Doctors Debate: Should Stage III Melanoma Be Treated in the Adjuvant or Neoadjuvant Setting?

Michael Lowe, MD, MA, FACS, FSSO

Providers treating resectable stage III melanoma after surgery have a plethora of options including immunotherapy, targeted therapies, or radiation therapy. Administering these agents before surgery is still an investigational practice, and a question of whether it is better to treat in the adjuvant or neoadjuvant setting lingers.

During the 2021 Debates and Didactics in Hematology and Oncology conference at Winship Cancer Institute of Emory University, Michael Lowe, MD, MA, FACS, FSSO, assistant professor, Department of Surgery, Emory University School of Medicine; and Ragini Kudchadkar, MD, associate professor, chair Protocol Review and Monitoring Committee Director melanoma and Skin Cancer Program, Winship Cancer Institute Emory University, debated about the topic. Lowe argued in favor of adjuvant therapy,¹ while Kudchadkar disputed for the neoadjuvant side of the debate.² However, Lowe explained that the debate is an ongoing one.

“Stage III melanoma will continue to be a debate until we have evidence from a clinical trial that randomized patients to 1 of those 2 treatment arms, as is undergoing and SWOG 1801 trial. Until then, we have very limited data to support the idea that every patient with resectable stage III melanoma should get neoadjuvant therapy,” Lowe told Targeted Oncology™ in an interview.

“The majority of those data are based on very small single-institution studies that do suggest the relationship between pathalogic complete response and recurrence-free survival but have not yet demonstrably proved that this is changing patients’ overall survival. These studies are all very small, and they have a relatively short follow-up. There are, however, numerous randomized phase 3 trials with long-term follow-up, that do show a benefit to adjuvant therapy, either over placebo or inferior agents that are associated with prolonged relapse-free survival and overall survival,” Lowe explained.

Adjuvant Treatment of Stage III Melanoma

With a focus on systemic therapy for stage III melanoma, Lowe’s presentation first highlighted that treatment with adjuvant nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated a significant improvement in recurrence-free survival compared with placebo in the CheckMate-238 study (NCT02388906).^1,3

Median follow-up in the study was 18 months. Results from the study showed a 70.5% (95% CI, 66.1%-74.5%) recurrence-free survival (RFS) rate at 12 months in the nivolumab group compared with 60.8% (95% CI, 56.0%-65.2%) in the ipilimumab group (hazard ratio [HR], 0.65; 97.56% CI, 0.51-0.83; P <.001).

When RFS was evaluated by PD-L1 expression, the patients with a PD-L1 expression of less than 5% showed a 12-month RFS rate of 64.3% (95% CI, 58.3%-69.7%) in the nivolumab arm versus 53.7% (95% CI, 47.6%-59.4%) in the ipilimumab arm. In the high expression PD-L1 group (5% or more), the 12-month RFS rate was 81.9% (95% CI, 74.7%-87.2%) in the nivolumab arm versus 73.8% (95% CI, 65.9%-80.1%) in the ipilimumab arm.

Based on this study, the benefit of nivolumab was irrespective of PD-L1 status. The safety results were also favorable in CheckMate-238, with grade 3 or 4 treatment-related adverse events occurring in only 14.4% of the patients treated with nivolumab and 45.9% of those in the ipilimumab arm. Treatment discontinuation occurred as a result of an AE in 9.7% of the nivolumab arm compared with 42.6% of the ipilimumab arm.

Nivolumab was granted regular FDA approval for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or in patients with metastatic disease who have undergone complete resection based on the CheckMate-238 findings.⁴

The next agent to be indicated for use in this patient population was adjuvant pembrolizumab (Keytruda), which was FDA approved based on results from the KEYNOTE-054 trial (NCT02362594).⁵

Adjuvant pembrolizumab achieved a distant metastasis-free survival (DMFS) rate of 65.3% (95% CI, 60.9%-69.5%) compared with 49.4% (95% CI, 44.8%-53.8%) with placebo (HR, 0.60; 95% CI, 0.49-0.73]; P < .0001). among those with PD-L1-postive tumors, the DMFS rate was 66.7% (95% CI, 61.8%-71.2%) in the pembrolizumab arm versus 51.6% (95% CI, 46.6%-56.4%) in the placebo arm (HR, 0.61; 95% CI. 0.49-0.76]; P <. 0001).^1,6

The RFS rate was also longer with pembrolizumab compared with placebo at 59.8% (95% CI, 55.3%-64.1%) versus 41.4% (95% CI, 37.0%-45.8%), respectively. In the PD-L1-positive subgroup, the RFS rate was 61.4% (95% CI, 56.3%-66.1%) in the pembrolizumab group compared with 44.1% (95% CI, 39.2%-48.8%) in the placebo group (HR, 0.59l; 95% CI, 0.49-0.73).

