ie, vemurafenib/cobimetinib [Cotellic] is associated with photosensitivity).”
“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.”