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TORONTO-Updated interim clinical data for LOXO-292 from the global phase I/II 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 Annual Meeting, were recently presented at the IASLC 19th World Conference on Lung Cancer (Abstract 13922).

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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 percent confirmed overall response rate in the presented subset.


"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, MD, 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, but the additional follow-up afforded by [this] data provides 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 II dose of 160 mg BID," he continued. "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 I/II trial of LOXO-292 in advanced cancer patients who primarily have activating RET alterations. The study contains a phase I dose-escalation phase and phase II dose-expansion phase.


The primary endpoint of phase I is the determination of the maximum tolerated dose or recommended dose for further study. Secondary endpoints include safety, overall response rate (by RECIST 1.1), and duration of response.


Key Data Presented

The data presented at IASLC were based on a July 19, 2018 data cutoff date and included the 38 patients with RET fusion-positive NSCLC who were initially included in the LOXO-292 presentation at ASCO.


Patients were heavily pre-treated, 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 ASCO, 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 cutoff 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 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 percent (26/38) (95% CI: 51%-83%) and the confirmed overall response rate was 68 percent (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 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 percent 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. The phase II dose is 160 mg BID, with dose exploration at 200 mg BID ongoing to further characterize LOXO-292 safety and efficacy.