TTX-030 Plus Budigalimab/mFOLFOX6 Induces Responses in PD-L1–Low Advanced Gastric/GEJ Cancer

The addition of the investigational anti-CD39 antibody TTX-030 to frontline treatment with the PD-L1 inhibitor budigalimab and mFOLFOX6 was determined to be safe and tolerable in patients with locally advanced or metastatic HER2-negative gastroesophageal junction (GEJ) adenocarcinoma, according to phase 1 findings recently presented at the 2022 AACR Annual Meeting.

Moreover, the agent produced encouraging antitumor activity in patients, including those with PD-L1 low tumors with a combined positive score (CPS) less than 5.

Investigators also observed that the combined therapeutic was linked to an increase of PD-L1 and CD8 T cells.

Overall, TTX-030 as monotherapy or in combination was not associated with any reported drug-limiting toxicities, and the maximum-tolerated dose of TTX-030 alone was also undetermined. Based on these data, investigators determined that TTX-030 can be safely combined with FOLFOX and anti–PD-1 agents and administered to patients, so long as there are no excessive or synergistic toxicities.

In the total evaluable population (n = 40), the confirmed overall response rate (ORR) was 52.5%. A total of 4 patients experienced a complete response (CR; 10%) and 17 patients experienced a partial response (PR; 42.5%). Sixteen patients (40%) achieved stable disease (SD) and the disease control rate was 92.5% (n = 37), and 3 patients (7.5%) experienced disease progression.

In a subgroup of patients with a CPS score less than 1 (n = 11), the confirmed ORR was 36.4%, compared with 66.7% in those with a CPS score between 1 and 5. In patients whose CPS score as at least 5, the ORR was 64.3%.

“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,” Zev A. Wainberg, MD, professor of medicine at University of California, Los Angeles (UCLA), and co-director of the UCLA GI Oncology Program, said in a presentation of the findings. “It revealed promising antitumor activity, including in patients [with] PD-L1 tumor CPS less than 5, [and] induced intertumoral increases in PD-L1 expression and CD8 eight cells. These results support further evaluation of TTX-030 combination treatment in patients with metastatic gastric cancer.”

TTX-030 is the first fully human IgG4 antibody designed to target CD39, as well as the first CD39 agent to undergo a phase 1 trial. The non-competitive allosteric inhibitor of CD39 ectoenzyme enzymatic activity functions by binding and inhibiting CD39 at sub-nanomolar potencies in an environment with high extracellular ATP. In doing so, the agent increases extracellular ATP and consequently prevents the generation of adenosine.

“The blockade of CD39 is the first step involved in [the] process by which extracellular ATP is converted to ANP,” explained Wainberg. “The value of that is twofold because first [there is] suppression of adenosine, which is an immunosuppressive agent, along with the maintenance and increased production in essence of extracellular ATP; extracellular ATP has the advantage of activating an innate immune function. Therefore, we have this dual strategy behind blockade CD39.”

In this study, patients with a histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic adenocarcinoma of the stomach or gastroesophageal junction with HER2-negative disease were enrolled to receive a 28 day-cycle of mFOLFOX6, budigalimab, and TTX-030.

To enroll, patients could not have received prior treatment for metastatic disease, nor could they have received neoadjuvant or adjuvant therapy within 6 months of trial enrollment. The study’s coprimary end points were safety and tolerability, while secondary end points included progression-free survival and ORR, per RECIST/iRECIST criteria.

In the dose-escalation and expansion phases, TTX-030 monotherapy doses ranged from 0.5 to 4.0 mg/kg every 3 weeks. The recommended phase 2 dose (RP2D) was determined to be a 40 mg/kg loading dose 7 days before day 1 of cycle 1. Once the cycle began, the RP2D was 20 mg/kg every 2 weeks.

The median age of patients was 61 years (range, 30-81), and 41% of patients were female; 57% of patients were Asian and 93% of patients were of non-Hispanic or Latino ethnicity. Most patients (61%) had an ECOG performance status of 1. Sixty-eight percent of patients had gastric adenocarcinoma, and the median number of prior therapies was 1.

Treatment is ongoing in 59.1% of patients, and the median time on study was 214 days (range, 8-464).

Overall, 11 patients (25%) experienced at least 1 grade 3 or greater adverse event (AEs) related to budigalimab, and 9 patients (20.5%) experienced at least 1 grade 3 AE related to TTX-030. Twenty-eight patients (63.6%) experienced at least 1 grade 3 AE regardless of relatedness. The most common AEs overall included increased gamma-glutamyl transferase (4.5%), hyperglycemia (4.5%), and deceased neutrophil count (34.1%), hyperglycemia (6.8%), febrile neutropenia (4.5%), and gastric perforation (4.5%).

“Many of us are aware [that] in the last 2 years, we have seen changes in the landscape of the treatment of metastatic gastric cancer, in which the addition of a PD-1 inhibitor, nivolumab, has been approved for patients with metastatic gastric cancer with chemotherapy,” explained Weinberg. “The important point there is that the advantage of the drug is [most prominent] in patients with PD-L1 CPS greater than 5. In the group of patients with a low PD-L1 score, [or a score] under 5, there is a lot of debate [regrading] the value of the addition of nivolumab.”

Investigators are also evaluating the combination as a potential treatment for patients with pancreatic cancer.

Reference

Wainberg ZA, Kang YK, Lee KW, et al. Efficacy and safety of TTX-030, an anti-CD39 antibody, in combination with chemoimmunotherapy for thefirst-line treatment of locally advanced or metastatic gastric/GEJ cancer. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT015.