Adding an anti-CD39 monoclonal antibody to standard treatment for early-stage non-small cell lung cancer (NSCLC) — neoadjuvant chemotherapy plus a perioperative immune checkpoint inhibitor — may increase pathological complete response (pCR) rates, according to a single-arm study.

Chemotherapy-checkpoint inhibitor combinations have improved NSCLC outcomes, but 5-year event-free survival remains only about 50%, leaving substantial room for improvement, said lead investigator Fabrice Barlesi, MD, PhD, while presenting the results at the American Association for Cancer Research (AACR) Annual Meeting. 

CD-39 is an extracellular enzyme that facilitates production of adenosine, which suppresses immune activity and blunts the effectiveness of PD-L1 inhibitors. The enzyme is overexpressed in NSCLC. It’s possible that blocking it reduces excess adenosine and enhances the effect of PD-L1 blockade. The MATISSE study put the idea to the test in 40 previously untreated patients with stage 2/3A NSCLC in Europe and the US. 

Study participants received neoadjuvant durvalumab and platinum-based chemotherapy for four cycles, along with the investigational CD39 blocker IPH5201. After surgery, treatment continued with durvalumab and IPH5201 in 4-week cycles for up to a year. 

Thirty-five patients ultimately went to surgery; 31 (88.6%) had R0 resections. 

The overall pCR rate — the study’s primary outcome — was 27.5%. 

Responses varied by baseline PD-L1 expression, with pCR rates of 8.3% in PD-L1 negative tumors, 35.7% in tumors with PD-L1 ≥ 1%, and 50% in those with PD-L1 ≥ 50%. Higher baseline CD39 expression was also linked with higher pCR rates.

Though early, the results compare favorably to AEGEAN, the phase 3 trial that won durvalumab FDA approval with platinum-based chemotherapy for resectable NSCLC. The overall pCR rate in AEGEAN was 17.2%, ranging from 9% in PD-L1 negative tumors to 27.5% with PD-L1 ≥ 50%.

“MATISSE is paving the way for CD39 and more broadly adenosine pathway inhibition in early-stage non-small cell end cancer,” said Barlesi, a thoracic medical oncologist at and professor of medicine at Université Paris-Saclay. “There are improved pathological complete response rates based on the PD-L1 tumor expression. To confirm this trend, MATISSE will continue recruitment with patients with PD-L1 of more than 1%.” 

Study discussant Tina Cascone, MD, PhD, a thoracic and head and neck medical oncologist at MD Anderson Cancer Center, Houston, said the findings support continued interest in the adenosine pathway.

“Blocking CD39 could be an important strategy in perioperative care for resectable lung cancer,” she said.

Cascone also pointed to the NeoCOAST-2 trial, where oleclumab — a CD73 inhibitor acting downstream in the same adenosine pathway — was tested alongside durvalumab and platinum chemotherapy in a similar perioperative design. The overall pCR rate was 20.3% in 74 patients, with a higher rate in PD-L1 negative tumors than MATISSE at 16%. 

“We are looking at small numbers, but targeting different components of the adenosine pathway might be more beneficial” depending on PD-L1 expression. There might also be a role for blocking CD39 and CD73 together, she said. 

No new safety signals were observed in MATISSE. Nearly three-quarters of patients had adverse events related to IPH520, with asthenia, arthralgia, hypothyroidism, and thrombocytopenia occurring in 10% or more. 

MATISSE is funded by Innate Pharma and AstraZeneca, the developers of IPH5201; AstraZeneca also makes durvalumab. Barlesi disclosed ties to both companies and others. Cascone is an advisor for and reported honoraria and research funding from numerous companies, including AstraZeneca. 

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@medscape.net