New combination therapy boosts survival in melanoma patients29 Sep 2015
Survival in advanced BRAF-mutant melanoma improved significantly with a combination targeted therapy versus a single agent, results of a large randomized trial showed.
Patients treated with dabrafenib (Tafinlar) and trametinib (Mekinist) had a 2-year overall survival of 51% compared with 38% for patients who received vemurafenib (Zelboraf). The updated survival analysis showed that advantage afforded by combination therapy has increased, as the absolute difference between treatment groups was 7% at 1 year.
“The trial is the second to show superiority for the combination versus vemurafenib monotherapy in advanced melanoma, making a strong case for standard of care for patients with unresectable, advanced melanoma”, commented Caroline Robert, MD, of Institute Gustave Roussy in Paris.
Characteristics of the combined drugs
Vemurafenib, the first novel agent for melanoma, targets the BRAF V600 mutation found in more than half of melanomas. Early clinical experience with the drug showed dramatic responses in a high percentage of patients with unresectable, BRAF-positive melanoma. However, most patients eventually progressed, and secondary non melanoma skin cancer emerged as a worrisome adverse effect of treatment.
Dabrafenib, a BRAF inhibitor like vemurafenib, also proved superior to chemotherapy, but with the risk of secondary cutaneous malignancy resulting from BRAF inhibition. The MEK inhibitor trametinib demonstrated superiority to chemotherapy, and preliminary clinical evaluation showed that adding it to dabrafenib enhanced treatment response and inhibited the emergence of secondary skin cancers.
Clinical trial’s details and results
A recently completed phase 3 trial (called COMBI-d) showed that the combination of dabrafenib and trametinib improved progression-free survival and overall survival, versus dabrafenib alone in patients with unresectable metastatic melanoma. The trial was initiated concurrently with the comparison of combination therapy versus dabrafenib alone.
Investigators randomized 704 patients with unresectable, BRAF-mutant, stage 3-4 melanoma to receive the combination or a standard dose of vemurafenib monotherapy. The trial had a primary endpoint of overall survival.
The initial report from the COMBI-v trial showed:
- A statistically significant improvement in 1-year survival with the combination.
- The 18-month survival was 60% with the combination and 50% with vemurafenib, increasing to a 13% absolute difference at 2 years.
- Median overall survival was 25.6 months with combination therapy and 18.0 months with single-agent vemurafenib, representing a 34% reduction in the hazard ratio.
- Median progression-free survival, a secondary endpoint, was 12.6 months with the combination and 7.3 months with vemurafenib.
- The combination led to a higher objective response rate, including complete responses in 17% of the combination group versus 10% with vemurafenib.
- Patients with lower baseline levels of lactate dehydrogenase (LDH), a widely used diagnostic and predictive biomarker for melanoma, did better with the combination and with vemurafenib.
- In the subgroup of patients with LDH at or below the upper limit of normal, the median overall survival has yet to be reached in the combination arm versus 21.5 months with vemurafenib. Median progression-free survival was 17.5 versus 9.2 months with the combination and monotherapy, respectively.
In the two groups, adverse events occurred in 9% and 10%, respectively, at the initial data cutoff in April 2014, and then increased slightly to 10% and 12%, respectively, at the March 2015 data cutoff.
Which other therapies have been administered at progression?
Patients in both treatment arms received a variety of different therapies at progression, including the CTLA-4 inhibitor ipilimumab (Yervoy), received by 21% of the combination arm and 29% of patients randomized to vemurafenib, and the PD-1/PD-L1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo), given to 7% to 8% of patients in each group. The extent to which subsequent therapies might have affected outcomes is unclear.
Peter Naredi, MD, of the University of Gothenburg in Sweden commented that clinicians and scientists are still learning how best to use the growing number of drugs that have become available for melanoma. Drugs that initially might not appear effective could eventually become a good option as ongoing treatment affects the disease process. “In this way, we must start considering advanced melanoma as a chronic disease," Naredi said.
Source: MedPage Today