Melanoma TIL Therapy Hits 62.5% Response Rate in ESMO 2026 Data

Lifileucel plus pembrolizumab produced an objective response rate of 62.5% in ICI-naïve advanced melanoma, with median progression-free survival of 19.8 months, according to final cohort 1A results of IOV-COM-202 presented at ESMO Congress 2026 (abstract 2072O). Andrew J. Furness presented the data, one of three melanoma trials — alongside MIZAR-003 and PLUG-IN GEM 2301 — that defined this year's emerging treatment landscape.

What did IOV-COM-202 show?

The single-arm cohort enrolled patients with ICI-naïve advanced melanoma. At the December 12, 2025 cutoff, 15 of 24 patients who received at least 5.58 billion TILs meeting manufacturing specifications had responded (ORR 62.5%; 95% CI 40.6–81.2). Seven patients achieved complete responses (29.2%) and eight partial responses (33.3%).

Disease control reached 83.3% (95% CI 62.6–95.3). Median duration of response was not reached; observed durations ranged from 4.3 to 57.7+ months, with median DOR follow-up of 26.9 months. Three of 15 responders completed five years of assessment without progression or death, and three more remained on study with ongoing responses. Median PFS was 19.8 months (95% CI 3.6–not reached).

Treatment combined nonmyeloablative lymphodepletion with cyclophosphamide and fludarabine, a lifileucel infusion and up to six doses of interleukin-2 within the pembrolizumab regimen. The abstract called safety consistent with known regimen profiles but gave no numerical adverse-event rates.

Translational analyses of 13 patients found greater persistence of tumor-derived T-cell receptor sequences in responders, and single-cell RNA sequencing in two patients showed sustained high proportions of predicted tumor-reactive T cells with reinvigorated phenotypes. The findings stay exploratory and don't validate a predictive biomarker. With 24 patients and no randomized comparator, the results can't isolate lifileucel's contribution over pembrolizumab alone — a question the phase III TILVANCE-301 trial will address.

Can a lighter TIL regimen hold up after anti-PD-1 failure?

Yes, on progression-free survival. Extended follow-up from the randomized phase II MIZAR-003 trial (abstract LBA55), presented by Lu Si, showed median PFS of 4.37 versus 1.61 months for the GC101 TIL regimen versus investigator-choice chemotherapy (HR 0.44; 95% CI 0.28–0.70; P = 0.0004), a 56% reduction in the hazard of progression or death.

The trial ran at 25 Chinese centers in patients aged 18–75 with unresectable or metastatic melanoma after at least two prior systemic regimens including anti-PD-1 failure. At the July 2, 2026 cutoff, median follow-up had grown from 5.2 to 8.3 months across 99 patients — 50 on GC101, 49 on chemotherapy. Acral and mucosal melanoma made up 72.8% of the population.

The GC101 regimen used lower-intensity preconditioning — cyclophosphamide 20 mg/kg daily for three days plus hydroxychloroquine 600 mg — omitted interleukin-2, and added sintilimab 100 mg every six weeks for up to five doses. Chemotherapy options included dacarbazine, temozolomide, paclitaxel, cisplatin and carboplatin, with IRC-confirmed crossover allowed.

ORR favored GC101 at 44.0% versus 8.2%, and disease control at 68.0% versus 40.8%. In mucosal melanoma (six GC101 patients versus ten on chemotherapy), median PFS was 4.81 versus 1.45 months (HR 0.23; P = 0.0215). In acral melanoma (31 versus 25 patients), PFS was 4.37 versus 1.38 months (HR 0.41; P = 0.0034).

Median OS was not reached with GC101 versus 12.55 months with chemotherapy (HR 0.61; P = 0.2571) — immature and not statistically significant, with 59% crossover complicating interpretation. Grade ≥3 treatment-related adverse events hit 42.0% with GC101 versus 30.6% with chemotherapy, so the gentler design didn't translate into lower observed toxicity. The strategy test also can't separate GC101's effect from preconditioning and sintilimab.

Did the NECTIN-4 antibody-drug conjugate deliver?

Partially. The single-arm phase II PLUG-IN GEM 2301 trial (abstract 2074RO), presented by Guillermo de Velasco, reported a confirmed ORR of 25% for enfortumab vedotin plus pembrolizumab in refractory advanced melanoma, against a best observed response rate of 31.7% — a figure that includes unconfirmed responses and shouldn't be read as the primary endpoint. Median follow-up was 6.5 months.

The study enrolled 60 patients: a BRAF-wild-type cohort of 45 after immunotherapy progression and a BRAF-mutated cohort of 15 after immunotherapy and targeted therapy. Dosing was enfortumab vedotin 1.25 mg/kg on days 1, 8, 22 and 29 with pembrolizumab 400 mg on day 1 of each six-week cycle, testing a historical ORR of 15% against a 30% target.

Median age was 63 (range 25–88); 20.0% had acral and 16.7% mucosal melanoma, and 28.3% had liver metastases. Confirmed ORR was 33.3% in acral, 20.0% in mucosal and 18.2% in cutaneous melanoma — small exploratory subgroups. Median DOR was not reached in either BRAF cohort.

Exploratory analyses found cytoplasmic NECTIN-4 dominance (median H-score 100 versus 2 at the membrane) but no significant associations with response, PFS or OS after multiple-testing adjustment. In the earlier abstract analysis, grade 3–4 toxicities occurred in 14 patients (23.3%), most often asthenia (6.7%); enfortumab vedotin dose reductions hit 25% and interruptions 50%.

Across all three trials, durability and survival questions remain open. TILVANCE-301, longer MIZAR-003 follow-up and extended PLUG-IN observation will determine whether these signals become standard-of-care options in advanced melanoma.