Abstract Background: Perioperative treatment with a PD- (L) 1 inhibitor plus CT has become the new standard of care for resectable early-stage NSCLC, as a high rate of pathological complete response (pCR) was associated with an improved event-free survival (EFS) and overall survival (OS). Despite these advances, innovative treatments are needed to further improve pCR/OS. In the tumor microenvironment, production of high concentrations of immunosuppressive adenosine is mediated by CD39 ectonucleotidase. IPH5201 is a blocking anti-CD39 monoclonal antibody that promotes antitumor immunity by accumulating immunostimulatory adenosine triphosphate (ATP) and reducing adenosine, turning anti-PD- (L) 1 resistant to sensitive tumors (Perrot, 2019). In a phase 1 clinical trial, IPH5201 as monotherapy or in combination with anti-PD-L1 durva was well tolerated and pharmacodynamically active (Powderly, 2025). To further optimize efficacy of perioperative treatment in resectable NSCLC, IPH5201 was added to durva in the current Phase 2 study. Methods: MATISSE (NCT05742607) is a single arm phase 2 study, investigating perioperative IPH5201+durva, in addition to neoadjuvant CT in previously untreated pts with resectable stage II to IIIA NSCLC. The primary efficacy endpoint was to assess the safety and efficacy based on the pCR rate. Exploratory biomarkers were assessed, such as soluble and membrane CD39 occupancy in blood and CD39 expression in the tumor. Two planned interim analyses were performed after the inclusion of 20 and 40 pts. Results: As of 11 Feb 2025, 40 pts were enrolled. The combination showed a favorable safety profile with no new emerging safety signal compared to durva+CT. 89. 5% of the pts experienced at least one treatment related adverse event of mostly grade 1 or 2. Overall, 35/40 pts (87. 5%) received the planned surgery. A pCR rate of 27. 5% 95%CI, 14. 6, 43. 9, n=11/40 was documented, with a clear trend towards higher pCR rates in PD-L1≥1% pts (35. 7% pCR, n=28). More importantly, in pts with PD-L1≥50%, the pCR rate reached 50% (n=14). Biomarker analysis showed that IPH5201 resulted in complete and sustained saturation of soluble and membrane CD39 in blood. Interestingly, a trend to higher baseline CD39+ cell density in the tumor (and CD8+ cell density) was observed in IPH5201+durva+CT treated pts with pCR/mPR (major pathologic response). Conclusions: Data suggest that combining IPH5201 on top of durva+CT was associated with improved 35. 7% and 50% pCR rates, in PD-L1≥1% and PD-L1≥50% NSCLC, respectively, comparing favorably with the 21. 2% and 27. 5% reported for durva+CT in the AEGEAN study (Heymach, 2023). To confirm this trend, MATISSE continues with the recruitment of PD-L1≥1% pts. CD39+ cell density in tumor is warranted to be further investigated as an emerging biomarker for predicting pCR in IPH5201+durva treatment. Citation Format: Fabrice Barlesi, Tibor Csoszi, Renata Duchnowska, Thomas Egenod, Laurent Greillier, Amanda Psyrri, Maurice Perol, Herve Lena, Agnes Boyer-Chammard, Veronia Todary, Julien Viotti, Pascale André, Carine Paturel, Markus Jensen. Dual CD39 and PD-L1 inhibition: Interim results from the phase 2 MATISSE trial of IPH5201 plus durvalumab (durva) and platinum-based chemotherapy (CT) in patients (pts) with resectable NSCLC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT231.
Barlesi et al. (Fri,) studied this question.