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Melanoma Patients See Magnified Benefit From Targeted Treatment Combo in Five-Year Outcomes Data

NEW YORK – New study results have confirmed that advanced melanoma patients treated with a combination of molecularly targeted drugs appear to see significant benefit from this approach compared to what would be expected based on data from older studies of non-targeted treatment.

The new evidence, from a five-year outcomes analysis of a prospective clinical trial, adds to growing affirmation of the positive impact of precision medicine, at least for certain subsets of cancer patients. 

In the study, published in Clinical Cancer Research on Friday, investigators led by UCLA professor Antoni Ribas studied the outcomes of patients with metastatic melanoma harboring BRAF V600E mutations who were treated with a combination of the BRAF V600E inhibitor vemurafenib (Zelboraf) and the MEK inhibitor cobimetinib (Cotellic) in the Phase I, Roche-sponsored BRIM7 clinical trial.

BRIM7 consisted of two cohorts of metastatic melanoma patients: 63 who had not previously been treated with a BRAF-targeted therapeutic and another 66 who had progressed on prior treatment with vemurafenib monotherapy. 

According to the study authors, earlier results from the trial showing strong responses in patients who had not previously been treated with a BRAF-targeted drug prompted a Phase III follow-up, which — along with studies of other BRAF-MEK drug combinations — have since led to these strategies becoming the new standard-of care therapy for patients with BRAFV600-mutated metastatic melanoma.

The vemurafenib-cobimetinib combo, specifically, was approved by the US Food and Drug Administration in 2015 for metastatic melanoma patients. The agency had previously greenlighted another pair, trametinib and dabrafenib (Mekinist and Tafinlar) for the same indication, and later approved encorafenib and binimetinib (Braftovi and Mektovi). 

As of last year, FDA had also extended the use case for the trametinib-dabrafenib combo to a post-surgery adjuvant setting in melanoma, and for certain BRAF-mutated patients with other tumor types, like lung and thyroid cancer.

In their new report, Ribas and colleagues updated their initial readout from the BRIM7 trial with much longer-term data on overall survival outcomes. "It is of great interest to understand the long-term effects ... in particular whether long-term use results in any increase in toxicities, and to assess the rate of long-term durable responses," the team wrote.

As of May 25, 2018, the authors reported that median overall survival for the BRAF inhibitor-naïve cohort was about 32 months, with the percentage of patients still alive plateauing at 39.2 percent at about four years of follow up.

In other words, nearly 40 percent of this subcohort of the trial were still alive moving into their fifth year after entering the study. Interestingly, Ribas and colleagues also found that with longer follow up there was an increase in patients who had a complete response to therapy, "highlighting that late conversions from partial to complete response can be achieved with continued therapy."

Data from studies of patient outcomes prior to the availability of molecularly targeted therapies, and of other melanoma populations help illustrate the achievement that is a 40 percent survival rate for the BRAF-mutated population.

"The fact that a subgroup of patients were alive and well at the five-year follow-up mark after this combination treatment is remarkable," Ribas said in a statement. "When this study was initiated, the treatments available yielded long-term benefit at four or five years for only about 10 percent of patients diagnosed with metastatic melanoma."

The authors also concluded that patients in the trial did not appear to suffer significant unexpected toxicities under longer-term treatment compared to what was seen in the initial analysis. That said, there were increases in the rates of some adverse issues, including increased photosensitivity and actinic keratosis, which the group wrote was likely due to the increased exposure time.

Importantly, although the data for the vemurafenib-naïve group showed a large proportion of patients surviving through a five-year timepoint, the results were less promising for patients in the second trial sub-cohort. In this group, which had progressed on prior BRAF treatment, median OS on the combination treatment was 8.5 months, with the percentage of survivors plateauing at 14 percent around three years in.

Ribas and colleagues wrote that one potential caveat to the five-year findings is that some patients treated in the trial could have received immunotherapy treatment after progressing in the trial, which could potentially extend their survival and confound the long-term OS calculation.

However, the authors wrote, the response rate to anti–PD-1 therapy in patients who have already been treated with BRAF drug is known to be lower than for those who haven't.