medwireNews: The selective RET inhibitor LOXO-292 has activity against tumors harboring a range of RET alterations, according to findings from the first-in-human LIBRETTO-001 trial.
Of the 82 participants enrolled in the dose-escalation part of the phase I study, 60% had RET fusion-positive cancers (most commonly non-small-cell lung cancer [NSCLC]), 35% had medullary thyroid cancer (MTC) with RET mutations, and the remaining 5% had other tumor types.
As reported at the ASCO Annual Meeting 2018 in Chicago, Illinois, USA, treatment with LOXO-292 at doses ranging from 20 mg/day to 240 mg twice daily was well tolerated. The only treatment-emergent toxicities observed in at least 10% of patients were fatigue, diarrhea, constipation, dry mouth, nausea, and dyspnea; the majority were grade 1 or 2 in severity and considered unrelated to LOXO-292.
Only two adverse events of grade 3 – one case each of tumor lysis syndrome and elevated alanine aminotransferase – were attributed to LOXO-292, and the maximum tolerated dose was not reached, said presenter Alexander Drilon (Memorial Sloan Kettering Cancer Center, New York, USA).
He noted that the favorable toxicity profile of LOXO-292 was “consistent with its high preclinical selectivity for RET,” and in contrast to the “significant off target liabilities of prior multikinase inhibitor therapy” used in patients with these alterations.
The RET inhibitor also showed promising efficacy. An overall response rate (ORR) was achieved by 77% of the 39 evaluable patients with RET fusion-positive cancers, with a rate of 77% in patients with NSCLC and 78% in those with other tumor types (thyroid and pancreatic cancer).
Among the 22 evaluable participants with RET mutation-positive MTC, the ORR was 45%, while none of the three evaluable patients lacking RET alterations had a response.
The responses were rapid, seen in most patients at the time of the first assessment post-baseline, and durable, with 91% of the participants harboring RET alterations continuing treatment at data cutoff, Drilon reported. Moreover, the anti-tumor activity appeared to be independent of the RET fusion partner, RET mutation, prior therapy, or starting dose, with responses observed even in patients given the lowest dose.
The presenting author summarized that “LOXO-292 demonstrated robust and durable anti-tumor efficacy in patients with RET fusion-positive cancers and RET-mutant MTCs,” adding that the dose-expansion part of the trial is currently recruiting patients with diverse RET-altered cancers.
Discussant Christine Lovly (Vanderbilt University Medical Center, Nashville, Tennessee, USA) described the findings as “very encouraging” and highlighted the lack of primary progressors in the trial, which she said “speaks to the potency of the drug.”
The commentator noted, however, that as the clinical development of selective RET inhibitors moves forward, some issues need to be addressed, such as the optimal sequencing of these drugs, the difference in response rates between patients with RET fusions and those with RET mutations, and the major mechanisms of acquired resistance to RET inhibitors.
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