Melanoma Trials You May Have Missed at ASCO 2026

The 2026 American Society of Clinical Oncology (ASCO) Annual Meeting brought meaningful advances across melanoma subtypes and Merkel cell carcinoma, a rare and aggressive skin cancer that continues to generate practice-informing data. Sarah Weiss, MD, spoke with CancerNetwork^® about the findings she found most impactful at the meeting, spanning a landmark efficacy readout in uveal melanoma, a 36-month update in resectable cutaneous melanoma, and 2 data points reshaping how clinicians sequence therapy in Merkel cell carcinoma.

Weiss is director of Melanoma/Cutaneous Oncology Program, a medical oncologist, and associate professor of medicine in the Division of Medical Oncology at Rutgers Cancer Institute.

Darovasertib Improves PFS in HLA-A*02:01–Negative Metastatic Uveal Melanoma

The phase 3 OptimUM-02 trial (NCT05987332) evaluated darovasertib (300 mg twice daily) plus crizotinib (Xalkori; 200 mg twice daily) vs investigator’s choice of checkpoint immunotherapy as first-line treatment for patients with HLA-A*02:01–negative metastatic uveal melanoma (mUM), a population for which no FDA-approved therapies previously existed.¹ The trial enrolled 210 patients in the darovasertib plus crizotinib arm and 103 in the investigator’s choice control arm; 76.7% of the control arm received ipilimumab (Yervoy) plus nivolumab (Opdivo), and 23.3% received pembrolizumab (Keytruda).

The combination demonstrated clinically meaningful and statistically significant improvement in the primary end point of progression-free survival (PFS) by blinded independent central review (BICR): the median PFS was 6.9 months (95% CI, 5.6-8.3) in the darovasertib plus crizotinib arm vs 3.1 months (95% CI, 1.8-4.2) in the control arm (HR, 0.42; 95% CI, 0.30-0.59; P <.0001), representing a 58% reduction in the risk of disease progression or death. The investigator-assessed analysis yielded a consistent HR of 0.36 (P <.0001).

The combination also significantly outperformed on key secondary end points. The objective response rate (ORR) was 37.1% (95% CI, 30.6%-44.1%) vs 5.8% (95% CI, 2.2%-12.3%) in each arm (odds ratio, 10.8; 95% CI, 4.4-26.4; P <.0001), with complete responses in 2.4% of patients in the experimental arm and none in the control arm. The disease control rate at 12 weeks was 73.3% (95% CI, 66.8%-79.2%) vs 31.1% (95% CI, 22.3%-40.9%). The median duration of response was 6.8 months (95% CI, 5.5-11.3) vs not estimable (NE).

“This combination will be [examined] with various other forms of therapy that are out there, particularly how it can fit in with the various liver-directed therapies we use now, and patient selection is key, and as much as possible, although this is a rare population, [we need] studies to address some of these questions. For patients who have a significant burden of tumor, is there a way that we can reduce that with various liver-directed therapy, and then maybe give this combination first than the other way around. Those are all questions that are out there and that are going to be being addressed,” Weiss said.

The most common all-grade treatment-related adverse effects (TRAEs) in the combination arm included diarrhea (84.9%), nausea (74.9%), peripheral edema (66.9%), vomiting (49.8%), and fatigue (39.3%). Among grade 3/4 TRAEs, diarrhea occurred in 10.0% and syncope in 7.1%. Dose reductions of darovasertib occurred in 23.4% of patients for and 26.4% for crizotinib; treatment discontinuation was rare, occurring in 0.8% of patients. Weiss emphasized proactive patient counseling, prophylactic antiemetics, and early toxicity management to minimize dose interruptions.

Regarding AE education, Weiss noted, “With all of our patients who are going on various anti-cancer agents, we have to be aware of what the potential AEs are, and we have to counsel the patients on that, make sure they have prophylactic medication, anti-emetics at home, that they communicate with the clinic team if they’re having issues, so they can come in for hydration, maybe [intravenous] antiemetics, and preempt some of the more serious issues that we’re seeing.”

Neoadjuvant Daromun Sustain EFS/RFS in Resectable Stage III Melanoma

The 36.8-month median follow-up update from the phase 3 PIVOTAL trial (NCT02938299) confirmed clinically and statistically significant improvements in recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) with neoadjuvant intralesional daromun (L19IL2/L19TNF) vs immediate upfront surgery in patients with resectable stage III melanoma.² A post-hoc analysis of event-free survival (EFS), defined as time from randomization to disease progression, treatment-related toxicity precluding surgery, R2 resection, disease recurrence, or death, was consistent with the primary RFS benefit, reinforcing the durability of the neoadjuvant approach.

Primary results, previously presented at the 2024 ASCO Annual Meeting, demonstrated a statistically significant improvement in RFS (HR, 0.59; P = .005) and DMFS (HR, 0.60; P = .029) favoring daromun.³ The current 36-month update confirm these improvements are sustained with longer follow-up. No new toxicities were reported.

