Vemurafenib (ZelborafTM) was the second drug approved for metastatic melanoma this year. In March, the FDA approved ipilimumab (YervoyTM), a monoclonal antibody that binds to CTLA-4, which normally blocks lymphocyte activation against melanoma. Ipilimumab led to greater overall survival compared to a peptide vaccine, and a subsequent phase III trial comparing ipilimumab + dacarbazine vs. dacarbazine alone found that the combination therapy led to greater overall survival compared to dacarbazine alone.
With two new approved treatments for metastatic melanoma, each of which improves overall survival, physicians now have unique options.
The two drugs are quite different, as shown in the table. Ipilimumab is an immune-boosting therapy with a slow onset of effect and a low rate of objective responses, though the complete responses seen are generally durable. It can result in durable stable disease even without objective tumor shrinkage. Vemurafenib blocks mutated BRAF and has a much higher rate of objective responses, which generally occur rapidly.
Because these two drugs each have been shown to improve overall survival but have very different and complementary actions, there has been pressure on both drug companies involved (Bristol-Myers Squibb and Roche/ Genentech) to combine them. There is reason to think that the two drugs could act synergistically. Evidence exists that inhibiting the MAPK pathway in BRAF-driven tumor cells can decrease production of immune-suppressive factors such as IL101 and enhance expression of differentiation antigens that could be recognized by the immune system.2 In this way, vemurafenib could render melanoma cells more susceptible to immune attack.
As attractive as this combination is, it could prove less effective than either drug alone. For example, vemurafenib might adversely affect T cell function, undermining ipilimumabís effects. Also, some of the toxicities seen with these drugs are overlapping (e.g., rash, elevated liver enzymes), which could limit the ability to administer the drugs together. Even if the combination is tolerable and not antagonistic, the combination may be no better than using the drugs in sequence. This will need to be tested.
To the credit of both drug companies, they overcame several difficulties to bring the combination trial about, and the phase I trial is about to start. This multicenter Phase I/II trial, headed by Drs. Jedd Wolchok, Stephen Hodi, and Antonio Ribas (from Memorial Sloan-Kettering, Dana-Farber Cancer Institute, and UCLA, respectively), will treat advanced melanoma patients who have a BRAFV600E mutation with both vemurafenib and ipilimumab at the FDA-approved doses (960 mg bid for vemurafenib; 3 mg/ kg for ipilimumab). Patients will start vemurafenib either 2 or 4 weeks prior to starting ipilimumab. The dose of ipilimumab will be escalated to 10 mg/kg, if tolerated. A phase II cohort will be treated at the maximum tolerated doses. Ultimately, a three-arm trial comparing overall survival in patients randomized to either drug alone or the combination therapy should be considered. Patients who are randomized to either drug alone will, upon progression, certainly receive the other drug, so the study will test de facto whether the combination is superior to the two drugs used sequentially in either order.
- Sumimoto H, Imabayashi F, Iwata T, Kawakami Y. The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells.J Exp Med 2006; 203:1651-6.
- Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res 2010; 70:5213-9.