Clinical Activity of LOXO-292, a Highly Selective RET Inhibitor, in Patients with RET Fusion+ Non-Small Cell Lung Cancer
Invited conference paper presented and published in conference proceedings

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RET kinase gene fusions are actionable drivers that occur in ~2% of non-small cell lung cancers (NSCLC). However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET fusion+ NSCLC patients has been limited. LOXO-292 is a highly selective RET inhibitor, with preclinical activity against diverse RET fusions, potential acquired resistance mutations, and against brain metastases.

LIBRETTO-001 is a multicenter global phase 1/2 study (26 sites, 9 countries) enrolling patients w/ advanced solid tumors (NCT03157128) including RET fusion+ NSCLC. Patients are dosed orally in 28-day cycles with dose escalation following a 3+3 design. The primary endpoint is MTD/recommended dose determination. Secondary endpoints include safety, overall response rate (ORR, RECIST 1.1) and duration of response (DoR). Initial data were presented at the ASCO 2018 Annual Meeting.

As of 02-April 18, 82 solid tumor patients (including 38 RET fusion+ NSCLC) were treated at 8 doses (20 mg QD-240 mg BID). The MTD was not reached. AEs (≥10% of patients) were fatigue (20%), diarrhea (16%), constipation (15%), dry mouth (12%), nausea (12%), and dyspnea (11%); most were grade 1-2. 2 TEAEs ≥ grade 3 were attributed to LOXO-292 (Gr3 tumor lysis syndrome, Gr3 increased ALT). Of the 38 RET fusion+ NSCLC pts, 30 had at least 1 post-baseline assessment or discontinued LOXO-292 prior to such assessment. 26 of 30 patients (87%) had >20% radiographic tumor reduction (range: -21 to -72%). The ORR was 77% (23/30, 3 responses pending confirmation) with a confirmed ORR of 74% (20/27, excluding 3 patients with unconfirmed responses). The response rate was similar regardless of prior MKI treatment (12/15 MKI-naïve, 11/15 MKI pretreated). Responses occurred independent of upstream fusion partner when known (13/16 KIF5B vs 9/11 other) and included patients w/ baseline brain metastases. Most patients remained on treatment (33/38), including all responders. The median DoR was not reached (longest response was the first responder: >10+ months). Rapid plasma clearance of RET variants was observed, with complete clearance by day 15 in 10 of 17 (59%) NSCLC patients with assessable baseline and day 15 ctDNA.

LOXO-292 was well-tolerated and had marked antitumor activity in RET-fusion+ NSCLC patients, including those w/ resistance to prior MKIs and brain metastases. Phase 2 cohorts are now open globally (160 mg BID). Updated safety and efficacy data as of 19 Jul 2018 will be presented.
All Author(s) ListGeoffrey R. Oxnard, Vivek Subbiah, Keunchil Park, Todd M. Bauer, Lori J Wirth, Vamsidhar Velcheti, Manisha Shah, Benjamin Besse, Valentina Boni, Karen L. Reckamp, Herbert H Loong, Lyudmila Bazhenova, Ben J Solomon, Daniel S.W. Tan, Jyoti Patel, Melissa L. Johnson, Anas Gazzah, Tony S. Mok, Steve Smith, Brian Tuch, Kevin Ebata, Edward Y Zhu, Michele M Nguyen, Xin Huang, Scott Cruickshank, S Michael Rothenberg, Alexander Drilon
Name of ConferenceWCLC 2018, 19th World Conference on Lung Cancer
Start Date of Conference23/09/2018
End Date of Conference26/09/2018
Place of ConferenceToronto
Country/Region of ConferenceCanada
Proceedings TitleJournal of Thoracic Oncology
Series TitleOral Abstract Session
Number in SeriesAbst: OA12.07
Volume Number13
Issue NumberSuppl 10
PagesS349 - S350
LanguagesEnglish-United Kingdom

Last updated on 2020-04-07 at 00:41