Pipeline

LOXO-292


LOXO-292 is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase. Genomic alterations in the RET kinase, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth. RET fusions have been identified in approximately 2% of non-small cell lung cancer, 10-20% of papillary and other thyroid cancers, and a subset of other cancers. Activating RET point mutations account for approximately 60% of medullary thyroid cancer (MTC).

Both RET fusion cancers and RET-mutant MTC are primarily dependent on a single activated kinase for their proliferation and survival. This dependency, often referred to as “oncogene addiction,” renders such tumors highly susceptible to small molecule inhibitors targeting RET. LOXO-292 was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms that could otherwise limit the activity of this therapeutic approach.

LOXO-292 is currently being studied in the global LIBRETTO-001 Phase 1 trial.

For more information about the LOXO-292 clinical trial, please refer to clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient RET Clinical Trial Hotline at 1-855-RET-4-292 or email clinicaltrials@loxooncology.com.


LOXO-292 Phase 1 Trial

LOXO-292 is currently being evaluated in a global, multi-center Phase 1 trial in patients with advanced solid tumors.

For more information about the LOXO-292 clinical trial, please refer to clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient RET Clinical Trial Hotline at 1-855-RET-4-292 or email clinicaltrials@loxooncology.com.

Policy for Access to Investigational Agents

Loxo Oncology is committed to helping patients who have not responded to available therapies and may benefit from its investigational therapies. Loxo Oncology’s Policy for Access to Investigational Agents describes the principles that the company will follow when considering a request, view here.


Interim clinical data were presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting. Read the presentation from ASCO here.

The data presented at ASCO were based on an April 2, 2018 data cut-off date. Eighty-two total patients had been enrolled to eight dose escalation cohorts: 20 mg QD (n=6), 20 mg BID (n=10), 40 mg BID (n=16), 60 mg BID (n=10), 80 mg BID (n=18), 120 mg BID (n=4), 160 mg BID (n=12) and 240 mg BID (n=6). RET alterations were identified by local laboratories either in tumor or plasma and included the following primary diagnoses: 

  • 38 patients with RET fusion-positive non-small cell lung cancer (NSCLC) (21 with prior MKI treatment, 17 without) 
  • 9 patients with RET fusion-positive thyroid cancer (8 with prior MKI treatment, 1 without) 
  • 2 patients with RET fusion-positive pancreatic cancer (1 with prior MKI treatment, 1 without) 
  • 29 patients with RET-mutated medullary thyroid cancer (MTC) (23 with prior MKI treatment, 6 without) 
  • 4 patients with no known activating RET alterations 

In addition to many patients with prior MKI treatment, 46% of patients had received prior chemotherapy and 24% had received prior immunotherapy (47% of those with NSCLC). 

Pharmacokinetic analyses during the dose escalation demonstrated dose-dependent increases in LOXO-292 exposure with increasing dose. Starting at the 40 mg BID dose and the 80 mg BID dose, respectively, LOXO-292 delivered sustained >IC90 RET fusion and >IC90 RET M918T-mutant target coverage, based on cell-based potencies. The data presented at ASCO, summarized below, are based on response assessments performed by each respective clinical trial site (local, investigator-assessed radiology).

 
RET Fusion-Positive Cancers
RET-Mutated MTC No Known Activating RET Alteration
  All NSCLC Other1    
Enrolled 49 38 11 29 4
Eligible for response evaluation2 39 30 9 22 3
Overall response rate (95% Cl)3 77% (61%-89%) 77% (58%-90%) 78% (40%-97%) 45% (24%-68%) 0% (0%-71%)
Confirmed overall response rate3,4 74% 74% 71% 33% 0%
CR -- -- -- 1 --
uCR5 -- -- -- 1 --
PR 25 20 5 5 --
uPR5 5 3 2 3 --
SD 6 4 2 9 2
PD -- -- -- 2 1
Not evaluable6 3 3 -- 1 --

1. Patients eligible for response evaluation include thyroid cancer (n=7), pancreatic cancer (n=2). 

2. Excludes patients recently enrolled that remain on treatment, but have not had a first post-baseline response assessment. 

3. Response status per RECIST 1.1. Overall response rate = CR+uCR+PR+uPR. Overall response rate, Confirmed overall response rate: all RET fusion-positive (30/39, 25/34), RET fusion-positive NSCLC (23/30, 20/27), RET fusion-positive other (7/9, 5/7), RET-mutant MTC (10/22, 6/18).

4. Excludes patients with unconfirmed CR/PR pending confirmation at time of data cut-off.

5. Unconfirmed responses in patients that remain on treatment awaiting a confirmatory response assessment.

6. Patients that discontinued treatment prior to a first post-baseline response assessment.

 

Anti-tumor activity was observed regardless of RET fusion partner (including KIF5B), RET mutation (including M918T and V804M gatekeeper mutations), and prior MKI treatment. Twelve patients with RET fusion cancers had central nervous system (CNS) metastases at enrollment and all remained on study without progression. Three of these patients had RECIST target lesions in the CNS, and all three exhibited intracranial partial responses. In patients with RET-mutant MTC, LOXO-292 treatment resulted in significant reductions in the serum tumor markers calcitonin and carcinoembryonic antigen (CEA). 

As of the data cutoff, LOXO-292 demonstrated early evidence of durable activity, with 90% of RET fusion-positive cancer patients and 93% of RET-mutant MTC patients remaining on therapy. All responding patients across all tumor types remained on therapy. The longest responding patient on therapy was the first RET fusion-positive NSCLC patient enrolled, who had been on therapy for more than ten months as of the data cut-off date. 

Most treatment-emergent adverse events were Grade 1 in severity. The treatment-emergent adverse events observed in ≥10% of patients, regardless of relationship to LOXO-292, were fatigue (12% Grade 1, 7% Grade 2, 0% ≥Grade 3), diarrhea (10% Grade 1, 6% Grade 2, 0% ≥Grade 3), constipation (13% Grade 1, 1% Grade 2, 0% ≥Grade 3), dry mouth (12% Grade 1, 0% ≥Grade 2), nausea (9% Grade 1, 4% Grade 2, 0% ≥Grade 3), and dyspnea (7% Grade 1, 2% Grade 2, 1% ≥Grade 3). Only two adverse events ≥Grade 3 were attributed to LOXO-292 (Grade 3 tumor lysis syndrome, Grade 3 increased ALT). An MTD had not been reached. At the 240 mg BID dose level, one dose limiting toxicity (DLT) was reported (aforementioned Grade 3 tumor lysis syndrome). 

Preclinical and clinical proof-of-concept data were also published in Annals of Oncology. That manuscript can be found here.

Preclinical data on the Loxo Oncology RET program were previously presented at the 2015 and 2016 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics meetings. Those posters can be found here.