A key finding in the updated analysis was the benefit observed in the recurrent patient subgroup, those who had previously received adjuvant immunotherapy including PD-1 inhibitors. Daromun significantly improved RFS in recurrent patients overall (HR, 0.50; P <.001), with consistent benefit in those who had relapsed after surgery with or without radiotherapy plus systemic therapies (HR, 0.53; 95% CI, 0.29-0.95) and in those who had relapsed after surgery with or without radiotherapy (HR, 0.46; 95% CI, 0.27-0.78).

“This study was somewhat reassuring in the sense that patients were able to proceed with surgery after the intratumoral neoadjuvant therapy, and this is, again about patient selection, and which patients are going to be appropriate for this therapy vs other standard neoadjuvant immunotherapies we have, or other trials that we’re looking at to study neoadjuvant therapy. It was interesting that this intratumoral therapy was effective in patients who had previously received, for example, adjuvant PD-1 inhibitors or other systemic therapies, and who had recurred. That population would be interesting to think about using this at some point in the future, patients who, for whatever reason, are not good candidates for immune checkpoint inhibitors. It’s about patient selection, but study after study has shown that a neoadjuvant approach is quite beneficial to the patients rather than just upfront surgery,” Weiss said.

Significant DMFS Improvement With Adjuvant Pembrolizumab After Complete Resection in Merkel Cell Carcinoma

The phase 3 STAMP trial (NCT03712605) evaluated adjuvant pembrolizumab vs standard of care (SOC) observation in patients with Merkel cell carcinoma (MCC) following complete surgical resection.⁴

The trial’s primary end point of RFS was numerically improved but did not reach statistical significance (HR, 0.77; 90% CI, 0.55-1.08; log-rank P = .102). Rates of 12-month RFS were 83% (90% CI, 77%-88%) vs 72% (90% CI, 65%-78%) and 24-month RFS were 72% (90% CI, 65%-77%) vs 66% (90% CI, 59%-72%) in the pembrolizumab and SOC arms, respectively.

However, the co-primary end point of distant metastasis-free survival (DMFS) was significantly improved in the pembrolizumab arm (HR, 0.58; 90% CI, 0.35–0.96; log-rank P = .035), with 18-month DMFS of 87% (90% CI, 81%-91%) vs 80% (90% CI, 74%-85%). Overall survival did not differ between arms (HR, 1.62; 90% CI, 0.94-2.81; P = .928); however, the number of events was limited, with 23 deaths in the pembrolizumab arm vs 15 in the SOC arm at the time of analysis.

“Merkel cell carcinoma remains an individualized decision making process, based upon the patient’s stage, the pathologic features, their risk of recurrence or their perceived risk of recurrence … and we still don’t know in the whole adjuvant space and skin cancer in general whether treating the patient now as a preventative measure is better than treating the patient if or when they recur, and that's important. Regardless, these patients have to be followed closely, whether or not they’re getting adjuvant therapy, and again, this is a rare population too,” Weiss said.

“This was quite a large study for Merkel cell, but based on the information we have so far, in some patients, adjuvant immunotherapy may be appropriate for patients who have very high-risk Merkel cell,” she added. “As time goes on, and maybe we learn more about how to predict which patients are going to recur, through the use of ctDNA monitoring, or other molecular factors, or prognostic and predictive markers that are hopefully discovered, that’s how we’re going to be making some of those decisions.”

Safety data showed grade 3 or higher all-cause immune-mediated AEs in 31.2% of the pembrolizumab arm vs 4.3% of the SOC arm. One grade 5 TRAE (pneumonitis) occurred in the pembrolizumab arm.

References

1. Orloff M, Ramelyte E, Butler MO, et al. Darovasertib plus crizotinib vs investigator’s choice as first-line treatment for patients with HLA-A2 negative metastatic uveal melanoma: primary results from the OptimUM-02 trial. J Clin Oncol. 2026;44(suppl 17):LBA9503. doi:10.1200/JCO.2026.44.17_suppl.LBA9503
2. Kähler KC, Ziemer M, Hassel JC, et al. Neoadjuvant intralesional daromun (L19IL2/L19TNF) in resectable locally advanced melanoma: an update on the primary outcome and sensitivity analyses (EFS) from the PIVOTAL phase 3 trial. J Clin Oncol. 2026;44(suppl 17):LBA9517. doi:10.1200/JCO.2026.44.17_suppl.LBA9517
3. Hauschild A, Hassel JC, Ziemer M, et al. Phase 3 study (PIVOTAL) of neoadjuvant intralesional daromun vs. immediate surgery in fully resectable melanoma with regional skin and/or nodal metastases. J Clin Oncol. 2024;42(suppl 17):LBA9501. doi:10.1200/JCO.2024.42.17_suppl.LBA9501
4. Mehnert JM, Lee S, Gastman B, et al. EA6174: STAMP: Surgically Treated Adjuvant Merkel Cell Carcinoma with Pembrolizumab, a phase III trial. J Clin Oncol. 2026;44(suppl 17):LBA0505. doi:10.1200/JCO.2026.44.17_suppl.LBA9505