Discussant of the abstract on the WEE1 inhibitor adavosertib, Shannon N. Westin, MD, MPH, FACOG, Associate Professor and clinical investigator at The University of Texas MD Anderson Cancer Center, called the interaction between P53 and WEE1 an “opportunity for synthetic lethality.” She continued: “This is exactly what we’ve seen in homologous recombination–deficient ovarian cancer and PARP inhibitors. If WEE1 is inhibited in the setting of a P53 mutation, there’s increased replication stress, genomic instability, and mitotic catastrophe in the cancer cells.”

Shannon N. Westin, MD, MPH, FACOG

‘Not Quite Ready for Prime Time’

According to Dr. Westin, however, although these findings are “intriguing,” adavosertib is “not quite ready for prime time.” Additional validation of these data is needed to move this drug forward in endometrial cancer, she observed. Moreover, she added, if adavosertib were to be approved, an obvious question in uterine serous cancer would be how to sequence this agent with existing options such as lenvatinib and pembrolizumab.

“We need to understand how the activity of this drug might be related to the type of P53 mutation as well as the presence of CCNE1 amplification,” said Dr. Westin.

Additional Commentary

Alexander Melamed, MD, MPH

Alexander Melamed, MD, MPH, Assistant Professor of Obstetrics and Gynecology at NewYork-Presbyterian/Columbia University Medical Center, agreed with Dr. Westin’s assessment of this novel agent. In an interview with The ASCO Post, Dr. Melamed said: “A 29% response rate in a heavily pretreated cohort of patients with recurrent uterine serous cancer is, without question, an impressive result.” According to Dr. Melamed, however, the fact that the abstract includes just seven confirmed responses means “more data are required to increase our confidence that adavosertib is as effective as these preliminary data suggest.” 

DISCLOSURE: Dr. Westin has received research support from AstraZeneca, ArQule, Clovis Oncology, Novartis, Roche/Genentech, Cotinga Pharmaceuticals, GSK/Tesaro, and Bayer and has consulted with AstraZeneca, Clovis Oncology, Roche/Genentech, Novartis, Circulogene, Pfizer, GSK/Tesaro, Merck, and Eisai. Dr. Melamed reported no conflicts of interest.