FDA Grants LOXO-292 Breakthrough Designation for NSCLC, MTC

Josh Bilenker, MD

The FDA has granted LOXO-292 a breakthrough therapy designation for the treatment of patients with RET fusion—positive non–small cell lung cancer (NSCLC) or RET-mutant medullary thyroid cancer (MTC), according to Loxo Oncology, the manufacturer of the selective RET inhibitor.

The breakthrough designation is specifically for the treatment of patients with metastatic RET fusion—positive NSCLC who require systemic therapy and have progressed following platinum-based chemotherapy and an anti–PD-1 or anti–PD-L1 therapy; and for the treatment of patients with RET-mutant MTC who require systemic therapy, have progressed following prior treatment, and have no acceptable alternative treatment options.

The designation, which will expedite the development and review of LOXO-292 for these indications, is based on findings from the phase I LIBRETTO-001 study presented at the 2018 ASCO Annual Meeting. In the ongoing trial, the objective response rate (ORR) was 77% (95% CI, 58%-90%) for patients with RET fusion—positive NSCLC. At the April 2018 data cutoff, no patients with NSCLC had developed progressive disease (PD), with 90% remaining on treatment with LOXO-292. Moreover, all patients (n = 3) with measurable intracranial lesions responded to LOXO-292.

In those with RET-mutated MTC, the ORR was 45%, with 1 complete response (CR) and 1 additional CR awaiting confirmation. Two patients in this group developed PD and 93% continued to receive treatment with LOXO-292. Moreover, in 2 patients with a resistance mutation in V804M, there was a substantial reduction in tumor size. In 4 enrolled patients with no known activating RET alteration, there was no response with LOXO-292.

“We look forward to working with FDA to streamline the development of LOXO-292 in the two patient populations that have comprised the bulk of our initial clinical trial enrollment,” Josh Bilenker, MD, chief executive officer at Loxo Oncology, said in a statement.

“Given the many available therapies for non—small cell lung cancer and medullary thyroid cancer, we are pleased that LOXO-292 has shown encouraging data in refractory patients, and hope to demonstrate the full potential of this treatment in additional populations over time,” added Bilenker.

At the April 2018 data cutoff, 82 patients had been treated across 7 cohorts of LOXO-292, with doses ranging from 20 mg every day to 240 mg twice daily. The study enrolled patients with RET fusion-positive cancer or those with RET mutations. The RET fusion group (N = 49) included 38 patients with NSCLC, 9 with papillary thyroid cancer, and 2 with pancreatic cancer. The RET-mutated arm consisted solely of patients with medullary thyroid cancer (n = 29).

The median age of patients in the trial was 61 years (range, 17-88) and the primary ECOG performance status score was 71%. The median number of prior therapies was 3 (range, 1-9). Nearly a third of patients received ≥2 prior multikinase inhibitors (29%), with 66% of patients receiving at least one of these agents prior to study entry. Prior immunotherapy was received by 24% of patients and brain metastases were present for 15% of patients.

For patients with RET fusion-positive NSCLC (n = 38), there were 20 partial responses (PRs) and 3 PRs that were still awaiting confirmation on subsequent scans. Four patients had stable disease and 3 were not yet evaluable. Across all patients with RET fusion-positive cancer, the ORR was 77% (95% CI, 61%-89%), which consisted entirely of partial responses. Six patients had stable disease.

Responses to LOXO-292 were seen across RET fusion partners for patients with NSCLC. In those with the most common partner, KIF5B (n = 16), the ORR was 81%. In those with non-KIF5B partners, the ORR was 82%. Additionally, responses were observed regardless of the starting dose and prior therapy.

For those with MTC, responses were also observed regardless of starting dose and mutation type. Moreover, there was a substantial decline in carcinoembryonic antigen (CEA) and calcitonin levels following treatment with LOXO-292.

Most treatment-emergent adverse events (TEAEs) in the study were grade 1 in severity. There were only 2 treatment-related grade 3 AEs and no grade 4 events. The 2 grade 3 events were tumor lysis syndrome and increased ALT levels, both events resolved. At the April 2018 data cutoff, a maximum tolerated dose had not yet been reached. Tumor lysis syndrome represented the only dose-limiting toxicity in the trial.

The most common TEAEs were fatigue (20%), diarrhea (16%), constipation (15%), dry mouth (12%), nausea (12%), and dyspnea (9%). The most common treatment-related AEs were fatigue (13%), dry mouth (6%), nausea (5%), diarrhea (2%), and constipation (2%).

Multikinase inhibitors targeting RET and other kinases have shown promise in previous studies, specifically vandetanib (Caprelsa) and cabozantinib (Cometriq), which are both approved for MTC. In the study that led to FDA approval for vandetanib, the ORR was 44% with the multikinase inhibitor compared with 1% for placebo. For cabozantinib, the ORR was 27% compared with 0% for placebo.

In a case study of a 57-year-old man with advanced MTC harboring a germline RET V804M gatekeeper mutation, LOXO-292 demonstrated a confirmed CR at the 80 mg twice daily dose, which was escalated to 160 mg twice daily. Prior to enrollment in the study, the patient had progressed on cabozantinib, vandetanib, and lenvatinib. The patient remained in response at month 6.

The phase I LIBRETTO-001 study exploring LOXO-292 continues to enroll patients with advanced RET-altered solid tumors. The full estimated enrollment for the trial is 180 patients and the primary completion date is August 2019 (NCT03157128).

Drilon AE, Subbiah V, Oxnard GR, et al. A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. J Clin Oncol. 2018;36 (suppl; abstr 102).