Opinion: Avasopasem—A Promising Approach to Enhance Efficacy and Minimize Toxicity in Pancreatic Cancer Radiation Therapy

Amanda Brink, DNP, APRN, FNP-BC, AOCNP

Pancreatic ductal adenocarcinoma stands as the third leading cause of cancer-related deaths in the United States,¹ despite being only the 10th most commonly diagnosed cancer among both men and women.² The lethality of pancreatic cancer is attributed to various factors. Often asymptomatic until reaching an advanced stage, only 15% to 20% of patients are eligible for surgical resection at the time of diagnosis—a procedure that offers the best chance for curing pancreatic cancer.³

Even in patients who undergo surgical resection, nearly 3 in 4 will experience recurrence within 2 years. This suggests that many patients harbor micrometastatic disease, with pancreatic cancer cells circulating before tumors become visible on imaging. Therefore, patients are often treated with both neoadjuvant (pre-surgery) and adjuvant (post-surgery) treatments in an attempt to eliminate these cells. Neoadjuvant treatment has the potential to shrink tumors in patients who may not otherwise be candidates for surgery, thereby making them eligible for surgical intervention.³

Research has demonstrated that a combination of neoadjuvant chemotherapy and radiation therapy results in a significantly improved 5-year overall survival compared to patients receiving surgery and adjuvant therapy alone (20.5% vs 6.5%).³

A Clinical Trial With Avasopasem Aimed at Enhancing the Efficacy of Radiation Therapy

Research has indicated that an ablative dose of radiation—meaning a higher dose aimed at destroying a tumor—results in more favorable patient outcomes compared to standard radiation therapy. However, employing an ablative dose of radiation therapy poses an increased risk of injury to surrounding tissue for the patient.⁴

Avasopasem manganese is a drug classified as a manganese pentaazamacrocyclic selective superoxide dismutase mimetic. This means that avasopasem transforms superoxide radicals—produced by radiation therapy and responsible for harming normal tissue near the radiation site—into hydrogen peroxide. Hydrogen peroxide is more toxic to tumors than normal tissue. Consequently, avasopasem has the potential to mitigate the side effects of radiation therapy in tissues surrounding the radiation field, while simultaneously enhancing the toxicity of radiation therapy to the tumor.⁴

Taniguchi et al⁴ conducted a phase 1b/2 adaptive, randomized, double-blind, placebo-controlled clinical trial at 6 academic medical centers in the United States. Participants were adult patients with pancreatic ductal adenocarcinoma, categorized as either borderline resectable or locally advanced, without distant metastatic disease. Patients underwent induction chemotherapy for at least 3 months before receiving radiation therapy. Subsequently, patients received either avasopasem or placebo (normal saline) as a 60-minute intravenous infusion before each radiation treatment. Assessment for surgical resectability was conducted after completing radiation therapy.

Researchers in this study examined the efficacy and toxicity of ablative radiation therapy in combination with avasopasem compared to ablative radiation therapy with a placebo. In the avasopasem group, 18 out of 24 patients (75%) received 50 Gy of radiation therapy in 5 fractions, while 6 patients (25%) received 55 Gy. In the placebo group, 6 out of 18 patients (33%) received 50 Gy, and the remaining 12 patients (67%) received 55 Gy. Notably, no patients required dose reductions in radiation therapy.

The placebo group was prematurely concluded due to the absence of any radiation dose meeting the predefined criteria for both acceptable toxicity and efficacy. This meant that accrual into the group of participants receiving the placebo was halted before the initially planned endpoint because the researchers had specific standards for how effective and safe treatment should be, and none of the tested radiation doses met both criteria. Consequently, an imbalance of patients with borderline resectable disease was created between the groups. Therefore, a sensitivity analysis was conducted solely in patients with locally advanced pancreatic cancer.

Among patients with locally advanced pancreatic cancer, in the avasopasem group, 8 out of 10 patients (80%) exhibited an efficacy response at 50 Gy, and all 6 patients (100%) demonstrated a response at 55 Gy. In contrast, in the placebo group, 3 out of 6 patients (50%) showed a response at 50 Gy, and 7 out of 10 patients (70%) exhibited a response at 55 Gy.

While the trial was not intended for comparing arms, median progression-free survival for patients in the avasopasem group was 12.4 months (95% CI, 6.1-14.9) and 3.4 months (95% CI, 1.9-8.3) in the placebo group. The overall response rate was 88% in the avasopasem group and 67% in the placebo group.

Five out of 24 patients (21%) in the avasopasem group underwent a complete surgical resection, whereas only 1 out of 18 patients (6%) in the placebo group did so.

No serious adverse events were attributed to the drug or radiation therapy in either group.

Nursing Considerations

Understanding the purpose of administering a medication like avasopasem to patients undergoing radiation therapy is crucial for oncology nurses, who play a pivotal role as patient educators translating scientific advancements to patients. Patients may rely on members of the nursing team to comprehend the advantages of this treatment and the significance of participating in clinical trials. Given that participating in a clinical trial is often more time intensive than receiving standard-of-care therapy, it is crucial for patients to grasp the potential benefits of the trial.

Unfortunately, the first author, Dr. Cullen Taniguchi, passed away suddenly before the publication of this study.⁵ He was committed to improving the care of patients with pancreatic cancer. Hopefully, this research can be the start of more breakthroughs in improving the use of radiation therapy for patients with pancreatic cancer, serving as a way to honor Dr. Taniguchi's dedication and contributions.

References

1. Common cancer sites - cancer stat facts. National Cancer Institute. Accessed December 14, 2023. https://seer.cancer.gov/statfacts/html/common.html.
2. Common cancer types. National Cancer Institute. Accessed December 14, 2023. https://www.cancer.gov/types/common-cancers.
3. Halbrook CJ, Lyssiotis CA, Pasca di Magliano M, Maitra A. Pancreatic cancer: Advances and challenges. Cell. 2023;186(8):1729-1754. doi:10.1016/j.cell.2023.02.014
4. Taniguchi CM, Frakes JM, Aguilera TA, et al. Stereotactic body radiotherapy with or without selective dismutase mimetic in pancreatic adenocarcinoma: an adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial. Lancet Oncol. 2023;24(12):1387-1398. doi:10.1016/S1470-2045(23)00478-3
5. Tracey Barnett, Galehouse M. In Memoriam: Cullen M. Taniguchi, MD, Phd. Graduate School of Biomedical Sciences. November 28, 2023. Accessed December 14, 2023. https://gsbs.uth.edu/news/story/in-memoriam-cullen-m-taniguchi-md-phd.