Late-Breaking Phase 3 Data Headline ESMO 2026 Presidential Symposium I

Four late-breaking abstracts presented during Presidential Symposium I at the 2026 European Society for Medical Oncology (ESMO) Congress in Madrid reported positive phase 3 results across melanoma, muscle-invasive bladder cancer, extensive-stage small cell lung cancer, and very high-risk prostate cancer. The session was chaired by Fabrice André and James Larkin.

Two of the trials, VOLGA and DeLLphi-305, showed significant overall survival (OS) benefits at interim analysis. The other two, INTerpath-001 and DASL-HiCaP, met their primary end points of recurrence-free survival (RFS) and metastasis-free survival, respectively, while OS results were not yet significant. Together, the trials tested an individualized mRNA neoantigen therapy, an antibody-drug conjugate plus immunotherapy, a bispecific T-cell engager, and an androgen receptor inhibitor against standard-of-care comparators.

LBA1: Intismeran Autogene Plus Pembrolizumab Reduces Recurrence Risk in Resected Melanoma

Adding the individualized mRNA-based neoantigen therapy intismeran autogene to pembrolizumab (Keytruda) significantly improved RFS vs pembrolizumab alone in patients with resected stage IIB to IV melanoma, according to the first interim analysis of the phase 3 INTerpath-001 trial (NCT05933577) presented by Georgina V. Long, MD, PhD, of Melanoma Institute Australia.

The double-blind trial randomized 1137 patients 2:1 to intismeran (1 mg intramuscularly every 3 weeks for 9 doses; n = 757) or placebo (n = 380), each with pembrolizumab at 400 mg intravenously every 6 weeks for 9 cycles. Eligible patients had resected cutaneous melanoma, an ECOG performance status of 0 or 1, and no prior systemic therapy. The primary end point was investigator-assessed RFS, followed hierarchically by distant metastasis-free survival (DMFS) and OS. At a June 30, 2026, data cutoff and a median follow-up of 24.6 months, the combination reduced the risk of recurrence or death by 42% (HR, 0.58; 95% CI, 0.45-0.75; P < .001). Estimated 24-month RFS rates were 82.2% vs 70.0%. A piecewise analysis showed no separation in the first 6 months (HR, 0.99; 95% CI, 0.66-1.49) and a pronounced benefit afterward (HR, 0.42; 95% CI, 0.30-0.58). DMFS also improved (HR, 0.62; 95% CI, 0.45-0.85; P = .002). OS data were immature and did not reach the prespecified significance boundary (HR, 0.77; 95% CI, 0.45-1.31; P = .33).

Grade 3 to 5 adverse events (AEs) occurred in 23.6% of patients in the intismeran arm vs 20.3% with placebo, and AEs led to discontinuation of any drug in 16.6% vs 9.5%. Higher rates of pyrexia (52.2% vs 8.2%), injection site pain (51.0% vs 9.5%), and influenza-like illness (25.4% vs 9.2%) were attributed to the intismeran injection and described as low grade and transient. AEs led to death in 8 patients (1.1%) vs none, and none were related to intismeran. Pembrolizumab-associated AEs of interest were similar between arms (36.0% vs 34.7%).

Long concluded that INTerpath-001 “sets a new benchmark for adjuvant therapy in melanoma and established intismeran as a landmark advance in personalized cancer medicine.”

LBA2: Perioperative Durvalumab Plus Enfortumab Vedotin Improves Survival in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer

Perioperative durvalumab (Imfinzi) plus neoadjuvant enfortumab vedotin (Padcev) significantly improved event-free survival (EFS) and OS vs upfront radical cystectomy in patients with muscle-invasive bladder cancer (MIBC) who were ineligible for or refused cisplatin, according to the first interim analysis of the phase 3 VOLGA trial (NCT04960709) presented by Thomas Powles, MD, of Barts Cancer Institute, Queen Mary University of London.

