2402 - Registrational Results of LOXO-292 in Patients with RET-Altered Thyroid Cancers

Background

To date, no targeted therapy is approved for patients with RET-altered cancers. LOXO-292 is a highly selective RET inhibitor with activity across known oncogenic RET fusions and mutations. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion+ non-small cell lung cancer (NSCLC), RET fusion+ thyroid cancer and RET-mutant medullary thyroid cancer (MTC).

Methods

The LIBRETTO-001 global phase I/II study (87 sites, 16 countries) enrolled patients with advanced RET fusion+ cancers and RET-mutant MTC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. Phase I established the RP2D. Phase II enrolled patients in one of six cohorts based on tumor type, RET alteration and prior therapy. The primary endpoint was ORR. Secondary endpoints included DoR, PFS and OS.

Results

As of 17-June 2019, 253 RET-altered thyroid cancer patients (n = 226 RET-mutant MTC, n = 27 RET fusion+ thyroid cancer) were treated. The primary analysis set (PAS) for LOXO-292 registration in MTC, defined with the US FDA, consisted of the first 55 consecutively enrolled RET-mutant MTC patients who received prior cabozantinib and/or vandetanib. Among these previously treated RET-mutant MTC PAS patients, the investigator-assessed ORR was 56% (95% CI 42-70%, n = 31/55, 2 PRs pending confirmation), including 3 patients with a RET V804M/L gatekeeper mutation (1 CR, 2 PR, all confirmed). Median DoR has not been reached (6 DoR events, 95% CI 11.1 months-NE) with median follow-up of 10.6 months. Biochemical response rates (≥50% decrease lasting ≥4 weeks) were 91% for calcitonin (n = 49/54) and 64% for CEA (n = 34/53). The ORR in evaluable RET fusion+ thyroid cancer patients was 62% (95% CI 41-80%, n = 16/26, 2 PRs pending confirmation). In the safety data set of 531 patients, 5 treatment-related AEs occurred in ≥ 15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.

Conclusions

LOXO-292 had marked antitumor activity in RET-altered thyroid cancer and was well tolerated. These data will form the basis of an FDA new drug application in late 2019.

Clinical trial identification

NCT03157128.

Editorial acknowledgement

Legal entity responsible for the study

Loxo Oncology.

Funding

Loxo Oncology.

Disclosure

L.J. Wirth: Advisory / Consultancy: Eisai; Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy: Genentech; Advisory / Consultancy: Loxo; Advisory / Consultancy: Merck. E. Sherman: Advisory / Consultancy: Loxo Oncology; Advisory / Consultancy: COTA consulting; Advisory / Consultancy: Novartis; Advisory / Consultancy: Goldilocks; Advisory / Consultancy: Eisai; Advisory / Consultancy: Bristol-Myers Squibb. A. Drilon: Advisory / Consultancy: Ignyta; Advisory / Consultancy: Loxo Oncology; Advisory / Consultancy: TP therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Takeda/Ariad/Millenium; Advisory / Consultancy: Helsinn; Advisory / Consultancy: Beigene; Advisory / Consultancy: BergenBio; Advisory / Consultancy: Hengrui Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy: Bayer; Advisory / Consultancy: Tyra Biosciences; Advisory / Consultancy: Verastem; Advisory / Consultancy: MORE Health; Advisory / Consultancy: Lilly; Research grant / Funding (institution): GlaxoSmithKlein; Research grant / Funding (institution): Teva. B. Robinson: Speaker Bureau / Expert testimony: Loxo Oncology; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Leadership role, Shareholder / Stockholder / Stock options: MaynePharma; Leadership role, Shareholder / Stockholder / Stock options: Cochlear; Research grant / Funding (institution): National Health and Medical Reasearch Council. J. Lorch: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Takeda; Speaker Bureau / Expert testimony: Genentech; Research grant / Funding (institution): Bristol-Myer Squibb. C. McCoach: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novaritis; Research grant / Funding (institution): Revolution Medicines; Honoraria (self): Guardant Health; Travel / Accommodation / Expenses: Loxo oncology; Honoraria (self): Takeda. J.D. Patel: Advisory / Consultancy: AbbVie; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Takeda. S. Leboulleux: Speaker Bureau / Expert testimony: Loxo Oncology; Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony: Sanofi. F. Worden: Honoraria (self), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Research grant / Funding (institution): Eisai; Honoraria (self): Cue Pharmaceuticals; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Loxo Oncology; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Pfizer. T.K. Owonikoko: Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Astellas Pharma; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Celgene; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Stem CentRx; Research grant / Funding (institution): Regeneron; Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Bristol-Myers; Research grant / Funding (institution): Corvus Pharmaceuticals; Research grant / Funding (institution): United Therapeutics; Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): Loxo/Lilly; Research grant / Funding (institution): Fujifilm; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Leadership role, Shareholder / Stockholder / Stock options: Cambium Oncology; Research grant / Funding (institution): Biotherapeutics; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Merck . M.S. Brose: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Loxo; Advisory / Consultancy: Progenics. M.H. Taylor: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai Inc; Advisory / Consultancy: Bayer; Advisory / Consultancy: Array Biopharma; Advisory / Consultancy: Blueprint; Advisory / Consultancy: Loxo oncology; Advisory / Consultancy: Novartis; Advisory / Consultancy: Arqule. A. Italiano: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: Epizyme; Advisory / Consultancy: ImmuneDesign; Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pharmamar. S..M. Rothenberg: Full / Part-time employment: Loxo Oncology. V. Subbiah: Research grant / Funding (institution): Loxo oncology; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Nanocarrier; Research grant / Funding (institution): Vegenics; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Northwest Biotherapeutics; Research grant / Funding (institution): Berghealth; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Fujifilm; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pharmamar; Research grant / Funding (institution): D3; Research grant / Funding (institution): Pfizer; Travel / Accommodation / Expenses: Astrazeneca; Travel / Accommodation / Expenses: Apollo Hospitals; Licensing / Royalties: Sathgen Biotech; Travel / Accommodation / Expenses: ASCO; Travel / Accommodation / Expenses: ESMO; Research grant / Funding (institution): Blueprint. M. Cabanillas: Speaker Bureau / Expert testimony: Loxo; Advisory / Consultancy: Bayer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Genentech; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis. All other authors have declared no conflicts of interest.