Anti-CD39 Combination Therapy Promising in Gastric/GEJ Cancer

NEW ORLEANS — More than 60% of patients with unresectable gastric/gastroesophageal junction (GEJ) cancer responded to the combination of a CD39 inhibitor and chemoimmunotherapy, a small clinical trial showed.

The data showed 25 responses, including four complete responses, in 40 patients treated with the monoclonal antibody TTX-030, the PD-1 inhibitor budigalimab, and modified FOLFOX6 chemotherapy. An analysis limited to confirmed responses showed four complete responses and 17 partial responses. Responses occurred across the range of PD-L1 expression.

Grade 3/4 adverse events (AEs) related to TTX-030 occurred in 20% of patients, but only one patient withdrew because of AEs related to the CD39 inhibitor, reported Zev Wainberg, MD, of the University of California Los Angeles, during the American Association for Cancer Research (AACR) meeting.

“TTX-030 in combination with budigalimab and modified FOLFOX6 for the treatment of patients with HER2-negative metastatic gastric cancer was well tolerated without excessive toxicities,” and “revealed promising antitumor activity,” including in patients with PD-L1-low tumors, a CPS (combined positive score) less than 5, and those with induced intratumoral increases in PD-L1 expression and CD8 T cells, Wainberg noted.

“The results support further evaluation of TTX-030 in combination treatment in patients with metastatic gastric cancer,” he added, noting that the CD39 inhibitor is also being evaluated in combination with gemcitabine and nab-paclitaxel (Abraxane) for patients with metastatic pancreatic cancer.

TTX-030 indirectly targets the adenosine production pathway, which has a major role in tumor progression and suppression of immune activation. Inhibition of CD39 increases extracellular adenosine triphosphate (ATP) and blocks production of adenosine, Wainberg noted. Preclinical studies documented that TTX-030 increases ATP accumulation, leading to inhibition of adenosine production and reversal of adenosine-mediated T-cell suppression.

In a phase I dose-escalation study, no dose-limiting toxicities (DLTs) occurred, and the maximum tolerated dose of TTX-030 was not reached. Safety trials evaluating TTX-030 in combination regimens also showed no DLTs.

The lack of safety issues led to a study of TTX-030 in combination with budigalimab in patients with newly diagnosed locally advanced or metastatic gastric/GEJ adenocarcinoma. Previous studies had provided evidence of CD39 in immune filtrates of gastroesophageal cancer (GEC). The recent approval of nivolumab (Opdivo) plus chemotherapy has changed the standard of care for first-line treatment of metastatic GEC, but additional improvements in therapeutic options are needed, said Wainberg.

Investigators in the multicenter trial enrolled a total of 44 patients (median age 61). Thirty (68%) patients had gastric cancer, and the rest had GEJ disease. After a median follow-up of 7 months, 26 (59.1%) patients remained on study.

AEs considered related to TTX-030 occurred in 27 (61.4%) patients, and grade 3/4 AEs related to the drug occurred in nine. One patient withdrew because of a treatment-related AE (TRAE). Additionally, 25 (56.8%) patients had TRAEs related to budigalimab, including 11 with grade 3/4 TRAEs.

Among 40 patients evaluable for response, the overall response rate was 62.5%, including unconfirmed responses, declining to 52.5% when considering only confirmed responses. The disease control rate was 92.5% whether considering confirmed or unconfirmed responses. Wainberg said that only three patients did not have some degree of tumor shrinkage during treatment.

Considering unconfirmed responses, five of 11 patients with PD-L1 CPS <1 responded, as did nine of 12 with CPS 1-5, and 11 of 14 with CPS ≥5. Limiting the analysis to confirmed responses, responses across CPS levels were four of 11, eight of 12, and nine of 14.

“If you look at how long these patients have been on study, in particularly the patients with CPS 1-5 versus 5 or greater, you see that the top four or five patients who have been on study the longest are CPS 1-5,” said Wainberg. “That indicates we are having impressive durable responses in patients with CPS 1-5, not just the patients with CPS greater than 5.”

The key unresolved question from the trial is whether the addition of TTX-030 provides an incremental benefit over PD-1 inhibition plus chemotherapy, said AACR invited discussant Ian Chau, MD, of the Royal Marsden Hospital in London. There are currently no survival data on TTX-030, whereas the CheckMate 649 trial with nivolumab and chemotherapy showed a significant improvement versus chemotherapy alone and a median progression-free survival of 7.7 months.

“So we still need to try to at least pass that mark to know whether there’s any incremental improvement with blocking CD39,” said Chau.

Clinical development of budigalimab has focused primarily on combination therapy with other drugs, he continued. Single-agent data are limited primarily to lung cancer and head and neck cancer. Response rates have been within the range of what would be expected with other anti-PD-1/L1 antibodies. That raises the question of whether the combination was one of collaboration or convenience, he said.

“How do we move forward with development of TTX-030 in advanced esophagogastric cancer?” asked Chau. “Do we think CD39 is a strong enough target? Do we have enough evidence to move straight to phase III studies?”