Selpercatinib Effective Therapy for RET Fusion-Positive Non-Small Cell Lung Cancer

Vivek Subbiah, MD

The FDA granted approval to the highly selective RET inhibitor selpercatinib (Retevmo) capsules for the treatment of patients with lung or thyroid cancer who harbor a RET alteration in May 2020, marking the first RET-targeted therapy approved. Among the 3 indications granted in this accelerated approval, adult patients with metastatic RET fusion-positive non–small cell lung cancer (NSCLC) may receive this therapy.

Selpercatinib gained its approval from the FDA based on the positive findings in the phase 1/2 LIBRETTO-001 study (NCT03157128), which is the largest study to date of patients with RET-driven cancers. The open-label multicenter trial explored the safety, tolerability, pharmacokinetics, and antitumor activity of this agent as treatment of patients with advanced solid tumors with RET fusions or alterations.

The co-primary end points of the study, which remains ongoing, include maximum tolerated dose and recommended phase 2 dose in the phase 1 portion of the study and objective response rate (ORR). Patients were treated with 160 mg selpercatinib orally twice daily, and among the population of patients with RET fusion-positive NSCLC, 105 had previously received a platinum chemotherapy, and 39 were treatment-naïve. Continuation of the FDA’s approval remains contingent on the verification of clinical benefit of selpercatinib in confirmatory trials.

In an interview with Targeted Oncology, Vivek Subbiah, MD, of the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the role of selpercatinib as treatment of patients with RET fusion-positive NSCLC, which is supported by findings from the LIBRETTO-001 study.

TARGETED ONCOLOGY: Could you provide some background to RET fusions in NSCLC?

Subbiah: RET alterations have been characterized as oncogenic drivers in multiple cancers, including NSCLC. As we all know, genome-driven precision oncology has altered the landscape of NSCLC, and lung cancer is becoming a rare cancer with multiple rare disease subtypes. RET fusions are seen in 1% to 2% of NSCLC patients, and what we see is about half of the patients with RET fusion-positive NSCLC have a 50% chance of developing brain metastases over the course of their lifetime.

TARGETED ONCOLOGY: Could you describe some of the data we have seen so far for selpercatinib?

Subbiah:LIBRETTO-001 is a phase 1/2 clinical trial of the selective RET inhibitor selpercatinib, also known LOXO-292, in patients with RET fusion-positive solid tumors and RET-mutant medullary thyroid cancer. About half of the patients enrolled on the trial have RET fusion-passive NSCLC.Previous publications, including our group, have shown that patients with RET fusion positive NSCLC have a 50% chance of developing brain metastases over the course of their lifetime.

Selpercatinib is a highly potent selective RET inhibitor in RET fusion-positive NSCLC patients treated with at least prior platinum-based chemotherapy. A total of 105 patients exhibited an ORR by independent review in the main trial. The ORR was 64% with the median duration of response (DOR) 18 months. The median progression-free survival (PFS) was 17 months with the median follow-up 14 months. The investigator assessment of the prior population was similar, and the ORR was 70% with a median DOR of 20 months and a median follow-up of 15 months. The median PFS was 18 months with a median follow-up of 16 months. Among the population of patients who are treatment-naïve, the ORR was 85%, and the median DOR was not reached with 95% confidence interval at 12 months to not estimable with the median follow-up of 7 months.

Again, the phase 1 dose-escalation portion of the multicenter global LIBRETTO-001 trial began May of 2017, and the first patient in the phase 2 cohort was enrolled at the recommended phase 2 dose of 160 mg twice a day in May of 2018. As of June 2019, 531 patients had been enrolled and treated, and this included a dataset of 253 RET fusion-positive NSCLC patients. Among the 253 RET fusion-positive patients, 80 patients at patients were judged by the investigators of having a brain metastasis at baseline, and 22 of these patients had brain metastases that were deemed measurable by a blinded independent radiology committee.

TARGETED ONCOLOGY: Could you elaborate on the findings in this population?

Subbiah:During the trial, the central nervous system (CNS) response was assessed by RECIST 1.1 every 8 weeks from cycle 3 to 13, and every 12 weeks thereafter. The primary end point for this analysis was intracranial ORR, as assessed by a blinded independent review committee. A secondary end point was intracranial DOR also by independent review for all patients. Treatment beyond progression was also permitted if the patient was to derive a clinical benefit.

Consistent with the previous analysis, the most common RET fusion partner is K5B, and most patients had received prior systemic therapy. Eight of the 22 patients had even received prior radiotherapy for the treatment of brain metastasis. In terms of the intracranial ORR rate to selpercatinib, we found 82% or 18 of the 22 patients with measurable brain metastasis had their CNS disease respond to the treatment. This included 23% of patients, 5 of the 22, with a complete response per RECIST. Patients who had received prior CNS radiotherapy responded to selpercatinib to an equal extent, including 6 of the 8 patients who had completed radiotherapy over 2 months prior to starting selpercatinib.

In addition to the 82% response rate, all other patients had stable disease with 2 exhibiting CNS tumor shrinkage, as well as most of the responders had also been treated with a multi kinase inhibitor and/or immunotherapy checkpoint-based therapy prior to the selpercatinib treatment. The median duration of CNS response was 9.4 months with a 95% confidence interval of 7.4 months to not estimable. Forty-four percent of the responses were censored at the time of data cutoff due to ongoing responses. Patients with and without prior CNS radiotherapy exhibited a DOR.

TARGETED ONCOLOGY: What are the key takeaways from the data from the LIBRETTO-001 study?

Subbiah:In conclusion, these data demonstrate that selpercatinib has marked and durable intracranial anti-tumor activity, as evidenced by intracranial response to date and DOR; 82% of patients had a partial or complete intracranial response. All other patients had stable disease, and no patient had CNS progressive disease. Interestingly, a randomized global phase 3 study of selpercatinib versus platinum pemetrexed plus or minus pembrolizumab in treatment-naïve RET fusion-positive NSCLC is currently ongoing, and in that study, patients with asymptomatic brain mets can enroll as well. This will enable us to further explore the intracranial activity of this agent.

Another thing I'd like to mention is that the FDA approved selpercatinib for lung and thyroid cancers with certain RET gene mutations or fusions. It was in May that the FDA granted an accelerated approval to selpercatinib for the following indications: other patients with metastatic RET fusion-positive NSCLC, adult and pediatric patients greater than 12 years of age with advanced metastatic RET-mutant thyroid cancer, and adult and pediatric patients greater than 12 years of age with advanced metastatic RET fusion-positive thyroid cancer who require systemic therapy and are who are radioactive-refractory. The important thing about this approval is that across these 3 tumor types, the drug has been approved line-agnostic. That means a patient can be in any line of therapy for them to receive the standard of care therapy right now.

TARGETED ONCOLOGY: Is there any other research in the field that you would like to highlight in the RET fusion-positive space?

Subbiah:There are several RET inhibitors in clinical trials. Now, successful clinical translation of the selective RET inhibitors is poised to alter the therapeutic landscape of multiple RET-positive cancers. Questions in the future that clearly need to be addressed are related to maintaining long-term inhibition of tumor growth, and how we can prepare for the potential mechanisms of acquired resistance, and also the development of next-generation selective RET inhibitors. It's an exciting time to be working in the best targeted therapy space, and my only pitch is we need to test for alterations in patients. These are rare aberrations, but the more we test patients, the more we find these patients. Patients derive enormous clinical benefit and the gift of time, even in the relapsed/refractory setting, as long as these patients harbor these mutations.