Phase 2 Trial Shows Promising Long-Term Survival

NCT04004572 is a Chinese multi-center, single-arm phase 2 trial evaluating patients with newly diagnosed stage IV NK/T-cell lymphoma who are unable to tolerate high-dose methotrexate. Thirty-seven patients received the LEAP regimen (sintilimab, pegaspargase, and anlotinib) for up to 8 cycles every 21 days, and the 24-week complete response (CR) rate was 72.9%, exceeding the pre-specified threshold of 55%. The median follow-up was 48 months, with a 4-year progression-free survival (PFS) rate of 56.6% and an overall survival (OS) rate of 75.2%. Unlike previous reports that only evaluated completed initial registration data, the 2026 Blood Advances publication provides evidence for the actual efficacy and safety.

Simultaneously Targets Immune, Metabolic, and Angiogenic Pathways

Sintilimab (TYVYT) is a PD-1 targeting antibody, pegaspargase (Oncaspar) is a PEGylated L-asparaginase that depletes asparagine, and anlotinib (FOCUS V) is a multi-tyrosine kinase inhibitor targeting VEGFR, FGFR, PDGFR, and c-Kit. The regimen consisted of sintilimab 200mg and pegaspargase 2,500 IU/m2 on day 1, and anlotinib 8mg from days 1 to 14. The design aims to restore anti-tumor immunity through PD-1 blockade and combine it with asparagine depletion and angiogenesis inhibition to reduce the reliance on high-dose multi-agent chemotherapy. Grade 3 or higher adverse events included neutropenia and hyperbilirubinemia, occurring in 10.8% of patients each, with no treatment discontinuation or treatment-related deaths due to toxicity.

Association with Transplantation Influenced Treatment Durability

Among the patients who achieved complete response, 17 underwent autologous hematopoietic stem cell transplantation (auto-HSCT), with relapse rates of 17.6% in the transplantation group and 60.0% in the observation group. The hazard ratio for PFS in the transplantation group was 0.23, with a p-value of less than 0.05, suggesting that LEAP may serve as an induction regimen for consolidation with curative-intent transplantation. However, the selection for transplantation was not randomized but based on investigator judgment and patient preference, so a randomized trial is needed to confirm its superiority. The comparator, high-dose methotrexate-based SMILE, and pegaspargase-based DDGP/P-GEMOX, are major treatment options for advanced NK/T-cell lymphoma, and modified SMILE has reported objective response rates of 79-81% and complete response rates of 50-56% after 2-3 cycles.

Commercial Value Lies in Expanding Indications for Rare Cancers

The global T-cell lymphoma market was valued at $2.1 billion in 2023 and is projected to grow to $3.7 billion in 2030, but NK/T-cell lymphoma is a rare submarket with a high proportion of Asian patients. Sintilimab is co-developed by Innovent Biologics and Eli Lilly and is marketed in China, while anlotinib is a product of Sino Biopharm's subsidiary, Zhengda Tianqing Pharmaceutical. Sintilimab was approved by China's NMPA for Hodgkin's lymphoma in December 2018, and anlotinib was first approved in China for non-small cell lung cancer in May 2018, but both products are still in phase 2 clinical trials for NK/T-cell lymphoma. Pegaspargase was approved by the FDA on February 1, 1994, and by the EMA on January 14, 2016, for acute lymphoblastic leukemia, but this use in rare lymphoma is a separate area for indication development.