Expert Insights on New Studies and Unmet Needs for Melanoma Monday

Melanoma Monday, which falls on May 3, is meant to raise awareness about melanoma, the deadliest type of skin cancer.

According to the American Academy of Dermatology, 1 in 5 Americans will develop skin cancer in their lifetime and it is the most common type of cancer in the United States. Every day, an estimated 9500 people are diagnosed with skin cancer in the United States alone.1

Combination therapies such as ipilimumab (Yervoy), nivolumab (Opdivo), and targeted therapies with BRAF and MEK inhibitors have helped to transform melanoma treatment. Development of adjuvant and neoadjuvant therapy have the potential to boost survival and advances in the later line setting has the potential to be practice changing.

In an interview with Targeted Oncology, Zeynep Eroglu, MD, of the Moffitt Cancer Center, discussed recent advances in melanoma treatment, exciting upcoming studies, and the evolving melanoma landscape.

TARGETED ONCOLOGY: How has the melanoma landscape evolved over the last few years?

EROGLU: One of the things that is interesting, in the last few years especially, has been the ongoing development in neoadjuvant and adjuvant treatments in melanoma. For example, in the neoadjuvant space, there's been a couple of clinical trials specifically exploring combination immunotherapy of ipilimumab and nivolumab prior to surgery. Of note, these trials include arms with alternative dosing of nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg for 2 cycles prior to surgery, which has less toxicity that standard dosing.2 While certainly data in other tumor types are further ahead in neoadjuvant therapy than in melanoma, it's really exciting research.

The next trials coming in the neoadjuvant space are now looking at whether to tailor the type of surgery based on pathological response, and the adjuvant treatment that these patients would receive afterwards versus just observation after surgery. It's interesting that oftentimes, the CT imaging response that will be seen in patients following neoadjuvant treatment prior to surgery does not always correlate with pathologic response.3 We have seen a lot of patients, for example, based on RECIST criteria using in trials just with stable disease or partial response on CT imaging, go on to have complete pathological response at surgery.

There's not just immunotherapy, but also BRAF/MEK inhibitor therapy neoadjuvant studies ongoing in that space as well, again tailoring the post-surgery treatment to the surgical pathologic response that the patient may have to the neoadjuvant treatment. Although we don't know yet if a neoadjuvant approach is superior to adjuvant treatment in melanoma.

TARGETED ONCOLOGY: How does a neoadjuvant treatment followed by surgery compare with upfront surgery followed by adjuvant therapy?

EROGLU: I think for that we really need the results of ongoing randomized trials that are exploring neoadjuvant versus adjuvant approaches with anti–PD-1 therapy specifically, such as SWOG S1801.

I think in that vein, we also look forward to the results adjuvant studies that are going on now for stage II disease. We know that anti–PD-1 antibody and BRAF/MEK inhibitor treatments are approved stage III melanoma post-surgery, but there is a lot of interest to determine if there is efficacy with these types of treatments in patients with stage IIB and IIC melanoma, who are high risk in terms of risk of relapse, even higher risk than stage IIIA disease. I think everyone is interested in the results of recently completed study looking at adjuvant pembrolizumab [Keytruda] versus placebo in stage IIB/IIC melanoma. There's currently an ongoing study of nivolumab versus placebo in patients with stage IIB and IIC disease. I think, hopefully within the next year or two, we'll get an idea of whether there is room for adjuvant systemic therapy in patients with stage IIB and IIC melanoma.

There are also questions about the role of ipilimumab with nivolumab in the adjuvant melanoma setting. There was a study that was exploring this combination in stage III/IV melanoma post-surgery, CheckMate-915 [NCT03068455] that recently reported negative results.4 Adjuvant ipilimumab plus nivolumab versus nivolumab did not meet the primary end point of relapse-free survival [RFS]. But there are of questions with that study around the use of alternative dosing of ipilimumab and nivolumab—at 1 mg/kg every 6 weeks of ipilimumab, it was quite different than the standard ipilimumab and nivolumab dosing. So, it is certainly possible that may have impacted the results.

There had been previous smaller studies, like the phase 2 IMMUNED trial, that looked at adjuvant ipilimumab and nivolumab standard dosing versus nivolumab specifically in patients with stage IV melanoma. That study found a clear relapse-free survival benefit with the 2-year RFS rate of 70% with the combination versus about 40% with nivolumab.5 Although there was significantly increased toxicity with the adjuvant combination arm versus nivolumab alone. So, we haven't really answered the questions about the role of adjuvant ipilimumab and nivolumab treatment yet, unfortunately.

In this stage III and IV adjuvant setting, there are trials now looking at newer immunotherapy drugs. So, for example, there's an ongoing study [NCT03470922] looking at nivolumab with LAG-3 antibody relatlimab versus nivolumab monotherapy. It will be interesting to see the results.

Also noteworthy is that there was a recent press release that the phase 3 combination of nivolumab with relatlimab versus nivolumab met its primary endpoint of progression-free survival in the first-line metastatic setting, so this might become a new approved treatment option for our patients with metastatic melanoma.6 Of course, we don’t know yet how this new combination might compare to nivolumab with ipilimumab in terms of efficacy and toxicity.

TARGETED ONCOLOGY: Are there any other targets in melanoma that you think are important?

EROGLU: In terms of the targets, there's still a lot of focus still on the MAP kinase pathway in a lot of ongoing studies. Not necessarily patients with BRAF V600 mutations only, but potentially encompassing patients with atypical BRAF mutations or NRAS mutations or others. There are ongoing trials looking at ERK inhibitors downstream of MEK, or atypical BRAF and CRAF inhibitors and combining them with MEK inhibitors. There are even studies that are looking at more novel brain-penetrating BRAF inhibitors, as we need to improve outcomes in patients with brain metastases.

