A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with <i>RET</i>-altered cancers.

102 Background: Multikinase inhibitors (MKIs) have limited activity in RET fusion-positive (+) and RET-mutant cancers, questioning the therapeutic potential of these targets. LOXO-292 selectively targets RET and has preclinical activity against activating RET fusions/mutations, potential resistance mutations, and brain metastases. Methods: This global phase 1 study for patients (pts) w/ advanced solid tumors included RET fusion+ NSCLC and papillary thyroid cancer (PTC), RET-mutant medullary thyroid cancer (MTC), and any other cancer w/ these alterations. Pts were dosed orally in 28-day cycles. Dose escalation followed a 3+3 design. The primary endpoint was MTD determination. Secondary endpoints included safety, overall response rate (ORR, RECIST 1.1) and duration of response (DoR). Results: As of 05-Jan-18, 57 pts were treated at 7 doses (20 mg QD→160 mg BID), including 35 RET fusion+ tumors (27 NSCLC, 7 PTC, 1 pancreatic) and 20 RET-mutant MTCs. 67% were MKI pre-treated (median 1, range 1-4; included pts w/ acquired MKI resistance). No DLTs were observed. The MTD was not reached. AEs (≥10% of pts) were fatigue (16%), diarrhea (16%) and dyspnea (12%); most were grade 1-2. No AEs ≥ grade 3 were attributed to LOXO-292. The ORR in evaluable RET fusion+ pts was 69% (95% CI 50%-84%, n = 22/32, 11 pending confirmation, 9/13 MKI-naïve,13/19 MKI pretreated): 65% (n = 17/26) in NSCLC and 83% (n = 5/6) in PTC. 84% (27/32) had radiographic tumor reduction (range -19% to -67%). NSCLC responses occurred independent of upstream partner when known (9/13 KIF5B vs 7/9 non-KIF5B) and included 3 pts w/ baseline brain metastases. Tumor reduction was achieved in 79% of MTC pts (n = 11/14 evaluable, range -9% to -45%), including 2 PRs, 1 in a patient w/ a hereditary RET V804M gatekeeper mutation treated w/ 3 prior MKIs. 79% (n = 11/14) of MTCs had a ≥50% decrease in serum calcitonin (for ≥4 weeks). Most pts (n = 52/57) remained on treatment. The median DoR was not reached (all responses ongoing, longest > 6 months). Conclusions: LOXO-292 was well-tolerated and had marked antitumor activity in pts w/ RET-altered cancers, including those w/ resistance to prior MKIs and brain metastases. Rapid development w/ registrational intent is planned. Clinical trial information: NCT03157128.