Neoadjuvant and Adjuvant Treatment Approaches Expand Options in CSCC and Melanoma

During a recent OncLive® Scientific Interchange and Workshop on melanoma and nonmelanoma skin cancers, which took place in Berlin, Germany, during the 2025 European Society for Medical Oncology Congress, expert faculty in the field gathered to discuss how recent updates in melanoma and cutaneous squamous cell carcinoma (CSCC) are reshaping the treatment landscapes of these diseases for patients.¹

“[Our goal is] to evaluate the current evidence and emerging trial data for adjuvant and neoadjuvant options in CSCC and cutaneous melanoma,” Heather Shaw, MD, FRCP, a consultant medical oncologist and lead for the medical oncology skin cancer service at University College London Hospital in England and the workshop moderator, said during the workshop. “[We will consider] the current standards of care and [will be] addressing specific challenges in the high-risk settings of CSCC and melanoma.”

How have new data in CSCC affected the treatment paradigm?

The faculty members opened their discussion by first highlighting updated data from the phase 3 C-POST trial (NCT03969004) presented during the 2025 ASCO Annual Meeting.² C-POST evaluated adjuvant cemiplimab-rwlc (Libtayo) for the treatment of patients with high-risk CSCC. The primary end point was disease-free survival (DFS).

Data from C-POST demonstrated that patients who received adjuvant cemiplimab (n = 209) achieved a median DFS of not reached (NR; 95% CI, not evaluable [NE] to NE) compared with 49.4 months (95% CI, 48.5-NE) among those who received placebo (n = 206; HR, 0.319; 95% CI, 0.199-0.511; P < .0001). Patients in the cemiplimab arm also experienced significant benefits compared with the placebo arm in terms of freedom from locoregional recurrence (HR, 0.20; 95% CI, 0.09-0.40) and freedom from distant recurrence.

Data from C-POST supported the October 2025 FDA approval of cemiplimab for the adjuvant treatment of adult patients with CSCC at a high risk of recurrence after surgery and radiation.³

“The HR was pretty compelling, all things considered, given the high risk of these patients and the fact that they'd all been irradiated before they entered study. [Additionally], cemiplimab generally favored all groups within the subset analysis,” Shaw commented. In the neoadjuvant setting, the faculty members discussed findings from a phase 2 study (NCT04808999) of neoadjuvant pembrolizumab (Keytruda) for the treatment of patients with PD-1–naive CSCC.⁴

Findings from the study revealed that patients with high-risk locally advanced CSCC who received neoadjuvant pembrolizumab (n = 27) achieved an overall response rate of 30% per RECIST 1.1 criteria. Radiotherapy was de-escalated in 67% of patients, including 94% who achieved a pathologic complete response (n = 16).

The phase 2 DESQUAMATE trial (NCT05025813) also examined de-escalated neoadjuvant pembrolizumab for the treatment of patients with resectable high-risk CSCC.⁵ Findings from DESQUAMATE showed that patients who received pembrolizumab (n = 17) had treatment de-escalated at a rate of 63%. Notably, all patients who achieved a clinical complete response, a pathologic complete response, or a pathologic partial response were relapse-free at 12 months.

“Response-adapted treatment [is how] our multidisciplinary team is looking at these sorts of malignancies,” Rahul Ladwa, MD, an associate professor at Queensland Head & Neck Cancer Centre in Brisbane, Australia, said. “[We] can stratify risk by the response to immune therapy. Ultimately, from my perspective, [we can] give immune therapy, see what happens, and then act upon it there afterward in a selected group of patients.”

What are the latest data in melanoma?

The faculty members transitioned their discussion to the neoadjuvant treatment of patients with resectable melanoma, beginning with the phase 3 NADINA trial (NCT04949113) of neoadjuvant ipilimumab (Yervoy) plus nivolumab (Opdivo).⁶ “NADINA was the mic drop moment for everybody last year,” Shaw commented.

At a median follow-up of 15.4 months (95% CI, 9.0-22.4), findings from NADINA showed that patients with resectable stage III melanoma who received neoadjuvant ipilimumab plus nivolumab (n = 212) achieved a significant event-free survival benefit compared with those who received adjuvant treatment with the combination (n = 211; adjusted HR, 0.32; 95% CI, 0.22-0.40; nominal P < .001).