The standard of care in the stage III melanoma landscape was solidified in 2021 when the combination of nivolumab and ipilimumab did not show a statistically significant benefit over nivolumab alone in the CheckMate-915 trial (NCT03068455). Therefore, adjuvant nivolumab monotherapy remains the golden standard.^1,7

“Regarding the clinical trials in the adjuvant setting using immunotherapy, while they did demonstrate an improvement in recurrence-free survival, there still isn't a definitive benefit on overall survival for immunotherapy in the adjuvant setting. And so, it really begs the question, is adjuvant therapy sufficient therapy for these patients? Or is it going to require the addition of a course of neoadjuvant therapy to show an improvement in melanoma-specific survival for patients with resectable stage II disease? I think the Checkmate-915 results suggested that may be the case.” said Lowe.

Ongoing research in the melanoma field may be able to answer some of the remaining questions about adjuvant therapy, according to Lowe. “From the surgical side, the question is, is it sufficient to remove the lymph node with known disease in it or does it require a formal lymphadenectomy to impact regional relapse rates? There are clinical trials peripherally asking this question, but not explicitly. I think that will help us have a better sense of the extensive surgery required after complete pathologic response following new adjuvant therapy, but it will require a more robust, randomized trial to answer that question definitively,” Lowe stated.

Neoadjuvant Treatment of Stage III Melanoma

A number of studies using neoadjuvant therapy to treat patients with stage III melanoma have shown consistent promise, according to Kudchadkar. And compared with clinical trials evaluating adjuvant therapy, patients treated in the neoadjuvant setting appear to have better overall outcomes.²

Ragini Kudchadkar, MD

“Although there hasn't been a large volume of patients treated with neoadjuvant therapy, it's very clear that the pathologic response can dictate overall outcomes for patients. And that pathologic complete response is a very good predictor of long-term survival with no relapse for those patients. That's also an important indicator prognostically for these patients, and in the future, it will likely guide what we do in the adjuvant setting,” Kudchadkar told Targeted Oncology™ in an interview.

In the phase 2, multicenter, randomized, controlled OpACIN trial of nivolumab/ipilimumab in the neoadjuvant setting versus nivolumab/ipilimumab in the adjuvant setting, neoadjuvant therapy was tolerable and achieved pathologic complete responses (PCRs) in a high number of patients. Specifically, PCRs were observed in 80% (95% CI, 61%-92%) of the patients treated with 2 cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks intravenously (group A), 77% (95% CI, 58%-90%) in those treated with 2 cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks intravenously (group B), and 65% (95% CI, 44%-83%) in the group that received 2 cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by 2 cycles of nivolumab 3 mg/kg once every 2 weeks intravenously (group C).^2,8

The difference in grade 3 to 4 toxicity between group B and A was −20% (95% CI, −46 to 6; P =.158). The difference in grade 3 to 4 toxicity between group C and group A was 10% (95% CI, −20 to 40; P =.591).

A pooled analysis conducted by the International Neoadjuvant Melanoma Consortium and published in 2021 also signaled that neoadjuvant anti-CTLA plus anti-PD-1 with the combination of nivolumab and ipilimumab may prolong RFS. The relapse rate in the study was only 20% at 2 years, Kudchadkar highlighted.^2,9

With the same immunotherapy combination, data published 1 year prior showed that neoadjuvant treatment induced a high pathologic response rate (pRR) and demonstrated tolerability in patients with resectable stage III melanoma. The pRR observed was 71%, (95% CI, 61%-79%).¹⁰

Other research exploring the efficacy and safety of the neoadjuvant BRAF/MEK combination of dabrafenib (Tafinlar) and trametinib (Mekinist) included the phase 2 Neo Combi study (NCT01972347) and a phase 2 trial Combi-Neo (NCT02231775). Both studies are ongoing, but early findings were encouraging.^11,2

