Adavosertib (AZD1775) in Combination with Chemoradiation Shows Near Doubling of Overall Survival in Phase 1 Trial for Locally Advanced Pancreatic Cancer

Recently, researchers at the University of Michigan reported positive results from a Phase 1 clinical trial evaluating AstraZeneca’s investigational therapy AZD1775, which targets DNA damage repair mechanisms, in combination with chemotherapy and radiotherapy for patients with newly diagnosed locally advanced pancreatic cancer. The treatment regimen extended overall survival in these patients. The study was published in the Journal of Clinical Oncology.

Pancreatic cancer is one of the most lethal cancers, often referred to as the "king of cancers." In 2018, approximately 55,000 people in the United States were diagnosed with pancreatic cancer, and more than 44,000 died from the disease. More alarmingly, therapeutic options for this aggressive disease are very limited, and most are ineffective. The five-year survival rate for patients with pancreatic cancer is less than 8%, and 80% of patients have already developed metastases at the time of diagnosis. The median overall survival (OS) for advanced pancreatic cancer is only three months.

Radiotherapy and the chemotherapy drug gemcitabine are standard treatments for pancreatic cancer, both exerting their effects by causing DNA damage. However, the robust DNA damage repair capability of pancreatic cancer cells limits the efficacy of these standard therapies. The Wee1 kinase plays a critical role in DNA damage repair, and AZD1775 is a Wee1 inhibitor. By inhibiting Wee1 function, AZD1775 restores the sensitivity of pancreatic cancer cells to radiotherapy and gemcitabine, while having minimal impact on normal cells.

The Phase I clinical trial enrolled 34 patients with locally advanced pancreatic cancer. In addition to radiotherapy and the chemotherapy drug gemcitabine, patients received AZD1775 at varying doses. The primary objective of this clinical trial was to determine the maximum tolerated dose (MTD) of AZD1775 in the combination regimen. During the trial, researchers also observed that this combination therapy resulted in overall survival (OS) rates exceeding historical outcomes for radiotherapy or gemcitabine monotherapy. The median OS for all patients in this clinical trial was 22 months, compared to 12–14 months for patients treated with gemcitabine alone.

▲Dr. Meredith Morgan, Dr. Kyle Cuneo, and Dr. Ted Lawrence (Image source: University of Michigan Rogel Cancer Center)

“If we can disable the DNA damage response in pancreatic cancer cells, we may be able to eliminate tumor drug resistance and sensitize cancers to the effects of radiation and chemotherapy,” said Dr. Kyle Cuneo, Associate Professor of Radiation Oncology at the University of Michigan Medical School. “The addition of AZD1775 to radiation therapy and the chemotherapy drug gemcitabine was relatively well tolerated, and the resulting prolongation of survival is encouraging. In the future, further research is needed on this promising combination therapy.” Researchers plan to initiate a Phase II clinical trial to further investigate the efficacy of this combination therapy in treating patients with pancreatic cancer.

References:

[1] AstraZeneca drug heads to phase 2 in pancreatic cancer after small trial extends survival. Retrieved August 15, 2019, from https://www.fiercebiotech.com/research/astrazeneca-drug-heads-to-phase-2-pancreatic-cancer-after-small-trial-extends-survival

[2] New drug shows encouraging survival in pancreatic cancer. Retrieved August 14, 2019, from https://www.eurekalert.org/pub_releases/2019-08/mm-u-nds081419.php

[3] Cuneo et al., (2019). Dose Escalation Trial of the Wee1 Inhibitor Adavosertib (AZD1775) in Combination With Gemcitabine and Radiation for Patients With Locally Advanced Pancreatic Cancer. Journal of Clinical Oncology, DOI: 10.1200/JCO.19.00730

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