FDA Grants LOXO-292 Breakthrough Designation for RET Fusion-Positive Thyroid Cancer

The FDA has granted LOXO-292 a breakthrough therapy designation for the treatment of patients with advanced RET fusion—positive thyroid cancer who require systemic therapy, have progressed on prior treatment, and have no other acceptable alternative treatment options, according to a statement from Loxo Oncology, the developer of the selective RET inhibitor.

This designation supplements the two other breakthrough therapy designations granted to LOXO-292 in September 2018 for the treatment of patients with RET fusion—positive non–small cell lung cancer (NSCLC) or RET-mutant medullary thyroid cancer (MTC).

LOXO-292 is an oral and selective investigational new agent being evaluated for the treatment of patients with cancers that harbor abnormalities in the RET kinase.

"We are pleased to receive this Breakthrough Therapy Designation for LOXO-292 in RET fusion—positive thyroid cancer, supplementing the breakthrough therapy designations in RET fusion—positive non-small cell lung cancer and RET-mutant medullary thyroid cancer," said Josh Bilenker, CEO of Loxo Oncology. "We look forward to continuing to work with the FDA as we advance the LOXO-292 clinical program and develop this potential new therapeutic option for patients with RET-altered cancers."

The decision is based on data from the ongoing phase I/II LIBRETTO-001 trial (NCT03157128), which is the basis for the other 2 breakthrough therapy designations. The first two designations are 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 those with RET-mutant MTC who require systemic therapy, have progressed following prior treatment, and have no acceptable alternative treatment options.

Updated interim data of the LIBRETTO-001 study, which included patients with RET-mutant MTC and RET fusion-positive thyroid cancer (n = 38), were presented at the 88th Annual Meeting of the American Thyroid Association.

Approximately 3.5 months of additional follow-up were available, as were first follow-up scans for the 9 most recently enrolled patients. At a median follow-up of 8.4 months, results showed that 94% (n = 16) responding RET-mutant MTC patients remained on therapy. A total 100% (n = 7) of responding patients with RET fusion-positive thyroid cancer remained on therapy, with a median follow-up of 8.5 months.

Inclusion of new restaging data for the most recently enrolled patients demonstrated a 59% overall response rate (ORR; 56% confirmed ORR) in the presented subset of RET-mutant MTC patients, and a 78% confirmed ORR (95% CI, 40-97) in the RET fusion-positive thyroid cancer subset.

The phase II LOXO-292 dose has been determined as 160 mg twice daily, with dose exploration at 200 mg twice weekly ongoing to further characterize LOXO-292 safety and efficacy.

Of the 82 patients in the safety analysis, most treatment-emergent adverse events (TEAEs) were grade 1 in severity and determined to not be related to LOXO-292. TEAEs observed in ≥10% of patients were diarrhea (15% grade 1, 7% grade 2, 1% grade 3), fatigue (9% grade 1, 13% grade 2, 0% grade ≥3), dry mouth (21% grade 1, 0% grade ≥2), constipation (17% grade 1, 2% grade 2, 0% grade ≥3), hypomagnesemia (12% grade 1, 1% grade 2, 0% grade ≥3), cough (11% grade 1, 1% grade 2, 0% grade ≥3), headache (10% grade 1, 1% grade 2, 1% grade 3) and nausea (9% grade 1, 4% grade 2, 0% grade ≥3). Four patients experienced grade 3 treatment-related adverse events (AEs), which comprised tumor lysis syndrome, increased ALT/AST, diarrhea, and thrombocytopenia. All AEs resolved with dose interruption.

Preliminary findings of LIBRETTO-001 were presented at the 2018 ASCO Annual Meeting. In the ongoing study, the 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. Also, all patients (n = 3) with measurable intracranial lesions responded to therapy with the selective inhibitor.

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. Additionally, 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.

At the April 2018 data cutoff, 82 patients had been treated across 7 cohorts of LOXO-292, with doses ranging from 20 mg daily to 240 mg twice daily. The trial 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 one-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%. Responses were observed regardless of the starting dose and prior treatment.

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.

The agency’s breakthrough therapy designation is intended to expedite the development and review of drugs designed to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the agent may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

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).