In Neo Combi, the PCR rate observed with the combination of dabrafenib and trametinib in 35 patients with stage IIIB-C BRAF V600E-mutated melanoma was 49%. The RFS at 2 years in the study was 63.3%. Safety findings from Neo Combi revealed serious treatment-emergent AEs in 17% of patients, of which 29% were grade 3 or 4 in severity.¹¹

In the other phase 2 Combi-Neo study of dabrafenib plus trametinib in stage IIIB-C melanoma with BRAF V600E mutation, the combination achieved a median event-free survival of 19.7 months. The pCR observed with the combination was also favorable at f 58%, with 17% being PRs. Further, both drugs were well-tolerated by the patient group. There were no grade 4 AEs or treatment-related deaths during the study.²

After sharing the data from these studies during her presentation, Kudchadkar stated, “Pathologic response predicts overall outcomes for surgery – patients with pCR can often have less systemic therapy and less surgery over the long run.”

Waiting for Definitive Research

Both physicians agreed that the debate about adjuvant versus neoadjuvant therapy for the treatment of resectable stage III melanoma requires more research.

“This is sort of a loaded question in terms of a debate question, simply because there's no data that actually supports either side of this argument because the questions never been asked in a clinical setting,” said Lowe.

In an ongoing study S1801 (NCT03698019), the use of adjuvant pembrolizumab will be compared with neoadjuvant pembrolizumab in approximately 500 patients with high-risk melanoma. To evaluate which treatment setting may be superior, the primary end point that will be assessed is EFS. The study will also evaluate overall survival, disease control, locoregional control, the total number of pembrolizumab doses, pCR, RECIST v1.1 response rate, and immune-related RECIST v1.1 response rate as secondary end points. The study is expected to complete at the end of 2022.¹²

“My biggest question is, especially in the neoadjuvant space, is what are we doing adjuvantly? Do we even need adjuvant treatment for some of those patients with a pCR? Should we be switching therapy? I think I think we don't know how to interpret the pathologic response in a way that allows us to adjust our therapy. But I think these are huge questions that remain that we're going to have to sort out through upcoming trials,” Kudchadkar concluded during the interview.

_References:

_{1. Lowe M. Adjuvant therapy for resected stage III melanoma. Presented at: 2021 Debates and Didactics in Hematology and Oncology Conference; July 29 - August 1, 2021.}

_{2. Kudchadkar R. Neoadjuvant therapy. Presented at: 2021 Debates and Didactics in Hematology and Oncology Conference; July 29 - August 1, 2021.}

_{3. Weber J, Mandala M, De; Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage iii or iv melanoma. N Engl J Med. 2017; 377 (19):1824-1835: doi: 10.1056/NEJMoa1709030}

_{4. FDA grants regular approval to nivolumab for adjuvant treatment of melanoma. News release. FDA. December 20, 2017. Accessed January 10, 2022. https://bit.ly/3GIYCuP}

_{5. FDA approves pembrolizumab for adjuvant treatment of melanoma. News release. FDA. February 15, 2019. Accessed December 10, 2022. https://bit.ly/3nWn0C3}

_{6. Eggermont AM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22 (5):643-654. doi: 10.1016/S1470-2045(21)00065-6}

_{7. Long GV, Schadendorf D, Del Vecchio M, et al. Cancer Res. Published July 2021. doi: 10.1158/1538-7445.AM2021-CT00}

_{8. Rozeman EA, Menzies AM, van Akkooi A, et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 2019; 20 (7): 948-960. doi: 10.1016/S1470-2045(19)30151-2}

_{9. Menzies AM, Amaria RN, Rozeman EA, et al. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC). Nat Med. 2021;27(2):301-309. doi: 10.1038/s41591-020-01188-3.}

_{10. Blank CU, Reijers I, Pennington T, et 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): 10002-10002. doi: 10.1200/JCO.2020.38.15_suppl.10002}

_{11. Long G, Saw R, Lo S, et al. Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB-C, BRAF V600 mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial. Lancet Oncol. 2019;20(7):961-971. doi: 10.1016/S1470-2045(19)30331-6.}

_{12. A study to compare the administration of pembrolizumab after surgery versus administration both before and after surgery for high-risk melanoma. Clinicaltrials.gov. Accessed January 18, 2022. https://bit.ly/3nCCn21}