On September 25, 2018 Loxo Oncology, Inc. (Nasdaq: LOXO), a biopharmaceutical company developing highly selective medicines for patients with genomically defined cancers, reported updated interim clinical data for LOXO-292 from the global Phase 1/2 LIBRETTO-001 trial in patients with RET fusion-positive non-small cell lung cancer (NSCLC) who were initially included in the LOXO-292 presentation at the 2018 ASCO (Free ASCO Whitepaper) Annual Meeting (Press release, Loxo Oncology, SEP 25, 2018, View Source [SID1234529597]). In these 38 patients, approximately 3.5 months of additional patient follow-up were available, as were first follow-up scans for the eight patients most recently enrolled. Twenty-five of 26 (96%) responding patients remained on therapy, with median follow-up of 9.5 months. Inclusion of new restaging data for the most recently enrolled patients resulted in a 68% confirmed overall response rate in the presented subset. These data are being presented today at the 2018 IASLC 19th World Conference on Lung Cancer in Toronto (abstract 13922).
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"I am pleased that the attendees of World Lung were able to see the activity of LOXO-292 in RET fusion-positive lung cancer," said Geoffrey R. Oxnard, M.D., associate professor of medicine at Harvard Medical School and thoracic oncologist at Dana-Farber Cancer Institute. "It has been just a few months since ASCO (Free ASCO Whitepaper), but the additional follow-up afforded by today’s data provide encouraging evidence that LOXO-292 can deliver durable responses in heavily pre-treated patients. It was additionally reassuring to see that that LOXO-292 appears to be well tolerated at the Phase 2 dose of 160 mg BID. With Breakthrough Therapy Designation in hand, LOXO-292 is moving rapidly through clinical development, so it is important for investigators and patients to pay attention to this emerging target and class of medicines."
Trial Background
LIBRETTO-001 is a Phase 1/2 trial of LOXO-292 in advanced cancer patients who primarily have activating RET alterations. LIBRETTO-001 contains a Phase 1 dose escalation phase and a Phase 2 dose expansion phase. The primary endpoint of the Phase 1 is the determination of the maximum tolerated dose (MTD) or recommended dose for further study. Secondary endpoints include safety, overall response rate (by RECIST 1.1) and duration of response. Initial clinical data were first reported at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.
Key Data Presented
The data presented today were based on a July 19, 2018 data cut-off date and included the 38 patients with RET fusion-positive NSCLC who were initially included in the LOXO-292 presentation at the 2018 ASCO (Free ASCO Whitepaper) Annual Meeting.
Patients were heavily pretreated, having received a median of three prior systemic treatment regimens. Thirty-nine percent had received both prior platinum-based chemotherapy and an anti-PD-1 or anti-PD-L1 therapy.
With 3.5 months of additional follow-up since the 2018 ASCO (Free ASCO Whitepaper) Annual Meeting presentation, LOXO-292 demonstrated encouraging, early evidence of durable activity, with 25 of 26 (96%) responding RET fusion-positive NSCLC patients remaining on therapy and 24 of 26 (92%) remaining in response (median follow-up of 8.5 months for all 38 patients; median follow-up of 9.5 months for responding patients). The longest responding patient on therapy was the first RET fusion-positive NSCLC patient enrolled, who had been on therapy for more than 14 months as of the data cut-off date.
The new data cutoff date allowed for the inclusion of first follow-up scans for eight patients who had not had any post-baseline response assessment as of the ASCO (Free ASCO Whitepaper) presentation. Of 38 patients with RET fusion-positive NSCLC, 26 demonstrated an objective response by RECIST 1.1 (all partial responses, including one patient with an unconfirmed partial response awaiting a confirmatory response assessment) and six additional patients demonstrated evidence of tumor regression (-3% to -29%). The overall response rate was 68% (26/38) (95% CI: 51%-83%) and the confirmed overall response rate was 68% (25/37) (95% CI: 50%-82%). Response assessments were performed by the local clinical trial sites.
Anti-tumor activity was observed regardless of RET fusion partner (including KIF5B) and prior treatment, including chemotherapy, immunotherapy and multikinase inhibitors. Four patients had RECIST target lesions in the central nervous system (CNS) and all four exhibited confirmed intracranial responses by RECIST 1.1 (one complete response, three partial responses).
Of the 82 patients in the safety analysis, most treatment-emergent adverse events were Grade 1 in severity and judged by the investigator as not related to LOXO-292. The treatment-emergent adverse events observed in ≥10% of patients, regardless of relationship to LOXO-292, were diarrhea (15% Grade 1, 7% Grade 2, 1% Grade 3), fatigue (9% Grade 1, 13% Grade 2, 0% ≥Grade 3), dry mouth (21% Grade 1, 0% ≥Grade 2), constipation (17% Grade 1, 2% Grade 2, 0% ≥Grade 3), hypomagnesemia (12% Grade 1, 1% Grade 2, 0% ≥Grade 3), cough (11% Grade 1, 1% Grade 2, 0% ≥Grade 3), headache (10% Grade 1, 1% Grade 2, 1% Grade 3) and nausea (9% Grade 1, 4% Grade 2, 0% ≥Grade 3). Four patients experienced adverse events ≥Grade 3 that were attributed to LOXO-292 (all Grade 3): tumor lysis syndrome, increased ALT/AST, diarrhea, and thrombocytopenia. All resolved with dose interruption. 160mg BID has been advanced as the Phase 2 dose, with dose exploration at 200mg BID ongoing to further characterize LOXO-292 safety and efficacy.
The presentation will be available online at View Source
About LOXO-292
LOXO-292 is an 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. RET fusions and mutations occur across multiple tumor types with varying frequency. 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 has been granted Breakthrough Therapy Designation by the U.S. FDA.
LOXO-292 is currently being studied in the global LIBRETTO-001 Phase 1/2 trial. For additional information about the LOXO-292 clinical trial, please refer to www.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 [email protected].
About RET-Altered Cancers
Genomic alterations in 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 this 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.