Melanoma Monday: Changes to Practice in Adjuvant, Neoadjuvant, and Metastatic Settings

Meredith McKean, MD, MPH

Long-anticipated changes to the treatment paradigms for patients with melanoma are taking place, providing new options for multiple subsets of patients with melanoma after years of slower development in this space.

Anti–PD-1 immunotherapy has made a particularly significant impact in patients with melanoma. Recent studies are showing new approaches with “old” agents such as pembrolizumab (Keytruda). The KEYNOTE-716 study (NCT03553836) demonstrated the efficacy of expanding adjuvant pembrolizumab from patients with stage III disease to those with stage IIB and IIC.¹ Neoadjuvant therapy, which enables patients to receive treatment before surgery,has been shown to improve relapse-free survival in the SWOG S1801 trial (NCT03698019).²

In the metastatic setting, pembrolizumab, nivolumab (Opdivo), and the combination of nivolumab and ipilimumab (Yervoy) have been the standard of care immune therapies since 2017. Now, a second combination therapy of nivolumab and relatlimab (Opdualag) has been approved.³ Additionally, the IMCgp100-202 trial (NCT03070392) investigating bispecific therapy led to the first treatment approval for metastatic uveal melanoma last year.⁴

Trials of sequential immunotherapy and targeted therapy have demonstrated how to optimize the 2 potent treatment types in patients with BRAF mutations. Other key mutations such as NRAS also have potential as molecular targets, making molecular profiling of patients with stage III and IV disease crucial. Finally, melanoma was the first disease setting to demonstrate the potential of personalized mRNA vaccine technology for boosting patient’s immune response with immunotherapy.

Patient outcomes have drastically improved over the past decade, according to Meredith McKean, MD, MPH. “We've seen 5-year survival for patients with metastatic melanoma go from less than 5% to more than 50% of patients with combination ipilimumab and nivolumab, but there's still a lot of work to be done,” she said.

In an interview with Targeted Oncology^TM, McKean, director of the Melanoma and Skin Cancer Research Program at Sarah Cannon Research Institute, discussed recent and upcoming advances in melanoma treatment.

TARGETED ONCOLOGY^TM: How has the field of melanoma care changed recently?

McKEAN: It's been an exciting last 1 to 2 years in melanoma. There had been a paucity in practice-changing trials and new therapies being approved. That has certainly not been the case over the last year and a half. We've had changes in practice everywhere from adjuvant to neoadjuvant, metastatic, and some of our rarer tumor types of melanoma.

Starting with neoadjuvant therapy, the SWOG S1801 trial was a practice-changing study demonstrating that transitioning our standard-of-care adjuvant anti–PD-1 therapy we offer for patients with stage III disease earlier as neoadjuvant therapy before surgery is beneficial to patients, with an improvement in their relapse-free survival.² That was an exciting study that was presented by Dr Patel at ESMO in Fall 2022.

In the adjuvant setting, we've always known that patients who had stage IIB and IIC melanoma have a high risk of recurrence. Now we have an FDA approval for the anti–PD-1 therapy pembrolizumab for those patients.⁵ So that's been an exciting option for those patients, to be able to offer them systemic therapy.

In the metastatic setting, after many years of not having any new approvals in the immune therapy space, we have a new target with relatlimab now FDA approved [in combination with nivolumab] as Opdualag.³ That's been a nice option to offer for those patients whom we would have previously given anti–PD-1 monotherapy, to now be able to offer nivolumab/relatlimab and be able to tell those patients you anticipate that this would give a higher response rate and improvement in their progression-free survival with very little additional toxicity given to those patients.

Finally, I think the other exciting research advance was the first FDA approval for patients with metastatic uveal melanoma. The bispecific tebentafusp-tebn [Kimmtrak] was approved for patients with metastatic disease and are HLA-A*02:01-positive.⁴ There's still a lot to learn here––we saw a very marginal response rate, but an improvement in overall survival. It is definitely an exciting option to be able to offer to patients and it's nice to at least for those about 50% of patients to have an FDA-approved option for them.

Are there any ongoing trials that you feel are very promising?

Some ongoing studies will be those targeting LAG-3 in the adjuvant setting. In the neoadjuvant setting, there are a number of studies ongoing. We understand that although anti–PD-1 before surgery is beneficial compared with adjuvant therapy alone, from prior neoadjuvant studies, we know that anti–PD-1 by itself isn't as good as what we can potentially expect from a combination therapy. In the neoadjuvant adjuvant space, we're going to continue to see new updates. In the metastatic setting a number of targets are being looked at. The data previously presented for the triplet of ipilimumab, nivolumab, and tocilizumab looked interesting,⁶ and I think we're going to continue to see more interesting triplet therapies coming in melanoma.

What therapies have become the standard of care when you treat patients with melanoma?

I always look for clinical trials, because that's where the next advances will be for patients and trials give them the opportunity for a better option than standard of care. But for standard-of-care treatment, the DREAMseq [NCT02224781] and SECOMBIT [NCT02631447] studies have been influential. I think most of us preferred to start with immune therapy for patients based on the data for responses in patients with brain metastases and the long-term survival that we are seeing. But the SECOMBIT and DREAMseq studies demonstrated that upfront immune therapy is primarily beneficial for those patients who have a BRAF mutation and targeted therapy is an option.^7,8 An important takeaway from [those studies] was that patients who come in with high volume disease—very symptomatic from their cancer—those are patients who need to get targeted therapy up front because [investigators] showed that a number of patients never went on to receive second-line therapy. Targeted therapy provides a fast, brisk response, and that can be beneficial for some patients with a BRAF mutation.