The trial randomized 695 patients 1:1:1 to 3 cycles of neoadjuvant durvalumab (1500 mg) plus enfortumab vedotin (1.25 mg/kg) every 3 weeks followed by cystectomy and 9 cycles of adjuvant durvalumab (n = 233); the same regimen plus tremelimumab (Imjudo; n = 233); or radical cystectomy followed by observation or locally approved treatment (n = 229). Dual primary end points were EFS by blinded independent central review for each experimental arm vs control, and OS was a key secondary end point.

At a March 2, 2026, data cutoff, durvalumab plus enfortumab vedotin reduced the risk of an EFS event by 49% (HR, 0.51; 95% CI, 0.38-0.67; P < .0001). Median EFS was not reached vs 12.1 months with control, and 24-month EFS rates were 64% vs 45%. OS also improved (HR, 0.58; 95% CI, 0.40-0.83; P = .0027), with 24-month rates of 78% vs 69%. Pathologic complete response rates were 45% vs 10% by local review. In an exploratory analysis of 112 patients, 60% of those with detectable circulating tumor DNA (ctDNA) at baseline cleared it before surgery; their 24-month EFS rate was 81% vs 55% for those with persistent ctDNA positivity.

The triplet with tremelimumab also improved EFS (HR, 0.61; 95% CI, 0.47-0.80; P = .0004), but OS did not reach significance at this interim analysis (HR, 0.77; 95% CI, 0.54-1.07; P = .123). Grade 3 or 4 AEs occurred in 64% of patients receiving durvalumab plus enfortumab vedotin vs 44% with control, rising to 70% with tremelimumab, and 21% in the doublet arm discontinued treatment because of an AE. Immune-mediated AEs occurred in 33% vs 3%. Powles noted that the excess toxicity with the triplet may account for the lessened OS improvement.

“VOLGA supports perioperative durvalumab plus 3 cycles of neoadjuvant enfortumab vedotin as a potential new standard of care for patients with muscle-invasive bladder cancer ineligible for or who refused cisplatin-based chemotherapy,” Powles concluded.

LBA3: Tarlatamab Plus Durvalumab Improves Survival as First-Line Maintenance in Extensive-Stage Small Cell Lung Cancer

Maintenance tarlatamab-dlle (Imdelltra) plus durvalumab significantly improved OS, progression-free survival (PFS), and objective response rate (ORR) vs durvalumab alone in patients with extensive-stage small cell lung cancer (ES-SCLC) who had not progressed after first-line platinum, etoposide, and durvalumab, according to the primary analysis of the phase 3 DeLLphi-305 trial (NCT06211036) presented by Jacob Sands, MD, of Dana-Farber Cancer Institute.

The open-label trial randomized 563 patients 1:1 to tarlatamab (10 mg every 2 weeks) plus durvalumab (1500 mg every 4 weeks; n = 282) or durvalumab alone (n = 281) until progression or unacceptable toxicity. OS was the primary end point and PFS the key secondary end point. Brain metastases were present in about 20% of patients and liver metastases in about one-third.

At a July 7, 2026, data cutoff, the interim OS analysis was conducted after 243 events (61% information fraction), with a median follow-up of about 16 months. Median OS was 21.1 months (95% CI, 20.8-not estimable) with the combination vs 12.7 months (95% CI, 11.2-14.8) with durvalumab alone (HR, 0.42; 95% CI, 0.32-0.54; P < .001); 12-month OS rates were 79% vs 53%. Benefit held across subgroups, including patients with brain metastases (HR, 0.49; 95% CI, 0.26-0.93) and liver metastases (HR, 0.41; 95% CI, 0.28-0.61). Median PFS was 7.4 months vs 1.9 months (HR, 0.34; 95% CI, 0.28-0.42; P < .001), and ORR was 26.4% vs 4.1% (P < .001), with a median duration of response of 12.7 vs 5.6 months.

