CD39/PD-L1 Inhibition May Improve pCR Rate in Resectable NSCLC

Adding IPH5201, an investigational CD39 inhibitor, to perioperative durvalumab (Opdivo) and neoadjuvant chemotherapy produced a promising pathologic complete response (pCR) rate among patients with resectable early-stage non–small cell lung cancer (NSCLC), according to findings from the phase 2 MATISSE trial (NCT05742607) presented at the 2026 American Association for Cancer Research (AACR) Annual Meeting.¹

Efficacy data revealed an objective response rate (ORR) of 62.5% (95% CI, 45.8%-77.3%), which included complete responses (CRs) in 7.5% of patients and partial responses (PRs) in 55.0%. Most patients proceeded to surgery (n = 35/40; 87.5%), and of this group, most achieved an R0 resection (88.6%) or an R1 resection (11.4%).

Overall, the study treatment yielded a pCR rate of 27.5% (95% CI, 14.6%-43.9%) and a major pathological response (MPR) rate of 32.5% (95% CI, 18.6%-49.1%). The pCR rate was higher in patients with a PD-L1 expression of 1 or higher (n = 28) at 35.7% (95% CI, 18.6%-55.9%) compared with those who had a PD-L1 expression of less than 1% (n = 12) at 8.3% (95% CI, 0.2%-38.5%). Additionally, the pCR rate was 50.0% (95% CI, 23.0%-77.0%) among those with a PD-L1 expression of 50% or higher (n = 14).

“MATISSE is the first clinical study to show the feasibility and preliminary activity of preoperative CD39 blockade by IPH5201 in combination with platinum-based chemotherapy and PD-L1 inhibition for patients with early-stage resectable NSCLC,” lead study author Fabrice Barlesi, MD, PhD, stated in the presentation. “MATISSE is paving the way for CD39 [and adenosine] pathway inhibition in early-stage NSCLC. MATISSE continues with the recruitment of [patients with PD-L1 expression of at least 1%] to further enrich the dataset.”

Barlesi is the chief medical officer and chief executive officer at Gustave Roussy and a Professor of Medicine at the Paris Saclay University.

Developers engineered IPH5201 as a humanized Fc-silent IgG1 to inhibit both membrane and soluble CD39. Prior data from preclinical models demonstrated the novel agent’s ability to sensitize tumors that were previously resistant to anti–PD-(L)1 therapy when administered in combination with durvalumab/chemotherapy.

Investigators of the single-arm, open-label phase 2 MATTISE study assessed IPH5201 plus chemotherapy and durvalumab among patients with resectable early-stage NSCLC. Neoadjuvant therapy consisted of IPH5201 at 3000 mg plus durvalumab at 1500 mg and chemotherapy for 4 cycles every 3 weeks. After surgery, patients received adjuvant IPH5201 plus durvalumab for up to 12 cycles every 4 weeks.

The trial’s primary end points were the pCR rate and safety as measured at the time of surgery. Secondary end points included event-free survival, disease-free survival, overall survival, MPR, ORR, and pharmacokinetics.

Patients 18 years and older with newly diagnosed and previously untreated stage IIA to IIIA NSCLC, a WHO or ECOG performance status of 0 or 1, and adequate organ and marrow function were eligible for enrollment on the trial.² Having a life expectancy of at least 12 weeks was another requirement for study entry.

Among 40 enrolled patients, the median age was 64.7 years (range, 48-83), and most were male (67.5%). Most of the study population had a performance status of 0 (80.0%), stage IIIA disease (50.0%), adenocarcinoma histology (47.5%), and chemotherapy with a carboplatin/paclitaxel backbone (40.0%). Of 40 who completed neoadjuvant therapy, 35 proceeded to surgery; 40 were evaluated for the primary end point of pCR. Additionally, 32 patients underwent adjuvant treatment.

Among patients who achieved an MPR or pCR during study treatment, investigators observed higher baseline CD39-positive and CD8-positive cell density. However, data showed no correlation between CD39 cell density in tumors and PD-L1 expression.

Treatment-emergent adverse effects (TEAEs) of any grade occurred in 97.5% of patients, with grade 3 or higher toxicities noted in 55.0%. TEAEs leading to permanent discontinuation of any study drug were highlighted in 22.5% of patients, and 1 patient experienced a grade 5 TEAE due to postoperative pneumonia.

The most common TEAEs included asthenia (40.0%), constipation (30.0%), nausea (30.0%), anemia (27.5%), and thrombocytopenia (25.0%). TEAEs related to IPH5201 included asthenia (20.0%), arthralgia (12.5%), hypothyroidism (12.5%), and thrombocytopenia (10.0%).

Disclosures: Barlesi noted institutional financial interests related to Abbvie, ACEA, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb (BMS), Boehringer–Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffman–La Roche Ltd, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, Summit Therapeutics, and Takeda. He also highlighted non-financial interests as a principal investigator for AstraZeneca, BMS, Innate Pharma, Merck, Pierre Fabre and F. Hoffman–La Roche Ltd, sponsored trials (or ISR).

References

1. Barlesi F, Csoszi T, Duchnowska R, et al. 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. Presented at the 2026 American Society for Cancer Research, San Diego, CA; April 17-22, 2026. Abstract CT231.
2. IPH5201 and durvalumab in patients with resectable non-small cell lung cancer (MATISSE) (MATISSE). ClinicalTrials.gov. Updated May 16, 2025. Accessed April 21, 2026. https://tinyurl.com/mry38ckv