Novel Therapies Expand Options in Melanoma, But Surgery Retains Role

Omid Hamid, MD

Although the emergence of more targeted and immunotherapies continues to expand the melanoma treatment paradigm, surgery remains an important tool in the management of these patients, according to Omid Hamid, MD.

“Targeted therapy is playing a huge role in the modern management of patients with melanoma,” said Hamid. “[These therapies] provide a survival advantage to patients; it's an option in the first- or second-line setting. Also, [these agents have induced] significant responses in [patients with] brain metastases.”

To build on the success seen with targeted therapies, investigators are examining the use of these therapies in different combination regimens. For example, the IMspire150 study, is investigating the combination of atezolizumab (Tecentriq), cobimetinib (Cotellic), and vemurafenib (Zelboraf) versus cobimetinib and vemurafenib in patients with BRAF V600 mutation—positive advanced melanoma. According to a press release from Roche, the triplet has shown a progression-free survival (PFS) advantage, meeting the primary end point of the study. Updated results are highly anticipated, according to Hamid.

Although the use of novel therapies continues to expand in melanoma, surgery retains an important role in this space. “Surgery has become even more important in the management of patients with malignant melanoma, either in the adjuvant or the metastatic setting,” said Hamid. “We also really rely on our surgeons now to help us with the neoadjuvant approach; this is a paradigm shift, that we can now treat patients with more tolerable regimens and get them to a pathological complete response, understand that they have that benefit, and then possibly not need to give them as much therapy, or for as long [as we typically would].”

In an interview with OncLive, Hamid, director of the Melanoma Center and Phase I Immuno-Oncology Program at The Angeles Clinic and Research Institute, discussed emerging treatment approaches, the role of surgery, and ongoing research efforts in melanoma.

OncLive: What role does targeted therapy play in the modern management of patients with melanoma?

Hamid: There is now the idea that some immune activity exists with targeted therapies and the ability to have a tolerable triplet regimen with immunotherapy and targeted therapy. Future efforts will be dedicated to understanding the benefits we can get with this triplet therapy. Multiple randomized trials are nearing completion and initial data show a progression-free survival benefit [with this approach]. For example, the [IMspire150] TRILOGY study of cobimetinib, vemurafenib, and atezolizumab versus cobimetinib and vemurafenib alone has been shown to have a PFS advantage. We look forward to those data being presented. Other triplets are being investigated in ongoing research efforts and those data will mature and eventually be presented, as well.

Despite the emergence of these targeted therapies in recent years, does surgery still have a role in this space?

Absolutely. Surgery is going to help us with predictive and prognostic markers. The tissue will help us in the neoadjuvant and in the metastatic setting to figure out what a response really means. In my practice, I have the pleasure of working with Mark B. Faries, MD, of The Angeles Clinic and Research Institute, who is a leader in melanoma surgical and adjuvant therapy. Through his work in the MSLT-II trial, we've learned that we don't need to do completion lymph node dissections. That’s an important thing for our patients in terms of morbidity and it also allows us to move further with adjuvant therapy in a more rapid fashion. Additionally, the role of metastasectomy is [in those with] progressive disease, so the patient who is either responding except for 1 area or who is responding and then progresses in an area where we can surgically remove that tumor and allow future therapy.

In addition, for immunotherapy, it’s important to remember that you need time for an immune response to happen. We have certain patients who have obstructions or areas that are troublesome and don't allow us to get that dose intensity. In these cases, our surgical colleagues can come in, take that area out, and allow us to treat those patients until they achieve a response. Even more importantly, there is this multidisciplinary idea of having your surgical oncologist, radiation oncologist, neurooncologist, medical oncologist, nursing staff all together to [contribute their own] expertise and experience [to improve] patient care.

What immunotherapies are showing promise?

Obviously, our checkpoint inhibitors are showing significant benefit and long-term survival. Combinations are showing 5-year survival [rates] of over 50%. We are understanding [how to approach] dosing and flip dosing in a better fashion, but the next frontier in melanoma is combination regimens that are more tolerable, with less grade 3 or 4 toxicity. We are also waiting to see what trials examining vaccine approaches and oncolytic therapies will show. Other checkpoints are agonistic and may also have less toxicity. All these regimens are not just in the first-line setting, but also for patients with refractory disease.

In addition, we're now looking elsewhere. In melanoma, CAR T-cell studies are opening [that will evaluate] the benefits of [this modality] for solid tumors. Adoptive T cell therapy is also becoming more and more available. I look forward to the maturation of the data [from Iovance Biotherapeutics with LN-144 (Lifileucel)], which was important in that it [showed] a 38% overall response rate in patients [with advanced metastatic melanoma] who had received a checkpoint inhibitor. Eighty percent of those patients never responded to PD-1 inhibition to begin with.

As we move forward, combinations of those therapies are [being evaluated] in clinical trials. For example, 1 clinical trial is now [examining] tumor-infiltrating lymphocyte therapy with PD-1 inhibition for multiple solid tumors. The ability to take those regimens and utilize them in the frontline and in patients with refractory disease is going to be key.

You are part of the International Neoadjuvant Melanoma Consortium. What are the goals of that effort and how do you envision this impacting melanoma treatment?

We have several goals for this neoadjuvant consortium in melanoma. The first one is to be able to set the rules of how to govern these trials. For example, what is the timeframe for imaging a biopsy? All the neoadjuvant trials work on a similar platform and, therefore, those trials can be compared with one another.

Another goal is to be able to utilize a majority of centers to do rapid startup and accrual of clinical trials to answer pressing questions. We also want to be able to have tissue to examine for predictive markers [of] who responds and who doesn't and be able to model that not just for our adjuvant therapies, but our metastatic therapeutics in the future. These [avenues] all lead to the personalized approach of immunotherapy.

Additionally, let's not overlook the role of high response rates [achieved with] targeted therapies in [patients with] melanoma. The role for immunotherapy and targeted therapies in the neoadjuvant setting is going to mimic what we're seeing in the metastatic setting and future trials are going to have triplet combinations [comprised of] BRAF, MEK, and PD-1. We look forward to those trials, those data, and a paradigm shift through neoadjuvant approaches.

Genentech announces phase III study results for Tecentriq plus Cotellic and Zelboraf in people with previously untreated BRAF V600 mutation-positive advanced melanoma [news release]. Genentech (Roche). Published December 12, 2019. bit.ly/34my7ap. Accessed April 8, 2020.