Patients in the neoadjuvant arm also experienced a significant distant metastasis-free survival benefit vs the adjuvant arm (adjusted HR, 0.37; 95% CI, 0.24-0.57; nominal P < .001). “In terms of selection, it’s [similar to] what we’re doing in the metastatic setting, in terms of who’s fit for combination treatment [vs] who’s fit for single-agent treatment,“ Paul Nathan, MD, PhD, FRCP, a consultant medical oncologist at Mount Vernon Cancer Centre in Northwood, England, said. “Unless there’s dose-limiting toxicity, I would complete a year of adjuvant single-agent PD-1 [therapy] ipilimumab plus nivolumab.”

The faculty members concluded their discussion by parsing primary findings from the phase 3 RELATIVITY-098 trial (NCT05002569) presented during the 2025 ASCO Annual Meeting.⁷

RELATIVITY-098 examined nivolumab plus relatlimab (Opdualag) vs nivolumab alone for the adjuvant treatment of patients with completely resected stage III to IV melanoma. Data from RELATIVITY-098 showed that the median relapse-free survival (RFS) among patients who received nivolumab plus relatlimab (n = 547) was NR (95% CI, 30.8 months to NR) vs 33.1 months (95% CI, 31.0-NR) among patients who received nivolumab alone. However, the RFS benefit was not statistically significant (HR, 1.01; 95% CI, 0.83-1.22; P = .928). Moreover, the combination of nivolumab plus relatlimab did not produce a significant benefit in terms of distant metastasis–free survival (HR, 1.07; 95% CI, 0.84-1.36).

“With the failure of the RELATIVITY-098 [regimen], we probably need to de-escalate adjuvant therapy,” Adil I. Daud, MBBS, the director of melanoma clinical research and a clinical professor in the Department of Medicine at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer, said. “We are doing a year, but is that really what we need? Maybe 2, 5, or 6 months, somewhere in the middle is probably what [we need]. [I believe we are] over the threshold for what we need to do, and that’s why these studies are negative.”

References

1. Advancing treatment in melanoma and non-melanoma skin cancers: navigating an evolving landscape. OncLive. October 19, 2025. Accessed December 18, 2025. https://www.onclive.com/scientific-interchange-and-workshop/advancing-treatment-in-melanoma-and-non-melanoma-skin-cancers-navigating-an-evolving-landscape
2. Rischin D, Porceddu SV, Day F, et al. Phase 3 trial of adjuvant cemiplimab (cemi) versus placebo (pbo) for high-risk cutaneous squamous cell carcinoma (CSCC). J Clin Oncol. 2025;43(suppl 16):6001. doi:10.1200/JCO.2025.43.16_suppl.6001
3. FDA approves cemiplimab-rwlc for adjuvant treatment of cutaneous squamous cell carcinoma. FDA. October 8, 2025. Accessed December 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-cemiplimab-rwlc-adjuvant-treatment-cutaneous-squamous-cell-carcinoma
4. Amatore F, Sridharan S, Karunamurthy A, et al. Pathologic response rates to neoadjuvant pembrolizumab in locally advanced (LA) resectable cutaneous squamous cell carcinoma (cSCC). J Clin Oncol. 2024;42(suppl 16):9591. doi:10.1200/JCO.2024.42.16_suppl.9591
5. Ladwa R, Lee J, Porceddu SV, et al. A phase 2 study of de-escalation in resectable, locally advanced cutaneous squamous cell carcinoma (cSCC) with the use of neoadjuvant pembrolizumab: De-Squamate. J Clin Oncol. 2024;42(suppl 16):9514. doi:10.1200/JCO.2024.42.16_suppl.9514
6. Blank CU, Lucas MW, Scolyer RA, et al. Neoadjuvant nivolumab and ipilimumab in resectable stage III melanoma. N Engl J Med. 2024;391(18):1696-1708. doi:10.1056/NEJMoa2402604
7. Long GV, Ascierto PA, Guo J, et al. Nivolumab plus relatlimab vs nivolumab alone for the adjuvant treatment of completely resected stage III–IV melanoma: primary results from RELATIVITY-098. J Clin Oncol. 2025;43(suppl 17):LBA9500. doi:10.1200/JCO.2025.43.17_suppl.LBA9500