Targeted Combos Improve OS in Melanoma, But Mitigating Toxicities Essential

Adil Daud, MD, a clinical professor in the Department of Medicine (Hematology/Oncology), at the University of California, San Francisco and the director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center

Adil Daud, MD

As more targeted therapies become available, the need for genomic testing in patients with melanoma is amplified, according to Adil Daud, MD. Although a dual targeted therapy approach can lead to survival gains, a management plan must be put in place to combat associated toxicities, he added.

“It’s important to test for BRAF mutations so that you know if someone is a candidate for a BRAF inhibitor or a BRAF/MEK combination therapy,” said Daud, a clinical professor in the Department of Medicine (Hematology/Oncology), at the University of California, San Francisco. “[These tests could also help us determine] what kind of agent to use.”

Patients with BRAF V600-mutant metastatic melanoma have seen promising activity with the combination of dabrafenib (Tafinlar) plus trametinib (Mekinist), according to 5-year data presented at the 2019 ASCO Annual Meeting.

At 5 years, one-third of patients with unresectable or metastatic BRAF V600-mutant disease remained alive following treatment with the combination of the BRAF and MEK inhibitor, according to an analysis of the COMBI-d and COMBI-v trials. Furthermore,19% of patients remained alive without experiencing disease progression. Treatment with the dual targeted therapy led to a 5-year overall survival (OS) rate of 34% in the 563 evaluable patients.

This was the largest data set with the longest follow-up in treatment-naïve patients with BRAF V600-mutant unresectable or metastatic melanoma treated with these targeted therapies, according to Daud.

“In terms of adverse events (AEs), in my clinic, if someone has a history of immune-related AEs or might be at risk of having these complications, that might be the patient population in which I would consider giving dabrafenib and trametinib,” said Daud.

Most patients will develop fever and chills. Doctor-patient communication on these types of complications early on can help prevent events from worsening, according to Daud. For example, it’s important for patients to know that if they develop a fever, they stop taking both drugs immediately until the fever has subsided, he added.

In an interview with OncLive at the 16th International Congress of the Society for Melanoma Research, Daud, who is also the director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center, discussed the role of dabrafenib plus trametinib in patients with advanced melanoma and highlighted other combinations under investigation.

OncLive: Why is testing in patients with stage III melanoma important right now?

Daud: Stage III melanoma spans across a wide variety of different clinical subtypes; that goes all the way from stage IIIA to stage IIIC disease. [Patients] are categorized based on their risk of recurrence, so some are candidates for adjuvant treatment. About 50% of them will have BRAF-mutant disease, and for that category of patients, you could consider BRAF inhibitor therapy.

What role does the combination of dabrafenib and trametinib play in these patients?

There are patients for whom this combination is an appropriate treatment and [even a] preventative treatment. The other option is to use immunotherapy in the same patients. There are pros and cons to using dabrafenib plus trametinib, immunotherapy, or just observing these patients. To some extent, it comes down to whether your patient wants something oral that may have a greater incidence of AEs that are more reversible versus a lower incidence of AEs [that may] be long-lasting and irreversible.

In the case of dabrafenib plus trametinib, we do have mature 5-year OS data at this point in time. For immunotherapies, we have some really exciting relapse-free survival data that is relatively short-term. The issue is just extrapolating that to 5-year OS to see how that translates.

How do you manage the toxicities associated with these agents?

What’s really important is to communicate with patients on what their likelihood is of experiencing fevers and chills and developing a management plan for those events. What we have been doing at my clinic, and we have published on this, is to tell patients that the minute they have a fever, we need them to stop taking both dabrafenib and trametinib at the same time and wait until the fever resolves to restart at the full dose; we find that is helpful.

What can happen if you don’t communicate that to patients is that they may develop fevers and continue to take the combination for a few days. Eventually, it can get to a point where it is a really persistent fever or a syndrome. In the past, some patients would go to the emergency department, where [because of their history] of cancer-related neutropenia, [doctors] will often check their blood counts and administer antibiotics in the hospital or give them fluid resuscitation. It can become a much bigger thing [that could be prevented] if patients are counseled in advance and know that they can avoid that whole [experience] simply by stopping the drugs.

That is an important learning point for us. We need to communicate with patients and ensure that they are aware that [these events] can and will happen. In all likelihood, about 60% of patients will experience at least 1 febrile episode, and if you look at the number of patients who have 4 more episodes, that number is pretty low. Between 1 and 4 [episodes] is pretty common.

What other exciting combinations are under investigation?

My personal interest is in examining immunotherapy combinations. I am especially interested in interleukin 12 (IL-12) in combination with PD-1. Looking back at all the data we have, it seems that once patients progress on a PD-1 inhibitor, it’s hard for other checkpoint inhibitors to show a lot of effectiveness in that population. One theory is that you just need a fresh set of T cells to come into the tumor, and that those cells can be stimulated with your checkpoint [inhibitor]. We are doing a trial right now where we are looking at patients who progressed on a PD-1 inhibitor, either ipilimumab (Yervoy)/nivolumab (Opdivo) or pembrolizumab (Keytruda) alone. We are basically using a gene therapy approach to increase the levels of IL-12, which is a kind of cytokine, into the tumor; that causes an influx of T cells. We also use pembrolizumab. I am excited about that research.

What are your key takeaways on the landscape of melanoma treatment right now?

We are learning a lot. At this conference in particular, there are many interesting talks on tumor biology and the immune system. I feel like that is going to be an ongoing source of data for ideas over the next few years. Specifically, [we’ll be] looking at patients who are resistant to targeted therapy, resistant to immunotherapy, and the large group of patients who are resistant to both. If you want to look at patients who are resistant to targeted therapy, many of those patients are also resistant to immunotherapy, and vice versa. My focus is now on that group of immunotherapy- and targeted therapy—resistant patients, and trying to understand what their immune microenvironment looks like, and what we can do to fix [whatever causes that resistance] or what manipulations could be done [to overcome that resistance].

Nathan PD, Robert C, Grob JJ, et al. Five-year analysis on the long-term effects of dabrafenib plus trametinib in patients with BRAF V600-mutant unresectable or metastatic melanoma. J Clin Oncol. 2019;37(suppl 15; abstr 9507). doi: 10.1200/JCO.2019.37.15_suppl.9507.

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