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2018 ASCO Annual Meeting!

Session: Tumor Genomics: Finding the Target, Hitting the Target

Type: Clinical Science Symposium

Time: Saturday June 2, 8:00 AM to 9:30 AM

Location: Hall D1

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

Small Molecules

Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics

2018 ASCO Annual Meeting

Abstract No:

J Clin Oncol 36, 2018 (suppl; abstr 102)

Author(s): Alexander E. Drilon, Vivek Subbiah, Geoffrey R. Oxnard, Todd Michael Bauer, Vamsidhar Velcheti, Nehal J. Lakhani, Benjamin Besse, Keunchil Park, Jyoti D. Patel, Maria E. Cabanillas, Melissa Lynne Johnson, Karen L. Reckamp, Valentina Boni, Herbert H. F. Loong, Martin Schlumberger, Ben Solomon, Scott Cruickshank, Stephen M. Rothenberg, Manisha H. Shah, Lori J. Wirth; Memorial Sloan Kettering Cancer Center, New York, NY; The University of Texas MD Anderson Cancer Center, Houston, TX; Dana-Farber Cancer Institute, Boston, MA; Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH; START Midwest, Grand Rapids, MI; Gustave Roussy, Villejuif, France; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; University of Chicago, Chicago, IL; Sarah Cannon Research Institute, Nashville, TN; City of Hope Comprehensive Cancer Center, Duarte, CA; START Madrid CIOCC Hospital Universitario Sanchinarro, Madrid, Spain; The Chinese University of Hong Kong, Shatin, Hong Kong; Institut Gustave Roussy, Villejuif, France; Peter MacCallum Cancer Centre, East Melbourne, Australia; Loxo Oncology, South San Francisco, CA; Loxo Oncology, Stamford, CT; The Ohio State University Comprehensive Cancer Center, Columbus, OH; Massachusetts General Hospital Cancer Center, Boston, MA

Abstract Disclosures


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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