New, Updated Data Demonstrate Promising Future in Advanced Melanoma

Jeffrey S. Weber, MD, PhD

Long-term and recent data readouts have fueled immunotherapeutic advances in the treatment of advanced melanoma. At the 6th Annual International Congress on Immunotherapies in Cancer^™: Focus on Practice-Changing Application, Jeffrey S. Weber, MD, PhD, presented findings from efficacious trials that have expanded the treatment options for patients with melanoma.

Notably, outcomes of the KEYNOTE 716 trial (NCT03553836) showed that at a median follow-up of 14.4 months pembrolizumab (Keytruda; n = 487) significantly prolonged recurrence-free survival (RFS) vs placebo (n = 489; HR, 0.65; 95% CI, 0.46-0.92; P = .00658) in patients with stage IIB (n = 624) and stage IIC (n = 339) melanoma. Specifically, 54 patients (11.1%) vs 82 patients (16.8%) had a recurrence event and 23 (4.7%) vs 38 (7.7%) had distant recurrence events in the pembrolizumab and placebo groups, respectively. The 12-month RFS rates were 90.5% vs 83.1%, respectively.¹

Investigators also presented updated findings from the KEYNOTE 029 trial (NCT02089685). At a median follow-up of 36.8 months, OS with pembrolizumab plus ipilimumab was not reached in patients with advanced melanoma (n = 153); the 36-month rate was 73.4%.²

Additionally, data from the CheckMate 238 trial (NCT02388906) demonstrated a 4-year RFS rate of 51.7% (n = 453; 95% CI, 46.8%-56.3%) in the nivolumab (Opdivo) group vs 41.2% (n = 453; 95% CI, 36.4%-45.9%) in the ipilimumab group (Yervoy; HR, 0.72; 95% CI, 0.6-0.86; P = .0003) in patients with stage IIIB-IC or stage IV melanoma. The median follow-up was 51.1 months with nivolumab and 50.9 months with ipilimumab.³

In CheckMate 067 (NCT01844505) treatment with an immunotherapy combination elicited median overall survival (OS) of 72.1 months with nivolumab plus ipilimumab (n = 314) vs 36.9 months with nivolumab alone (n = 316) and 19.9 months with ipilimumab alone (n = 315) in patients with untreated, unresectable stage III or stage IV melanoma. The minimum follow-up was 6.5 years.⁴

And findings from the RELATIVITY-047 study (NCT03470922) show that median progression-free survival (PFS) in the relatlimab plus nivolumab group was 10.1 months (n = 355; 95% CI, 6.4-15.7), which was significantly longer than that in the nivolumab alone group at 4.6 months (n = 359; 95% CI, 3.4-5.6) in patients with previously untreated advanced melanoma (HR, 0.75; 95% CI, 0.6-0.9; P = .0055).⁵ The median follow-up was 13.2 months.^1-5

“There will continue to be progress in the melanoma field,” Weber said. “Anyone who thinks the melanoma problem is licked should take another look; that is not the case. We continue to see patients with bad disease. We’ve come a long way, but there’s [still] a long way [to go].”

In an interview with OncLive^®, Weber, deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center in New York, New York, overviewed the successes made in the melanoma setting in the past decade and the challenges to overcome in the future.

OncLive: Please provide an overview of the current clinical trial landscape for melanoma therapies.

Weber: Most of the news in melanoma in advanced disease relates to a few recently mature trials and some updates on older trials.

For example, we recently heard good news about the KEYNOTE 716 trial, which was a large randomized trial, and now for the first time, [there is] adjuvant treatment for patients with stage IIB and IIC resected melanoma. The initial data were presented at [the European Society for Medical Oncology Congress 2021] and then updated at [the 2021 Society for Melanoma Research Congress; SMR], and clearly there’s a significant difference in the RFS in the overall group. [We] found that the hazard ratio got better; if the initial hazard ratio was 0.65, then it dropped to 0.61. So as the data matured, the difference in RFS between the pembrolizumab arm and the placebo arm for the stage IIB and IIC patients only got better.

The initial concern about the IIC patients not having that much of a difference between the 2 arms was allayed somewhat as the curves began to widen out, so that was reassuring. At SMR, for the first time we heard about the quality-of-life information and it looked encouraging. I suspect that will eventually get approved and we will have a new element in the armamentarium for resected high-risk melanoma.

We also have heard updates on the CheckMate 238 trial—a trial that I was the [primary investigator] on—which was the original trial of nivolumab and ipilimumab for resected stage IIIB, IIIC, and IV melanoma. And again, finally we have reached the median RFS; it is approximately 5 years, which is impressive. Go back 10 years, and the median RFS in high-risk melanoma was more like 2 or 2.5 years; now, it is doubled.

In the metastatic mode, we had updates from the CheckMate 067 study; it is the study that keeps on giving. There is 7 plus years of data. In that study, the classic 3 arm study of [nivolumab plus ipilimumab] vs nivolumab alone vs ipilimumab alone, we are finally at 72 months at a median survival. Ten years ago, the median survival in melanoma was, on a good day, maybe 1 year, maybe even less. Now we are at a 6-month median survival for a large group of patients who get ipilimumab and nivolumab, and that is impressive. Those data provide encouraging news to us.

