Immunotherapy, MEK Inhibitor Combo Effective for BRAF Wild-Type Melanoma

Jeffrey R. Infante, MD

The combination of atezolizumab (Tecentriq) and cobimetinib (Cotellic) may lead to a higher overall response (ORR) and a longer progression-free survival (PFS) than either agent alone in patients with metastatic melanoma, according to findings presented at the 2016 Society for Melanoma Research (SMR) Annual Meeting.

The findings were part of a phase Ib dose-escalation and dose-expansion study, which looked at the PD-L1 inhibitor and MEK inhibitor together in advanced solid tumors. Data on a cohort of 22 patients with ocular melanoma (n = 2) and non-ocular melanoma (n = 20) was presented at the meeting. Among patients in the non-ocular cohort, the ORR was 45% and the disease-control rate (complete response, partial response, and stable disease) was 75%. Median PFS was 12 months (95% CI, 2.8-16.7).

Patients with BRAF-mutant and wild-type metastatic melanoma both responded similarly. In those with wild-type BRAF melanoma, the median PFS was 15.7 months and in those with BRAF mutations the median PFS was 11.9 months. After a median follow-up of 18.9 months, the median overall survival had not yet been reached.

To learn more about these findings, OncLive spoke with Jeffrey Infante, MD, who presented the data at the SMR Annual Meeting. In his interview, Infante, director, drug development program, principal investigator, Sarah Cannon Research Institute, discussed the rationale behind the combination, its efficacy compared to single-agent treatment, and future steps in this research.

OncLive: What are the key findings from the combination study thus far?

Once we found out that the combination was safe, there was a planned 20 patient melanoma cohort, which I presented on at the SMR Congress. There were also 2 melanoma patients that were included in the escalation portion, so we added that to the data. In total there were 22 melanoma patients that we reported on with this combination. Twenty of them had non-ocular melanoma; 16 came from the skin and 4 from the mucosa. There were 2 ocular melanomas.

The data looks interesting. If you were to give this particular PD-L1 inhibitor by itself—this has been done and was presented on at the 2014 SMR Congress—the response rate is around 33% and the median PFS is 5.5 months. In this trial, even though the numbers are small, we had 9 partial responses. So the response rate was higher, it was 45% and the median PFS was around 1 year. Atezolizumab in combination with cobimetinib looks better than atezolizumab did as a monotherapy.

Then we took that information and we tried to classify if this would be better in patients that had a BRAF mutation or were wild-type for BRAF. It turns out that it looked about the same in both groups. Five of the responders were BRAF wild-type and 4 of the 10 patients that were BRAF-mutated responded. It seems that we have activity in both settings.

How might these agents work together synergistically?

There is a single-agent MEK inhibitor, trametinib, that is approved by itself in BRAF-mutated melanoma, so we know that this class of drugs has activity in BRAF-mutated patients. Cobimetinib is already FDA-approved in combination with vemurafenib in BRAF-mutant melanoma.

What is interesting is that as a monotherapy the MEK inhibitor had very little activity in patients that were BRAF wild-type. The premise of this combination for the BRAF wild-type patients is that it’s really an immune modulator. What this drug can do is change the T cells or the tumor microenvironment. There has been preclinical data that suggests that the MEK inhibitor could increase the MHC class I expression and potentially make the tumors more visible to the immunotherapy and also CD8 T-cells within the tumor, increasing the immune system’s ability to get into the tumor. It kind of has two different ways to enhance the immune response and hopefully synergize with the PD-L1 inhibitor.

What toxicities were seen with this combination?

The safety profile is also early at this point, but it looks manageable. About 6 out of 10 patients will have a grade 3/4 adverse event at one point while on study, but it is usually one that is manageable and patients don’t have to come off trial. In fact, when we looked at the number of patients on our trial that had to come off, of the 22 patients only 3 patients stopped drugs. One of them stopped both medications and that is the only one that had to stop both. The other 2 patients just stopped cobimetinib and were able to stay on the PD-L1 inhibitor.

I think the toxicities are manageable. As we get more experience managing patients and letting them stay on, and giving the drugs more time to work, we will get a feel for how these effective these drugs really are.

What are the next steps in this research?

The data we have now are early. There were 10 patients with BRAF wild-type melanoma that were treated, and 5 of those patients had a partial response. Some of these responses were very durable, we have patients that are out a year and half at this point. That is very encouraging. However, these are still small numbers. It will be great as we get more numbers and treat more patients.

Infante J, Kim TM, Friedmann J. Safety and clinical activity of atezolizumab combined with cobimetinib in metastatic melanoma. Presented at: Society for Melanoma Research Annual Meeting; Boston, Massachusetts, November 6-9, 2016.

There is a planned phase III trial looking at this combination of atezolizumab with a MEK inhibitor, versus the PD-L1 inhibitor, but that trial is not planned for 6 months to 1 year from now.

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Infante: This was an early study that looked at 3 different cohorts to make sure the drugs could be safely given together. Atezolizumab, the immunotherapy, was given at 800 mg via IV every 2 weeks for a 4-week schedule. The cobimetinib was started at 20mg to make sure it was safe and then went up to 40 mg, and eventually got to 60 mg daily, which is its recommended dose. Patients will take that for 3 weeks on and 1 week off.