Cancer Immunotherapy Updates: STAR-221 Misses OS Endpoint; Pembrolizumab-IL-2 Shows Durable Responses

The phase 3 STAR-221 trial demonstrated that adding the anti-TIGIT antibody domvanalimab to zimberelimab and chemotherapy did not improve overall survival compared with nivolumab plus chemotherapy in patients with previously untreated HER2-negative advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma. The first interim analysis of the trial was presented at the ESMO GI Cancers Congress 2026.

STAR-221 is a randomized, international phase 3 trial (NCT05568095) that randomized 1,040 patients 1:1 to receive domvanalimab + zimberelimab + chemotherapy or nivolumab + chemotherapy, with chemotherapy consisting of either FOLFOX or CAPOX. The primary endpoint was overall survival, tested hierarchically in the intention-to-treat population, followed by patients with tumor area positivity (TAP) ≥5% and TAP ≥1%. After a median follow-up of approximately 13 months, median OS was 14.0 months with domvanalimab + zimberelimab + chemotherapy compared with 13.4 months with nivolumab + chemotherapy (HR 1.01; P = 0.526). No improvement was observed in the biomarker-defined subgroups: in patients with TAP ≥5%, the HR for OS was 1.10, and in those with TAP ≥1%, the HR was 0.99. Median progression-free survival was 8.4 months versus 8.3 months, and objective response rates were 55% versus 56%. Safety profiles were consistent across arms, with similar rates of treatment-emergent adverse events, comparable incidence of immune-mediated adverse events, similar frequencies of treatment interruptions and discontinuations, and no new safety signals.

Domvanalimab is an Fc-silent anti-TIGIT antibody, while zimberelimab is an anti-PD-1 antibody. TIGIT is an inhibitory receptor expressed on T cells and natural killer cells that suppresses antitumor immune responses; dual blockade of TIGIT and PD-1 has emerged as a promising strategy to enhance T-cell activation beyond PD-1 inhibition alone. Earlier studies suggested encouraging clinical activity when these agents were combined with chemotherapy, leading to the global phase 3 STAR-221 trial. The findings indicate that dual TIGIT/PD-1 inhibition did not provide additional clinical benefit over the current PD-1-based standard of care in this setting.

In a separate single-arm phase 2 trial (ClinicalTrials.gov identifier NCT02964078), a fixed-duration regimen of anti-PD1 pembrolizumab plus high-dose interleukin-2 was evaluated in treatment-naive advanced clear cell renal cell carcinoma. Long-term follow-up (median 76.4 months) showed an objective response rate of 73%, with complete responses in 42% of patients among 26 patients treated. Median overall survival was >84 months, with a 5-year restricted mean survival time of 48.6 months. Median progression-free survival was 19.3 months, and the median treatment-free interval was 23.8 months; 42% of patients remained treatment-free at the 5-year timepoint. No grade 5 adverse events occurred, and no patients with durable disease control experienced persistent grade ≥2 toxicities. Correlative analyses identified exploratory immune patterns associated with durable benefit, including enrichment of CD16⁺ natural killer cells, suppression of PD-1⁺ T-cell frequencies, and coordinated chemokine, complement, and PKC/TGF-β pathway activation.

A new randomized phase II clinical trial, OPTIM, is testing whether escalating immune therapy can improve outcomes for people with recurrent or metastatic squamous cell carcinoma of the head and neck. Reported in British Journal of Cancer, the study evaluates a treatment strategy that begins with nivolumab and then selects the next step based on disease status at progression. Patients who show progression are randomized to either nivolumab-ipilimumab, pairing PD-1 blockade with CTLA-4 inhibition, or docetaxel. By comparing an immunotherapy intensification route against a conventional cytotoxic option after initial nivolumab failure, the trial aims to identify which sequence is more effective in real-world progression scenarios. Although phase II trials are not definitive for practice-changing guidance, OPTIM is expected to generate important signals about response rates, progression patterns, and clinical benefit under different post-nivolumab pathways. The trial reflects a growing shift in oncology toward rational sequencing—using biomarkers of clinical behavior, such as progression after first-line immunotherapy, to guide the next line.