The selective RET inhibitor selpercatinib is now approved for RET fusion–positive lung and thyroid cancers. New evidence presented at the virtual edition of the American Association for Cancer Research (AACR) Annual Meeting 2021 shows that selpercatinib is active against other RET fusion–positive cancers as well. Although RET fusions are expressed in only a small percentage of patients with other solid tumors, selpercatinib may be an effective option for those patients, according to the interim results of the phase I/II LIBRETTO-001 trial.1
“RET fusions in tumors other than lung or thyroid cancer are uncommon but potentially actionable. Selpercatinib demonstrates promising activity across a variety of advanced solid tumors, including multiple treatment-refractory gastrointestinal malignancies. In this heavily pretreated population with various advanced tumor types, the objective response rate was 47%. Efficacy was observed across cancer types and a spectrum of fusion partners. Selpercatinib was well tolerated with no new safety signals,” reported Vivek Subbiah, MD, of MD Anderson Cancer Center, Houston.
Vivek Subbiah, MD
“These results underscore the importance of broad-based genomic profiling. It is essential to identify oncogenic drivers, including RET fusions,” he stated. RET fusions occur predominantly in non–small cell lung cancer (NSCLC) and thyroid cancer. RET fusions are rare, recurrent events in other malignancies. “The therapeutic relevance of RET fusions occurring outside of NSCLC and thyroid cancers has not been established,” Dr. Subbiah told listeners.
Selpercatinib is a first-in-class, selective RET inhibitor with minimal activity against other kinases. LIBRETTO-001 is an ongoing global multicenter phase I/II trial conducted in 16 countries and 89 sites; it included 441 patients with advanced metastatic RET fusion–positive solid tumors. Phase I is a dose-escalation trial, and phase II is a dose-expansion study that includes multiple cohorts.
At the AACR meeting, Dr. Subbiah presented data on 38 patients with other cancer types, excluding NSCLC and thyroid cancer; 32 patients were evaluable for efficacy. Follow-up was at least 6 months after the first dose of selpercatinib. Selpercatinib treatment beyond disease progression was allowed if the investigator judged the drug was of clinical benefit.
At baseline, 62.5% had gastrointestinal cancers. Other cancer types included, but were not limited to, breast, salivary gland, ovarian, sarcoma, and unknown tumor of primary origin. The median patient age was 48 years; 53% were female; and 94% had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median number of lines of prior therapy was two; more than one-third of patients had three or more prior lines of systemic therapy. A total of 84% had prior chemotherapy; 28% had radiation therapy; and 50% had surgery. Other RET fusion partners included NCOA4 (the most common), CCDC6, KIF5B, and others.
Across all tumor types with measurable disease, the objective response rate was 47%, with two complete responses. Three patients with a response in nontarget lesions were not included. “Responses were observed across all tumor types and across the spectrum of RET fusion partners,” Dr. Subbiah said.
“The swimmer plot illustrates the rapid and durable antitumor activity of selpercatinib, with a median time to response of just under 2 months,” he continued. At a median follow-up of 13 months, the median duration of response was not reached. He showed slides of three patients with different tumor types who have achieved improvement with selpercatinib and continue with an ongoing response—one of them for 25 months and another for 3 years.
In 38 patients, the safety of selpercatinib was consistent with previous reports in the overall study population. “Of note, no patient discontinued treatment due a treatment-related adverse event,” reported Dr. Subbiah.
DISCLOSURE: Dr. Subbiah has served as a consultant or advisor to Helsinn Therapeutics, Loxo, MedImmune, QED Pharma, and R-Pharm US; has received institutional research funding from AbbVie, Agensys, Alfasigma, Amgen, Bayer, Berg Pharma, Blueprint Medicines, Boston Biomedical, D3 Oncology Solutions, Exelixis, Fujifilm, Genentech/Roche, GlaxoSmithKline, Idera, Incyte, Inhibrx, Loxo, Multivir, NanoCarrier, Northwest Biotherapeutics, Novartis, Pfizer, PharmaMar, Takeda, Turning Point Therapeutics, and Vegenics; has been reimbursed for travel, accommodations, or other expenses by Bayer, Helsinn Therapeutics, Novartis, and PharmaMar; and has held other relationships with Medscape.
1. Subbiah V, Konda B, Bauer T, et al: Efficacy and safety of selpercatinib in RET fusion–positive cancers other than lung or thyroid cancers. AACR Annual Meeting 2021. Abstract CT011. Presented April 11, 2021.
Ezra E.W. Cohen, MD
Formal discussant of the -LIBRETTO-001 trial, Ezra E.W. Cohen, MD, Associate Director for Translational Science and Leader of the Solid Tumor Therapeutics Research Program at the Moores Cancer Center at UC San Diego Health, was encouraged by this trial and said that...