The highly-selective RET inhibitor LOXO-292 demonstrated robust clinical activity across RET-altered solid tumors, including in patients with brain metastases and the RET V804M gatekeeper mutation.
Alexander Drilon, MD
The highly-selective RET inhibitor LOXO-292 demonstrated robust clinical activity across RET-altered solid tumors, including in patients with brain metastases and the RET V804M gatekeeper mutation, which usually confers resistance to multikinase inhibitors, according to 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 non—small cell lung cancer (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 medullary thyroid cancer (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.
"The activity of LOXO-292 is durable, with nearly 90% of patients still on treatment as of the data cutoff, including all of those responding to treatment. The longest duration of treatment exceeded 10 months," said lead investigator Alexander E. Drilon, MD, a medical oncologist at the Memorial Sloan Kettering Cancer Center. "All 12 patients with CNS metastases at baseline remained on treatment."
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.
"In response to LOXO-292, disease regression was observed in the vast majority of patients. This activity did not differ by cancer type, in this patient population composed of those with lung, thyroid, and pancreatic cancer," said Drilon. "Antitumor activity was observed across the entire range of dose levels, including in the 20 mg per day dose."
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 majority of MTC patients also experienced substantial stable reductions in the cancer tumor markers—CEA and calcitonin—together with improvement in tumor-related symptoms, like diarrhea and flushing," said Drilon.
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, Drilon noted. 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," he said.
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%).
"LOXO-292 was well-tolerated, consistent with its high preclinical selectivity for RET," said Drilon. "Only 6 treatment-emergent adverse events were observed in greater than or equal to 10% of patients. The majority of these were grade 1 or 2 and deemed unrelated to LOXO-292."
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 vandetinib, 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 contrast with prior multikinase inhibitors, LOXO-292 is highly selective, with minimal inhibition of other targets," said Drilon. "It’s potent both in vitro and in vivo against diverse RET fusions and mutations, including the V804M gatekeeper mutations."
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, Drilon noted.
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).
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).