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Authors AE. Drilon, V Subbiah, GR. Oxnard, TM Bauer, V Velcheti, NJ. Lakhani, B Besse, K Park, JD. Patel, ME. Cabanillas, ML Johnson, KL. Reckamp, V Boni, HHF. Loong, M Schlumberger, B Solomon, S Cruickshank, SM. Rothenberg, MH. Shah, LJ. Wirth
Title A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers.
Abstract Text 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET fusion thyroid gland papillary carcinoma sensitive Selpercatinib Phase I Actionable In a Phase I trial, Retevmo (selpercatinib) treatment resulted in an objective response rate of 83% (5/6) in RET fusion-positive papillary thyroid cancer patients (J Clin Oncol 36, 2018 (suppl; abstr 102); NCT03157128). detail...
RET V804M thyroid gland medullary carcinoma sensitive Selpercatinib Case Reports/Case Series Actionable In a Phase I trial, Retevmo (selpercatinib) treatment resulted in partial response in a thyroid medullary cancer patient harboring RET V804M (J Clin Oncol 36, 2018 (suppl; abstr 102); NCT03157128). detail...