Neoadjuvant Momentum Builds for Treatment in Melanoma as Adjuvant Questions Persist

Anti–PD-1 therapy remains the backbone of adjuvant treatment for high-risk resected melanoma, but emerging neoadjuvant data, most notably from the phase 3 NADINA trial (NCT04949113), have triggered new questions, according to Mario Sznol, MD.

“If, in fact, the treatments that are being studied in the adjuvant and neoadjuvant settings work very effectively, a very large number of patients may never get metastatic disease. We have to discuss the risks of benefits of this approach for individual patients but reducing the burden of metastatic disease has undeniable benefits,” Sznol said.

In an interview with OncLive®, Sznol, professor emeritus at Yale School of Medicine in New Haven, Connecticut, and recently appointed faculty at the University of Miami in Florida, unpacked the evolving evidence, the pull between adjuvant and neoadjuvant strategies, and the next wave of investigational therapies that could further shift the survival curve.

OncLive: As immunotherapy moves into adjuvant and neoadjuvant settings, what questions remain about its optimal timing, duration, and clinical trial end points—particularly in the context of evolving targeted therapies for patients with oncogenic drivers?

Sznol: Right now there are only two relevant clinically actionable oncogenic drivers that could be targeted in the adjuvant setting; BRAF/MEK inhibitors for the 40-50% of patients whose tumors have BRAF V600 E/K mutations, and possibly the small subset whose tumors express KIT mutations. To my knowledge there have been no attempts to use KIT inhibitors for adjuvant melanoma treatment.

What is the best way to treat a patient who has had their primary tumor removed, has involved sentinel nodes and is at relatively high risk for recurrence? Without a BRAF mutation, the only option is anti–PD-1 therapy. Trials adding anti–CTLA-4 inhibitors or relatlimab to anti–PD-1 did not improve outcomes compared with anti–PD-1 therapy alone. While anti-PD-1 produces a very meaningful improvement in relapse-free survival, it is not clear that treating all patients in the adjuvant setting is better than waiting until progression, because so far, none of the data show an improvement in overall survival [OS]. These data indicate that treatment at the time of metastatic recurrence can be very effective. If there was no toxicity from anti-PD-1, it would make sense to give all high-risk patients adjuvant treatment. But anti-PD-1 is associated with severe adverse events in about 10% of patients, and there is a substantial cost to treatment and to the management of the adverse effects. As the risk of metastatic recurrence goes down, the risk-benefit ratio of giving adjuvant treatment becomes less favorable, particularly if there is no documented survival effect. If the tumor expresses a BRAF V600 mutation, BRAF/MEK inhibitors in the adjuvant setting have similar reductions in risk of recurrence when compared to anti-PD1 across studies. BRAF/MEK inhibitors are overall not as well tolerated, but they’re also not associated with long-term AEs. So perhaps BRAF/MEK inhibitors have an advantage over anti-PD-1 in this particular setting.

There was a small, randomized phase 2 trial of a personalized neoantigen vaccine combined with pembrolizumab [Keytruda] in the adjuvant setting, showing a marked improvement in relapse-free survival.¹ It was very promising result, and we are waiting confirmation from a larger phase 3 trial, which I believe is fully accrued. Even without survival data, a positive result would change the standard of care in this population. It is curious that a vaccine plus pembrolizumab would improve outcomes in the adjuvant setting when ipilimumab or relatlimab added to anti-PD-1 did not.

The standard of care is now evolving for patients presenting with clinically detectable regional nodal metastases, for example, by PET or detected by physical exam. These patients are now considered for neoadjuvant therapy. Preliminary data in the neoadjuvant setting suggest that the combination of ipilimumab [Yervoy] and nivolumab is more active than anti–PD-1 therapy alone or targeted therapies, when looking at pathologic response rates in the surgical specimen.

The very large investigator-led NADINA study showed that 2 cycles of neoadjuvant therapy was better than surgery followed by adjuvant anti–PD-1 therapy, for the endpoint of event-free survival, which was the [primary] end point.² Although OS data were not yet mature, the EFS differences were so large between neoadjuvant and adjuvant treatment that most investigators would likely choose neoadjuvant therapy for these patients. For patients with near complete or complete pathological response [pCR], additional adjuvant therapy would not be required.

The neoadjuvant approach may evolve even further to reduce the amount of required surgery. Rather than a full node dissection, initial sampling after two cycles of ipilimumab and nivolumab could be limited to a single involved node identified before therapy. If the node demonstrates a complete or near-complete pathologic response, the chances of melanoma recurrence are very low. Indeed, future studies may examine complete elimination of surgery in patients identified to have outstanding clinical responses to neoadjuvant treatment.

