Immunotherapy and BRAF-Targeted Therapy Fill Expanded Roles Across Melanoma

Hussein A. Tawbi, MD, PhD

Immunotherapy and targeted therapy combinations containing BRAF and MEK inhibitors have carved out roles in different settings of melanoma, which has given clinicians different options for treatment sequencing, according to faculty from an OncLive^® Institutional Perspectives in Cancer webinar on skin cancer.

The event, chaired by Hussein A. Tawbi, MD, PhD, professor, deputy chair, director of Personalized Cancer Therapy, Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, covered updates in immunotherapy and targeted therapy for melanoma, including the optimal settings for each treatment type.

Tawbi was joined by:

• Michael A. Davies, MD, PhD, professor, chairman, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center
• Michael K. Wong, MD, PhD, professor, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center
• Sapna Patel, MD, medical oncologist, associate professor, director, Uveal Melanoma Program, Melanoma Fellowship Program, The University of Texas MD Anderson Cancer Center

Below, Tawbi, Davies, Wong, and Patel summarized the main messages from their presentations.

Immunotherapy Vs Targeted Therapy in Melanoma

Tawbi: I [aimed to convey] that immunotherapy is the current standard [of care] in the metastatic setting, [along with the] adjuvant setting and possibly the neoadjuvant setting.

Targeted therapy [has a role in the adjuvant setting], and there are multiple different lines where [targeted therapy] could be the most useful approach. Further, [targeted therapy–containing] triplets are interesting and they may have a role [in select patients], but they [are not applicable] across the board.

Clinicians need to continue accruing patients to clinical trials and continue thinking about long-term analyses and subgroup analyses that will help tease out who should be treated with [specific regimens] in our current armamentarium.

BRAF Inhibitor–Based Combinations

Davies: As of 2022, we have 3 FDA-approved targeted therapy regimens [combining a BRAF inhibitor and a MEK inhibitor: vemurafenib (Zelboraf) plus cobimetinib (Cotellic), dabrafenib (Tafinlar) plus trametinib (Mekinist), and encorafenib (Braftovi) plus binimetinib (Mektovi)]. The hallmark of these [combinations] is a high and rapid initial response rate, with a median duration of response of approximately 1 year. However, only about 20% of patients are going to be long-term responders [with a duration of response of more than 5 years].

What we want to do is figure out how to predict who those [long-term responders] are. Additionally, for the 80% of patients who are progressing, how can we prevent that? We do know that patients can respond to immunotherapy after targeted therapy and can respond to targeted therapy after immunotherapy. However, in [the latter sequence], we see more adverse effects [from targeted therapy] compared with patients who are immunotherapy naïve.

Resistance to targeted therapy is very common, but it is not necessarily permanent. A patient who progressed on [prior] targeted therapy can be rechallenged with targeted therapy and respond again.

As far as the triplets go, we do have the FDA-approved regimen of vemurafenib, cobimetinib, and atezolizumab [(Tecentriq) for patients with BRAF V600 mutation–positive advanced melanoma]. Although the triplet is approved in the frontline setting, it is not used much there. There are still open questions in the field [about] the right place to use those triplets, or if there is a specific subset of patients that benefit from [the triplet] in the up-front setting.

[It is important to] keep in mind that although clinical trials evaluating triplets did not have an immunotherapy arm and [these regimens] cause toxicity, they produce high response rates. However, most of the questions [surrounding triplets involve] how they potentially play a role in the second-line setting, in patients with symptomatic brain metastases, or other scenarios where immunotherapy hasn’t been very effective.

Cutaneous Squamous Cell and Basal Cell Carcinoma

Wong: Hedgehog inhibitors [should be utilized as] first-line therapy. Cemiplimab-rwlc [(Libtayo) should be used] for locally advanced basal cell carcinoma refractory to or intolerant to hedgehog inhibitors. Further, it is important to remember that basal cell carcinoma [is a] slow, indolent disease, both in the way it grows and its response to immunotherapy.

One of the remaining questions [involves finding] the sweet spot for hedgehog inhibitor use. Should hedgehog inhibitors be used in combination, or should we use one before the other? What is the best sequence? This is all yet to be determined.

Uveal Melanoma

Patel: There may be a novel therapy coming for primary treatment of the eye, and there are a number of treatments being tested for metastatic uveal melanoma, including liver-directed, targeted, epigenetic, and cell therapies.

Getting access to a clinical trial remains a top priority for our patients, and more importantly, [we need to do] a deep dive on blood and tumor specimens to help us understand responses [and resistance to treatment].