There are also combination of CDK4/6 inhibitors, BCL2 inhibitors and other targets, and adding those to BRAF/MEK inhibitors to try to prolong the duration of response in those patients. Certainly, there have been recent triplet clinical trials as well, combining anti–PD-1 or PD-L1 therapies with BRAF/MEK inhibitors, and the approval of the first triplet regimen in metastatic melanoma. So, there's quite a bit that’s also happening in the targeted therapies space.

TARGETED ONCOLOGY: What are some unmet needs in the melanoma space that you haven't touched on yet?

EROGLU: I would say uveal melanoma, unfortunately. It's a rare tumor type but metastatic uveal melanoma is still very challenging to treat. The response to nivolumab and ipilimumab immunotherapy in metastatic uveal melanoma is pretty dismal, with about a 15% tumor response rate. So, dramatically lower than what we tend to see in cutaneous melanomas. But the recent results with IMCgp100 or tebentafusp, a bispecific fusion protein targeting gp100+ cells has been encouraging, with one-year overall survival rate of about 70% versus 58% with investigator’s choice in these patients.7 There’s also been ongoing approaches, for example, with liver-directed therapy with Delcath-PHP, which essentially delivers high-dose melphalan chemotherapy directly to the liver. I believe there will be some upcoming results from that study as well.

I think treating melanoma brain metastases, especially symptomatic brain metastases, also remains very challenging. With nivolumab and ipilimumab, the intracranial response rate in melanoma brain metastases is around 55%. But when the patient has symptomatic brain mets requiring steroids, that drops to about a 20% intracranial response rate. So, there are various approaches now to try to improve upon this. For example, we have a clinical trial, SWOG 2000 [NCT04511013], that's looking at a triplet approach for BRAF-mutant melanoma brain metastases of encorafenib [Braftovi], binimetinib [Mektovi], and nivolumab versus nivolumab and ipilimumab, including in symptomatic patients that may require steroids. Potentially with a triplet approach we can improve upon what we see with nivolumab and ipilimumab, especially in the symptomatic cohort.

Along that vein, leptomeningeal melanoma metastases remain one of the greatest unmet needs. With leptomeningeal metastases for most patients unfortunately, survival amounts to weeks after diagnosis of leptomeningeal spread. There has been some innovative work exploring intrathecal administration of anti–PD-1 therapy, so essentially delivering the drug right into the cerebral spinal fluid.8 I think there'll be more to come from that. But still, there's a lot more we need to do for patients with leptomeningeal melanoma. Unfortunately, oftentimes, they also get excluded from a lot of clinical trials.

Mucosal melanoma is also a rarer melanoma type. Generally, there is more resistance to immunotherapy than cutaneous melanoma. So, these are melanomas that may start in the nasal tract, the sinuses, the gastrointestinal tract. For example, the response in metastatic disease to nivolumab and ipilimumab is only 40%. So, there has been in the last year presentation of results of a Chinese trial looking at axitinib [Inlyta], a VEGFR inhibitor, in combination with anti–PD-1 therapy in first line, metastatic mucosal melanoma that showed a response rate of about 48%.9 That's promising.

References:

1. Do you use protection? American Academy of Dermatology. Accessed April 29, 2021. https://bit.ly/2QAaeM2

2. Rozeman, E.A., Hoefsmit, E.P., Reijers, I.L.M. et al. Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma. Nat Med. 2021;27:256–263. doi:10.1038/s41591-020-01211-7

3. Blank CU, Reijers ILM, Pennington T, at al. First safety and efficacy results of PRADO: A phase II study of personalized response-driven surgery and adjuvant therapy after neoadjuvant ipilimumab (IPI) and nivolumab (NIVO) in resectable stage III melanoma. J Clin Oncol. 2020;38(suppl 15):10002. doi:10.1200/JCO.2020.38.15_suppl.10002

4. Bristol Myers Squibb announces update on CheckMate -915 Evaluating Opdivo (nivolumab) plus Yervoy (ipilimumab) versus Opdivo in resected high-risk melanoma patients. News release. Bristol Myers Squibb. Published October 2, 2020. Accessed April 29, 2021. https://bit.ly/3u6wono

5. Zimmer L, Livingstone E, Hassel JC, et al; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020;395(10236):1558-1568. doi:10.1016/S0140-6736(20)30417-7

6. Bristol Myers Squibb Announces RELATIVITY-047, a Trial Evaluating Anti-LAG-3 Antibody Relatlimab and Opdivo (nivolumab) in Patients with Previously Untreated Metastatic or Unresectable Melanoma, Meets Primary Endpoint of Progression-Free Survival. News release. Bristol Myers Squibb. Published March 25, 2021. Accessed May 3, 2021. https://bit.ly/3uhttbM

7. Piperno-Neumann S, Hassel JC, Rutkowski P, et al. Phase 3 randomized trial compared tebentafusp with investigator’s choice in first line metastatic uveal melanoma. Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual. CT002.

8. Glitza IC, Phillips S, Brown C, et al. Single-center phase I/Ib study of concurrent intrathecal (IT) and intravenous (IV) nivolumab (N) for metastatic melanoma (MM) patients (pts) with leptomeningeal disease (LMD). J Clin Oncol. 2020;38(suppl 15):10008. doi:10.1200/JCO.2020.38.15_suppl.10008

9. Sheng X, Yan X, Chi Z, et al. Axitinib in combination with toripalimab, a humanized immunoglobulin G4 monoclonal antibody against programmed cell death-1, in patients with metastatic mucosal melanoma: an open-label phase IB trial. J Clin Oncol. 2019;37(32):2987-2999. doi:10.1200/JCO.19.00210