What is the importance of molecular profiling for melanoma?

Sequencing the tumor is very important. Patients with stage III melanoma should at least have BRAF mutation testing done. At the time of metastatic diagnosis, patients should have full profiling performed. We have FDA approved treatments for BRAF mutation, but we now also have a number of ongoing clinical trials, targeting NRAS, MTAP loss, CDKN2A loss, other targets that we haven't had treatments for in the past. This may open up additional clinical trial options for these patients.

There are a number of different pan-RAF and ERK inhibitors that patients with NRAS and BRAF mutations would be eligible for. Additionally, for patients with atypical BRAF mutations, the non-V600 mutations, there are a number of clinical trials ongoing for those patients. It is an exciting time and profiling is definitely helpful to understand the full treatment landscape possible for those patients.

What is some advice that you would give to community oncologists who don't usually see patients with melanoma?

We know that many patients with metastatic melanoma are treated in the community and are treated by their local provider. But we also recognize that those providers may not see many patients with melanoma. So feel free to reach out to melanoma specialists and [describe] the situation, maybe as a formal consultation, or at least by email or discussion. In general, everyone is happy to weigh in and give some advice on the latest standard of care or trials available to help with the care of that patient as close to home as possible.

The last 10 years of research progress in melanoma has been very exciting. We've seen survival for patients with metastatic melanoma go from less than 5% to more than 50% of patients, but there's still a lot of work to be done. Those outcomes were for patients who were eligible for a clinical trial at the time of diagnosis. We all see those patients who, unfortunately, come in at time of diagnosis or soon after who would not be eligible for clinical trials. There's a lot of work to be done. Trying to keep up with standard of care and to make sure to look for clinical trial options for patients is important.

What else is new in this setting that you'd like to highlight?

Some novel technology under investigation in melanoma is TIL [tumor-infiltrating lymphocytes]. There have been some exciting advances with TIL therapy, and we all look forward to seeing where that develops in melanoma. It could potentially become an FDA-approved treatment at some point for patients in the refractory setting.

Another treatment under investigation that's been exciting is the personalized cancer vaccines. Moderna's mRNA-4157 was evaluated in a phase 2 clinical trial [KEYNOTE-942; NCT03897881] in the adjuvant setting for patients with high-risk melanoma. The early data have shown significant improvement in the relapse-free survival for these patients with pembrolizumab compared with patients that received pembrolizumab alone.⁹ There are going to be a lot of data presented at upcoming meetings to explore that further. There's been a lot of excitement in the field in the area of personalized cancer vaccines because vaccines historically have not been a successful avenue despite the interest and excitement, but mRNA technology may be a game changer.

It’s been an exciting time in melanoma clinical trial research, and I can't say enough to make sure to look for clinical trial opportunities for your patients.

_REFERENCES

_{1. Luke JJ, Rutkowski P, Queirolo P, et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022;399(10336):1718-1729. doi:10.1016/S0140-6736(22)00562-1}

_{2. Patel S, Othus M, Prieto V, et al. Neoadjuvant versus adjuvant pembrolizumab for resected stage III-IV melanoma (SWOG S1801). Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/j.annonc.2022.08.039}

_{3. FDA approves Opdualag for unresectable or metastatic melanoma. News release. FDA. March 21, 2023. Accessed April 21, 2023. https://bit.ly/3LudOkx}

_{4. FDA approves tebentafusp-tebn for unresectable or metastatic uveal melanoma. News release. FDA. January 26, 2023. Accessed April 21, 2023. https://bit.ly/43Mek4p}

_{5. FDA approves pembrolizumab for adjuvant treatment of Stage IIB or IIC melanoma. News release. FDA. December 6, 2021. Accessed April 21, 2023. https://bit.ly/3N3lxqF}

_{6. Ipilimumab, nivolumab and tocilizumab as first-line therapy for advanced melanoma. J Clin Oncol. 2021;39(15_suppl). Published online May 28, 2021. doi:10.1200/JCO.2021.39.15_suppl.TPS9589}

_{7. Atkins MB, Lee SJ, Chmielowski B, et al. Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: The DREAMseq Trial-ECOG-ACRIN EA6134. J Clin Oncol. 2023;41(2):186-197. doi:10.1200/JCO.22.01763}

_{8. Ascierto PA, Mandalà M, Ferrucci PF, et al. Sequencing of ipilimumab plus nivolumab and encorafenib plus binimetinib for untreated braf-mutated metastatic melanoma (secombit): a randomized, three-arm, open-label phase II trial. J Clin Oncol. 2023;41(2):212-221. doi:10.1200/JCO.21.02961}

_{9. Moderna and Merck announce mRNA-4157/V940, an investigational personalized mRNA cancer vaccine, in combination with Keytruda(R) (pembrolizumab), met primary efficacy endpoint in phase 2b KEYNOTE-942 trial. Moderna. December 13, 2022. Accessed April 21, 2022. https://bit.ly/3Pwoake}