LOXO-292 Granted Breakthrough Designation for Thyroid Cancer

Gina Columbus

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.

The decision is based on data from the ongoing phase 1/2 LIBRETTO-001 trial (NCT03157128), which is the basis for the other two 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 (38 patients), 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 nine most recently enrolled patients. At a median follow-up of 8.4 months, results showed that 94 percent (16 patients) responding RET-mutant MTC patients remained on therapy. A total 100 percent (seven patients) 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 percent overall response rate (ORR; 56 percent confirmed ORR) in the presented subset of RET-mutant MTC patients, and a 78 percent confirmed ORR in the RET fusion-positive thyroid cancer subset.

The phase 2 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 percent or more of patients were diarrhea (15 percent grade 1, 7 percent grade 2, 1 percent grade 3), fatigue (9 percent grade 1, 13 percent grade 2, 0 percent grade 3 or higher), dry mouth (21 percent grade 1, 0 percent grade 2 or higher), constipation (17 percent grade 1, 2 percent grade 2, 0 percent grade 3 or higher), hypomagnesemia (12 percent grade 1, 1 percent grade 2, 0 percent grade 3 or higher), cough (11 percent grade 1, 1 percent grade 2, 0 percent grade 3 or higher), headache (10 percent grade 1, 1 percent grade 2, 1 percent grade 3) and nausea (9 percent grade 1, 4 percent grade 2, 0 percent grade 3 or higher). 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 percent for patients with RET fusion–positive NSCLC. At the April 2018 data cutoff, no patients with NSCLC had developed progressive disease (PD), with 90 percent remaining on treatment with LOXO-292. Also, all patients (three patients) with measurable intracranial lesions responded to therapy with the selective inhibitor.

In those with RET-mutated MTC, the ORR was 45 percent, with one complete response (CR) and one additional CR awaiting confirmation. Two patients in this group developed PD and 93 percent continued to receive treatment with LOXO-292. Additionally, in two patients with a resistance mutation in V804M, there was a substantial reduction in tumor size. In four 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 seven 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 (49 patients) included 38 patients with NSCLC, nine with papillary thyroid cancer and two with pancreatic cancer. The RET-mutated arm consisted solely of patients with medullary thyroid cancer (29 patients).

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

For patients with RET fusion-positive NSCLC (38 patients), there were 20 partial responses (PRs) and three PRs that were still awaiting confirmation on subsequent scans. Four patients had stable disease and three were not yet evaluable. Across all patients with RET fusion-positive cancer, the ORR was 77 percent, 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 (16 patients), the ORR was 81 percent. In those with non-KIF5B partners, the ORR was 82 percent. 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.

This article originally appeared on under the title "FDA Grants LOXO-292 Breakthrough Designation for RET Fusion-Positive Thyroid Cancer."
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