Precision Medicine Advances: Pivotal Studies Led by MSK Published in the New England Journal of Medicine

Alexander Drilon, MD

Results Mark Significant Advances in Targeted Treatment for RET-Driven Cancers, Advancing the Field of Precision Medicine

Following an approval from the U.S. Food and Drug Administration (FDA) in May 2020, the New England Journal of Medicine has published data from the phase I/II LIBRETTO-001 clinical trial of selpercatinib (Retevmo™) in advanced RET (REarranged during Transfection)-driven lung and thyroid cancers. Memorial Sloan Kettering’s Alexander Drilon, MD, the recently appointed Chief of the Early Drug Development Service, serves as the lead investigator for multi-site clinical trial. These studies add to a vast body of work led by the MSK Early Drug Development Service, in cooperation with the Thoracic Oncology Service and Eric Sherman, MD of the Head and Neck Service, including the first published basket trial, the first FDA approval with an initial tumor-agnostic indication, and more.

“This data – and the recent approval – confirm that RET-driven cancers are specifically targetable in the same manner as activating EGFR and ALK alterations, across all lines of therapy, marking another important step in the field of precision medicine,” explained Dr. Drilon. “MSK has not only played a critical role in many of the recent advances in precision oncology, but it has been a center of center of excellence, for RET-driven cancers particularly since the fusion gene was discovered in lung cancers in 2012.”

Published data from the LIBRETTO-001 phase I/II trial – the largest clinical trial in patients with RET-driven cancers – provided follow-up safety and efficacy findings in two distinct patient populations. Dr. Drilon was the first author on the data regarding non-small cell lung cancer (NSCLC) along with co-corresponding author, Vivek Subbiah, MD, of The University of Texas, MD Anderson Cancer Center. The thyroid cancer data was authored by Dr. Sherman and Lori Wirth, MD, from Massachusetts General Hospital.

The NEJM study reported that selpercatinib was well tolerated and demonstrated durable efficacy in both treatment-naïve and platinum chemotherapy treated patients with RET fusion-positive NSCLC, including intracranial activity. In the first 105 consecutively enrolled RET fusion-positive NSCLC patients treated with at least prior platinum-based chemotherapy, the objective response rate (ORR) was 64 percent. The median duration of response was 17.5 months, with 63 percent of responses ongoing at a median follow-up of 12.1 months. Among 39 treatment-naïve patients, the ORR was 85 percent, with 90 percent of responses ongoing at 6 months.

It was also reported that selpercatinib was well tolerated and demonstrated durable efficacy in MTC patients with and without prior vandetanib or cabozantinib treatment, and promising activity in RET fusion-positive thyroid cancer. In the first 55 consecutively enrolled RET-mutant MTC patients previously treated with vandetanib and/or cabozantinib, the ORR was 69 percent and 1-year progression free survival rate was 82 percent. In 88 patients with RET-mutant vandetanib and cabozantinib-naïve MTC, the ORR was 73 percent and 1-year PFS rate was 92. In 19 patients with previously-treated RET fusion positive thyroid cancer, the ORR was 79 percent.

MSK’s research into RET-driven cancers has now moved towards understanding mechanisms of resistance to selective RET inhibition and strategies to target these cancers.

Dr. Drilon previously provided compensated advisory services to Loxo Oncology (acquired by Lilly in 2019).