Pancreatic cancer is one of the most aggressive, lethal malignancies, and life-extending treatments represent a critical unmet need. A pilot study suggests a potential way forward for patients with nonmetastatic unresectable or borderline resectable pancreatic cancer may be a combination of stereotactic body radiation therapy (SBRT) with avasopasem (formerly known as GC4419), a superoxide dismutase mimetic. This approach extended overall survival, according to interim results of a late-breaking phase I/II study presented at the 2020 American Society for Radiation Oncology (ASTRO) Annual Meeting,¹ which was held virtually.

“Local progression of pancreatic cancer causes substantial morbidity and mortality, particularly in patients with localized disease who cannot undergo resection. The survival rate is dismal. Surgery remains the only potential curative option for pancreatic cancer,” noted senior author Cullen Taniguchi, MD, Associate Professor of Radiation Oncology at The University of Texas MD Anderson Cancer Center, Houston. “The interim data from this pilot trial signal the potential of dismutase mimetics when combined with SBRT to prolong survival in patients with locally advanced pancreatic cancer. Further study of dismutase mimetics to expand the utility of SBRT in pancreatic cancer treatment is warranted,” he said.

“This study shows the feasibility of integrating surgery into this combination approach. Surgery is still the only potentially curative option for pancreatic cancer.”

— Cullen Taniguchi, MD

Tweet this quote

“Previous studies in patients with pancreatic cancer with favorable anatomy suggest that achieving a biologically effective dose > 70 Gy may improve local control and 2-year overall survival compared with standard doses of SBRT. Additional improvements with SBRT or radiomodulation might enable more patients to be treated with this approach,” he explained.

Ionizing radiation produces superoxide radicals, which damage cells. Superoxide dismutase breaks down superoxide radicals into hydrogen peroxide, which is a chemical that normal tissues can remove, but cancer cells cannot. When radiation is given along with avasopasem, hydrogen peroxide builds up in cancer cells, leading to potentially better radiation responses.

“The observation that dismutase mimetics kill cancer cells when combined with radiation formed the basis of this randomized pilot trial,” Dr. Taniguchi continued.

Study Details

Dr. Taniguchi reported results on the first 19 patients treated with this strategy at a single center who had follow-up of 1 year; he also reported late-breaking results for a second group of 23 patients treated at three additional centers with 3 to 6 months of follow-up.

All patients had locally advanced or borderline resectable pancreatic cancer and had completed initial chemotherapy, with no metastatic disease present. They were randomly assigned 1:1 to SBRT plus placebo vs five fractions of SBRT plus 90 mg intravenously of avasopasem. SBRT was given in three different doses assigned in real time according to an adaptive Bayesian model used to identify the optimal dose per each arm. In total, there were 18 patients in the placebo arm and 24 in the experimental arm.

The primary endpoints were the recommended dose of SBRT with avasopasem or placebo based on grade 3 or 4 toxicity or death within 90 days post-SBRT and the attainment of local stable disease or better at 90 days post-SBRT. Secondary endpoints included progression-free survival, overall survival, local control, distant metastasis rate, overall response rate, and resectability.

For the first 19 patients with mature follow-up, 54% of patients in the experimental arm vs 13% in the placebo arm had at least a partial response. Overall survival, progression-free survival, local control, and time to distant metastasis were all improved in the experimental arm in this small initial cohort.

At 1 year, progression-free survival was 29.3 weeks in the experimental arm vs 12.7 weeks in the placebo arm. The median overall survival was not reached in the experimental arm vs a median of 40.4 weeks in the placebo arm (P < .0463).

In the multicenter trial of 23 patients with 3 to 6 months of follow-up, endpoints were met by May 2020, and early analysis includes data through August 24, 2020. Follow-up is ongoing.

Baseline characteristics were comparable in both studies. In both arms, patients received SBRT in five fractions. There were more patients with borderline resectable disease in the experimental arm, and controls received chemotherapy for a longer period.

A waterfall plot showed that most patients on the avasopasem arm had some degree of response. Seven patients went on to surgery: five from the avasopasem arm and two from the placebo arm. Six underwent complete resection. There were no significant perioperative complications in the surgically treated patients.

“This study shows the feasibility of integrating surgery into this combination approach,” Dr. Taniguchi said. “Surgery is still the only potentially curative option for pancreatic cancer.”

At this early point, there was no significant difference in progression-free survival for the entire study population. Median overall survival has not been reached in the avasopasem arm vs 38.7 weeks in the placebo arm (P = .0643).

There were no grade 4 or 5 toxicities, and no significant differences in grade 3 or higher acute and late toxicities were observed between the two treatment arms, suggesting that avasopasem does not add to the toxicity of SBRT.

“These data support further investigation of this approach in this population. I hope this therapy may benefit patients with this terrible disease,” Dr. Taniguchi stated.

A news release from Galera Therapeutics noted: “The company plans to leverage observations from this pilot trial to further develop GC4711, its second superoxide dismutase mimetic clinical candidate, specifically for use in combination with SBRT, and anticipates initiating a follow-on Phase 2 trial in pancreatic cancer with GC4711 in combination with SBRT in the first half of 2021.”

DISCLOSURE: Dr. Taniguchi has served as a consultant or advisor to Accuray and Xerient and has received research support from the National Institutes of Health.

REFERENCE

1. Hoffe SE, Frakes J, Aguilera TA, et al: Randomized, double-blinded, placebo-controlled multicenter adaptive phase 1-2 trial of GC4419, a dismutase mimetic, in combination with stereotactic body radiation therapy in locally advanced pancreatic cancer. 2020 ASTRO Annual Meeting. Abstract LBA-5. Presented October 27, 2020.