We also heard updates on the KEYNOTE-029 trial. It was a similar trial [to CheckMate 067], but it looked at pembrolizumab [in combination with] ipilimumab and they flipped the doses around. In that study, whether you gave ipilimumab every 6 weeks or every 12 weeks, the OS between 3 to 5 years looked good.

The RELATIVITY-047 study was a new study that was presented first at [the 2021 American Society of Clinical Oncology Annual Meeting; ASCO] and then updated at ESMO, suggesting that the combination of the relatlimab with nivolumab had clearly superior PFS to nivolumab alone. We have not heard much about response rate or OS yet. But the data looked good, and the primary end point for the FDA was PFS. I think there is high hopes that when that [Prescription Drug User Fee Act] PDUFA date comes by, we are going to see an approval for that regimen.

[There is] nice data in the advanced melanoma setting, [including] some new data and some updates on old data. And we continue to do well with our patients. Thinking about median survivals and median RFS in the current era compared with what it was like 10 years ago, [there is] just a phenomenal improvement over time. It is not like we are putting ourselves out of work anytime soon, but we have made a lot of progress.

Have there been any recent trials in melanoma with negative outcomes?

There was a negative trial, the MASTERKEY-265 trial [NCT02263508], the trial of pembrolizumab plus talimogene laherparepvec [Imlygic] vs pembrolizumab alone was absolutely, unequivocally dead negative. The curves overlapped more than any other study I have ever seen for PFS and OS at 1 year, 2 years, 2 years plus. There is no evidence that the direct injectable oncolytic herpes virus injected directly into a tumor adds anything to the efficacy of pembrolizumab.

What notable ongoing studies should physicians look out for?

Some earlier phase 2 studies—1 of which I presented recently at ESMO of ipilimumab and nivolumab at flipped doses with tocilizumab [Actemra], an interleukin[IL]-6 blocking antibody [NCT03999749]—suggesting we had a nice response rate in the range of 58% and a low rate of toxicity in a trial that was designed to reduce the side effects by blocking IL-6 signaling. [There was] only 29 patients, but we are going to hear more about that.

The updated phase 2 trial [NCT03645928] data on tumor infiltrating lymphocytes with high dose IL-2 from Iovance [Biotherapeutics] is a study that is well along in its follow up, confirming a 36-plus percent response rate with interestingly 17% of patients having further reduction more than 6 to 12 months after the response. [There is] a waterfall plot that looks impressive with 81% of the patients having some reduction in tumor burden.

We have an ongoing adjuvant study [PIVOT-12; NCT04410445] with bempegaldesleukin plus nivolumab vs nivolumab alone. Nivolumab is the standard control arm; it is the established therapy that we have high hopes for. We have a metastatic frontline trial [NCT03635983] of the same drugs, nivolumab plus bempegaldesleukin vs nivolumab alone that should read out early in the year.

If those studies are positive, that will add yet drug another pegylated IL-2 molecule to the armamentarium. We know that IL-2 can be an effective drug for melanoma. It was approved in 1998; it is rarely used because at the approved dose, it is toxic. But now we have got probably 7 different modified IL-2 products being tested and bempegaldesleukin is probably furthest along.

What are the unmet needs that still need to be addressed?

We have a 50% median survival at 6 years with [nivolumab plus ipilimumab]; that means half the patients are going to die. Anyone who does not think that half the patients needing further therapy is not an unmet need needs to take another look. Anybody who thinks that the melanoma problem is licked needs to take another look.

We still have 1 approved therapy for ocular melanoma, the IMCgp100 drug [tebentafusp]. But when you look at the survival data, there is room for improvement. There is no other drug or drugs that work in ocular melanoma once it spreads; we have no adjuvant data for ocular melanoma.

Mucosal melanoma remains an area of some unmet need because [nivolumab plus ipilimumab] does not work as well in mucosal melanoma compared to cutaneous. The majority of unknown origin melanomas are probably cutaneous based on their genomic profile, but you have a group of 5% of patients who have disease that is are mucosal or ocular origin or acrolentiginous, and they have low mutational burden and do not respond as well to immunotherapy. That is a huge area of unmet need, no question.

References

1. Luke JJ, Rutkowski P, Queirolo P, et al. Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: Efficacy and safety results from the KEYNOTE-716 double-blind phase III trial. Ann Oncol. 2021;32(5): S1283-S1346. doi:10.1016/annonc/annonc741
2. Carlino MS, Atkinson V, Cebon J, et al. KEYNOTE-029: efficacy and safety of pembrolizumab (pembro) plus ipilimumab (IPI) for advanced melanoma. J Clin Oncol. 2017;35(15):9545. doi: 10.1200/JCO.2017.35.15_suppl.9545
3. Ascierto PA, Del Vecchio M, Mandala M, et al. Adjuvant nivolimab versus ipilimumab in resected stage IIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020;21(11):P1465-1477. doi:10.1016/S1470-2045(2)30494-0
4. Wolchok JD, Chiarion-Sileni V, Gonzalez R. CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma. J Clin Oncol. 2021;39(suppl 15):9506. doi:10.1200/JCO/2021.39.15_suppl.9506
5. Lipson EJ, Tawbi AHH, Schadendorf D, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: Primary phase III results from RELATIVITY-047 (CA224-047). J Clin Oncol. 2021;39(suppl 15):9503. doi:10.1200/JCO.2021.39.15_suppl.9503