GSK Overall Survival Data Clinches Role For BRAF/MEK Combo In Melanoma

In the COMBI-v study, BRAF/MEK combination Tafinlar/Mekinist improves overall survival by 31% compared to BRAF monotherapy. GSK’s combination and Genentech’s cobimetinib/Zelboraf combination both improve progression-free survival and reduce cutaneous malignancies compared to monotherapy.

In the COMBI-v first-line melanoma study, GlaxoSmithKline PLC’s BRAF/MEK inhibitor combination of Tafinlar and Mekinist improved overall survival by 31% over BRAF monotherapy with Genentech Inc.’s Zelboraf, results that could help preserve the role of the combination approach in early treatment.

The COMBI-v study tested Tafinlar (dabrafenib) with Mekinist (trametinib) vs. Zelboraf (vemurafenib) alone in 704 untreated patients who were positive for BRAF V600E/K mutations. In July, the company announced that the study was terminated early due to the overall survival benefit in an interim analysis and patients on the monotherapy arm were allowed to cross over, but at the time the details had not been disclosed.

Updated results from COMBI-v study were presented on Sept. 29 at the European Society for Medical Oncology meeting in Madrid. Overall survival benefit was 31%. Progression-free survival, a secondary endpoint, was improved by 44% (11.4 months for the combination vs. 7.3 months for Zelboraf).

The data come at time when the oncology community is increasingly becoming enamored with immunotherapy in melanoma and had been questioning whether combination therapy was adding enough over monotherapy in BRAF+ patients.

At the American Society of Clinical Oncology meeting in late May/early June, researchers presented striking response and promising survival results in single-arm studies of Merck & Co. Inc.’s pembrolizumab in treatment-naïve and -experienced patients, as well as data for Bristol-Myers Squibb Co.’s combination of Yervoy (ipilimumab) with its PD-1 inhibitor nivolumab. Pembrolizumab was approved as Keytruda in late September for relapsed melanoma (Also see "Merck’s Keytruda Opens Door, But Combination Trials Could Unlock Efficacy" - Pink Sheet, 8 Sep, 2014.).

The ESMO meeting also featured results from the CoBRIM study of Roche/Genentech’s Zelboraf with its investigational MEK inhibitor cobimetinib, which is slated for a filing in the U.S. by the end of 2014, in 495 untreated BRAF-positive melanoma patients. Cobimetinib was developed with Exelixis Inc.

In CoBRIM, the combination demonstrated a PFS benefit of 3.7 months (9.9 months vs. 6.2 months) and overall survival data were not yet mature.

In a comment sent by e-mail from the meeting, the University of Zurich’s Reinhard Dummer said that we now have proof that with targeted therapy, PFS translates into an overall survival benefit and, in his opinion, the scientific community will not doubt that the cobimetinib/vemurafenib combination will also generate an OS advantage.

For both studies, adverse events were similar between the monotherapy and combination arms, though the number of cutaneous squamous cell carcinomas was lower with combination treatment and response rates were higher (see table below).

In an ESMO press statement, Dummer said that results from coBRIM and COMBI-v “provide convincing evidence that combination therapy with either dabrafenib and trametinib or vemurafenib and cobimetinib will be the standard systemic therapy for this patient population.”

Dummer also noted that lower risk for new cutaneous malignancies is of “special relevance,” because it “might be a surrogate for other secondary malignancies associated with the use of monotherapy BRAF inhibitors.”

The combination’s potential to reduce certain side effects was identified in a Phase II study in late 2012 (Also see "The Next Wave For Melanoma" - Pink Sheet, 18 Jun, 2012.). Adding the MEK inhibitor helps the body escape the development of resistance and also avoid the malignancy side effects.

However, results from the COMBI-d first-line trial of Tafinlar/Mekinist vs. Mekinist alone, presented at the ASCO meeting and published in the New England Journal of Medicine on Sept. 29, had been disappointing.

In the 433-patient trial, which was a confirmatory study following accelerated approval of the combination, median PFS for the combination was 9.3 months compared to 8.8 months for monotherapy. This was a statistically significant result, but the margin was a lot smaller than in the initial Phase II trial – raising questions about whether the result was a fluke, or a sign that monotherapy was getting so good that combination therapy might not be adding so much.

“The combination therapy, as compared with monotherapy, was associated with a 37% relative reduction in the risk of death at the interim survival analysis, but this result did not cross the prespecified stopping boundary,” lead author Georgina Long, University of Sydney, et al., said in the NEJM publication. “Notably, this difference in survival was observed despite the increased use of new therapies after the discontinuation of monotherapy, including therapies with a proven survival benefit (e.g., ipilimumab).”

She noted that there is a role for avoiding resistance to BRAF inhibition. “Resistance to single agent BRAF inhibition is acquired predominantly through reactivation of the MAPK pathway,” the article states. “Our study shows that the inhibition of the MAPK pathway at two nodes rather than one decreases the risk of progression (and therefore delays resistance) by 25%.”

The study publication of co-BRIM also concludes that there’s a valid role for combination therapy, though its place versus immunotherapy needs to be considered. “The data combining BRAF and MEK inhibitor-targeted therapies need to be put in context with the rapidly evolving melanoma-treatment landscape – namely, the development of immunotherapies that are based on checkpoint blockade with ipilimumab or anti-programmed death 1 antibodies,” lead author James Larkin, Royal Marsden Hospital, and colleagues wrote. “Evidence suggests that these agents can lead to durable tumor responses in patients with metastatic melanoma, albeit with lower response rates than have been observed with BRAF and MEK inhibition.”

Comparison Of Combination Study Results: First-line BRAF+ Melanoma
Study*	PFS**	OS	Response Rate	Adverse events
COMBI-v: GSK’s Tafinlar/Mekinist vs. Roche’s Zelboraf in 704 patients	11.4 months vs. 7.3 months (4.1 months)	Statistically significant 31% advantage in interim analysis, trial stopped early		Similar between arms, according to company
CoBRIM: Roche’s Zelboraf with cobimetinib vs. Zelboraf in 495 patients	9.9 months vs. 6.2 months (3.7 months).	9-month survival rates of 81% and 73% in interim analysis did not cross prespecified stopping boundary	68% vs. 45%	Nonsignificant higher rate of Grade 3+ adverse events (65% vs. 59%); lower number of secondary cutaneous cancers; no difference in discontinuation
COMBI-d: GSK’s Tafinlar/Mekinist vs. Tafinlar in 423 patients	9.4 months vs. 8.8 months (0.6 months)	At 6 months, interim OS 93% vs. 85% (did not cross pre-specified stopping boundary)	67% vs. 51%	Similar adverse event rates; lower rate of cutaneous squamous cell carcinoma; more pyrexia
*Results from COMBI-v and CoBRIM presented at the ESMO 2014 meeting; results from COMBI-d presented at ASCO 2014. **All PFS results statistically significant.