For neoadjuvant non-responders with tumors harboring a BRAF V600 mutation, it would be reasonable to offer BRAF/MEK inhibitors as adjuvant therapy after surgery. This question may be tested in a future study. Moreover, the high-risk non-responders to neoadjuvant therapy are an ideal population for future post -surgery adjuvant studies. Perhaps this latter population would be offered the neoadjuvant vaccine if results from the phase 3 trial we discussed above confirm the phase 2 data.

Speaking of vaccines and newer approaches, which of these modalities are most likely to be practice changing in the next 3 to 5 years, and what will be required to get them there?

Several approaches are being studied in the clinic. A positive neoantigen vaccine trial will have an enormous impact for the adjuvant setting, and perhaps would be studied again in the metastatic disease setting. For most agents, demonstrated activity in advanced disease usually drives studies conducted in the adjuvant and neoadjuvant setting. Among the candidates, the nearest to a readout includes the RP1 oncolytic virus, a PRAME T cell engager, the tebentafusp T cell engager and a PRAME TCR-T cell therapy. I would guess there are other promising therapies which I’m forgetting to include here.

The Immatics’ cell therapy is a TCR [T-cell receptor] T-cell therapy made from autologous peripheral blood lymphocytes, targeted to PRAME peptide bound to HLA-A*02:01. If the ongoing randomized trial is positive, it would of course add to our options for metastatic disease but perhaps might also be considered in earlier lines of disease treatment. The requirement for lymphodepletion is somewhat of a disincentive to move it into an adjuvant setting.

Tebentafusp-tebn [Kimmtrak] is a T cell engager targeted to a GP100 peptide presented by HLA-A201, and it provided a significant survival advantage for patients with metastatic uveal melanoma. Its activity alone or in combination has been underexplored in cutaneous melanoma. A similar PRAME T-cell engager is being studied in combination with anti–PD-1 therapy compared with nivolumab and relatlimab in the first-lime metastatic setting. A positive trial would have substantial implications for treatment of advanced disease, and we could expect exploration of the regimen in the adjuvant setting.

The ultimate goal for our patients is to improve survival, reduce toxicity from treatment, andavoid treating patients who don’t need therapy. The agents currently in advanced disease phase 3 trials, if the trials are positive, could improve long-term survival rates. The impact of neoadjuvant therapy and novel adjuvant therapies such as the neoantigen vaccine on OS is not yet known. For therapies first developed in metastatic disease and with toxicities considered excessive for the adjuvant setting, biomarkers such as ctDNA could identify patients for more intense treatments before developing overt metastatic lesions, and perhaps treatment would be less morbid and more effective in this setting. There is good reason to be optimistic that at least some of these approaches will improve patient outcomes. Nevertheless, a substantial unmet need will continue to exist and demand novel approaches.

Disclosures: Sznol has stock and stock options with Actym (stock options only), Asher Bio, Evolveimmune, GSK (stock), Intensity (stock options only), Johnson & Johnson (stock), Nextcure, Normunity, Oncohost, and Thetis; and has received consulting fees from Asher Bio, BioInvent, Biond (DSMC), BioNTech (DSMC), Bristol Myers Squibb, Cullinan Therapeutics, DynamiCure, EvolveImmune, GI Innovation, IDEAYA (DSMC), Immatics, ImmunoGenesis, Innate Pharma, IO Biotech, Lyvgen, Nimbus, NextCure, Pathios, Pfizer, Pliant Therapeutics, Regeneron, Sanofi (DSMC), Simcha Therapeutics, Teva, Turnstone Biologics, and Xilio Therapeutics.

References

1. Weber JS, Khattak MA, Carlino MS, et al; INT Research and Development Author Group. Individualized neoantigen therapy mRNA-4157 (V940) plus pembrolizumab in resected melanoma: 3 year- update from the mRNA-4157-P201 (KEYNOTE-942) trial. J Clin Oncol. 2024;42(suppl 17):LBA9512. doi:10.1200/JCO.2024.42.17_suppl.LBA951
2. Blank CU, Lucas MW, Scolyer RA, et al. Neoadjuvant nivolumab plus ipilimumab versus adjuvant nivolumab in macroscopic, resectable stage III melanoma: the phase III NADINA trial. J Clin Oncol. 2024;42(suppl 17):LBA2. doi:10.1200/JCO.2024.42.17_suppl.LBA2