Grade 3 or higher treatment-emergent AEs occurred in 46.8% of patients receiving the combination vs 40.6% with durvalumab alone; treatment-related grade 3 or higher AEs occurred in 20.9% vs 10.8%. Tarlatamab was discontinued for AEs in 5.7% of patients. There were no treatment-related deaths with the combination vs 2 (0.7%) with durvalumab alone. Cytokine release syndrome occurred in 49.6% of patients receiving the combination, with a single grade 3 event, and immune effector cell–associated neurotoxicity syndrome occurred in 1.1%.

Sands concluded that the DeLLphi-305 outcomes “support tarlatamab plus durvalumab as a new standard of care first-line maintenance therapy in extensive-stage small cell lung cancer.”

LBA4: Darolutamide Added to Radiation Therapy and Androgen Deprivation Therapy Improves Metastasis-Free Survival in Very High-Risk Prostate Cancer

Adding darolutamide (Nubeqa) to androgen deprivation therapy (ADT) and definitive or salvage radiation therapy significantly improved metastasis-free survival by conventional imaging (MFS-CI) in patients with very high-risk localized prostate cancer, according to a planned interim analysis of the phase 3 DASL-HiCaP trial (ANZUP1801; NCT04136353) presented by Tamim Niazi, MDCM, of McGill University and the Jewish General Hospital in Montreal.

The placebo-controlled trial randomized 1106 patients 1:1 to darolutamide (600 mg twice daily) or placebo for 96 weeks, each with 96 weeks of ADT and radiation therapy to the prostate or prostate bed and pelvic lymph nodes. Of the participants, 935 (84.5%) received primary radiation and 171 (15.5%) received salvage radiation after prostatectomy. Median age was 70 to 71 years, 71% to 74% had Gleason scores of 9 or 10, and 29% had pelvic nodal involvement. MFS-CI was the primary end point, and the interim analysis was triggered after 87 events (67% of 130 planned).

Darolutamide reduced the risk of metastasis or death by 58% (HR, 0.42; 95% CI, 0.27-0.66; P = .0001), crossing the prespecified rejection boundary of .012. There were 27 MFS-CI events (5%) with darolutamide vs 63 (11%) with placebo, and 4-year MFS-CI rates were 95% vs 88%. Benefit was consistent across prespecified subgroups, including pelvic nodal involvement, age, and Gleason score. Secondary end points favored darolutamide, including PSA progression-free survival (HR, 0.47; 95% CI, 0.33-0.67), time to castration resistance (HR, 0.22; 95% CI, 0.09-0.52), and time to subsequent hormonal therapy (HR, 0.36; 95% CI, 0.21-0.60). OS was not significantly different at this interim analysis (HR, 0.88; 95% CI, 0.49-1.59), with 21 vs 24 deaths.

The presentation concluded that MFS-CI is an established surrogate for OS in this setting. AEs of special interest occurred at similar rates, including vasodilatation and flushing (66% vs 64%) and fatigue (64% vs 57%). Fewer patients in the darolutamide arm received subsequent anticancer therapy (4% vs 10%).

REFERENCES

1. Long GV et al. INTerpath-001: phase 3 study of the mRNA-based individualized neoantigen therapy (INT) intismeran autogene (intismeran) plus pembrolizumab (pembro) vs pembro alone for adjuvant treatment of resected stage IIB-IV melanoma. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA1.

2. Powles T et al. Perioperative durvalumab with or without tremelimumab plus neoadjuvant enfortumab vedotin in muscle-invasive bladder cancer: results from the phase 3 VOLGA trial. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA2.

3. Sands J et al. Tarlatamab plus durvalumab (durva) as 1L maintenance (1LM) therapy following durva, platinum, and etoposide (1L durva + EP) in extensive-stage small cell lung cancer (ES-SCLC): primary analysis of the phase 3 DeLLphi-305 trial. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA3.

4. Niazi T et al. Darolutamide with androgen deprivation therapy (ADT) and definitive or salvage locoregional radiation therapy (RT) for localised, very high-risk prostate cancer: interim analysis of an international, placebo-controlled, randomised phase 3 trial (DASL-HiCaP; ANZUP1801). Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA4.