LOXO-292 Phase I Results Show Promise in the Treatment of RET-Altered Cancers

LOXO-292 Phase I Results Show Promise in the Treatment of RET-Altered Cancers

Dr. Alexander Drilon
Dr. Christine Marie Lovly
Rearranged during transfection (RET) is an oncogene activated by RET fusions or RET mutations. RET fusions are associated with 2% of non–small cell lung cancers (NSCLCs), 10%-20% of papillary and other thyroid cancers, and smaller proportions of other cancers. In addition, RET mutations are commonly found in medullary thyroid cancers (MTCs).

LOXO-292 is a highly selective RET inhibitor that has shown efficacy in preclinical models. Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center, presented data from the phase I open-label study of the RET inhibitor LOXO-292 (LIBRETTO001; Abstract 102). Eligible patients were age 12 or older with advanced or metastatic solid tumors refractory to or intolerant of standard treatment. LOXO-292 was administered in 28-day cycles, with the dose escalation following a 3 + 3 design. Dose escalation among patients and additional enrollment at doses considered safe were allowed. The primary endpoint of the study was the determination of the maximum tolerated dose (MTD). Secondary endpoints included safety, pharmacokinetics, overall response rate (ORR; RECIST 1.1), and duration of response.

As of April 2, 82 patients (40 women, 42 men) had been treated. Forty-nine patients (59%) had RET fusion–positive tumors (38 NSCLC, nine thyroid, two pancreatic), 29 (35%) had RET-mutant MTC, and four patients (5%) had other types of cancer. Twelve patients (15%) had brain metastases. “This was a heavily pretreated population, with two-thirds of patients having previously received a multikinase inhibitor, many of whom were treated with more than one agent,” Dr. Drilon noted.

Patients received LOXO-292 at doses ranging from 20 mg once daily to 240 mg twice a day; the MTD has not been reached. LOXO-292 was well tolerated. The most frequently reported (≥ 10% overall) treatment-emergent adverse events (AEs) were fatigue (20%), diarrhea (16%), constipation (15%), dry mouth (12%), nausea (12%), and dyspnea (11%). Most AEs were grade 1. Two grade 3 treatment-related AEs occurred: tumor lysis syndrome (the only dose-limiting toxicity) and increased alanine aminotransferase.

The ORR was 77% (95% CI [61, 89]) in 39 evaluable patients with RET fusion–positive cancers, 77% (95% CI [58, 90]) in 30 evaluable patients with NSCLC, and 78% (95% CI [40, 97]) in patients with other RET fusion–positive cancers. Importantly, responses in RET fusion–positive cancers occurred regardless of tumor type, RET fusion partner, starting dose, or prior therapy. Confirmed intracranial responses were observed in the three patients with intracranial disease (Fig. 1). In the 22 evaluable patients with RET-mutant MTC, the ORR was 45% (95% CI [24, 68]). Disease regression occurred in most patients, independent of starting dose or RET mutation. No responses were seen in the three evaluable patients without a known activating RET alteration. 

“The activity of LOXO-292 was durable, with over 90% of patients still on treatment as of the data cutoff, including all responding patients,” Dr. Drilon said. The study expansion cohorts are currently enrolling additional patients with RET fusion–positive solid tumors, MTC, and other cancers with RET activation.

Discussant Christine Marie Lovly, MD, PhD, of Vanderbilt University, congratulated the investigators on the findings of the trial. As multikinase inhibitors are not specific to RET, they can come with off-target effects when treating patients with RET rearrangements. “Multikinase inhibitors have modest activity, with a response rate of about 30%, and came with the cost of significant toxicity,” Dr. Lovly said.

She found the LOXO-292 AE profile encouraging, with RET selectivity leading to better tolerability. Determining the optimal sequence of treatment, the durability of the central nervous system response, effects across different RET mutations, and mechanisms of acquired resistance are areas for further study.  

–Muriel Cunningham