ASCO: Loxo sees boosted response rates with LOXO-292

Josh Bilenker, Loxo Oncology
Above: Josh Bilenker, CEO of Loxo. The interim numbers come after the biotech gained an FDA review for its later stage drug larotrectinib. (Loxo Oncology)

Loxo made a big splash with its larotrectinib data at last year’s ASCO Annual Meeting, and in 2018 it’s hoping to make waves with its earlier-stage RET inhibitor LOXO-292.

Let’s rewind two weeks, when Loxo reported encouraging data from the phase 1 trial of LOXO-292 in solid tumor patients. In this test, the drug shrunk the tumors of most patients in the trial.

This was as of Jan. 5, when Loxo had treated 57 people. Almost half of the patients had RET fusion-positive non-small cell lung cancer (NSCLC). Most of the remaining participants had either RET fusion-positive papillary thyroid cancer (PTC) or RET-mutant medullary thyroid cancer (MTC). Patients with these RET alterations are poorly served by older multikinase inhibitors (MKIs).

In the abstract, released ahead of its updated ASCO data, Loxo focused on the response rate in the NSCLC and PTC patients. The overall response rate (ORR) in these RET fusion-positive patients came in at 69%. The tumors of the patients shrunk in size by as much as 67%.

Loxo also reported tumor shrinkage in the majority of MTC patients, but in most cases the change fell short of a partial response. Just two of the 14 evaluable MTC patients experienced partial responses.

The performance of LOXO-292 in the MTC cohort in fact dragged the ORR across the whole trial down to 52%. But the caveat was that Loxo was to show off data from an April cutoff, and that those were better than the data shared from the abstract.

Today, Loxo says it has those interim numbers for the "LOXO-292 global phase 1 LIBRETTO-001 dose escalation trial," which are based on an April 2 data cutoff date.

In all, 82 patients had been enrolled to eight dose escalation cohorts, and were broken down into:

• 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


• 4 patients with no known activating RET alterations

In addition to a number of patients with prior MKI treatment, 46% of patients had received prior chemo, while 24% had received prior immunotherapy (47% of those with NSCLC).

The numbers are: 77% ORR for all patients enrolled with RET fusion-positive cancers, hitting the same in the RET-positive NSCLC group. In the "Other" box, which includes patients with thyroid (seven patients) and pancreatic cancers (two patients), ORR was 78%.

In RET-mutated medullary thyroid cancer (MTC), the ORR was 45%, with one complete response. Confirmed ORRs were 74% for both all RET and lung cancer patients, 71% for other, and 33% for MTC.

There were 25 partial responses in the all RET group, 20 for the NSCLC group, and five for the other and MTC group. The biotech notes that 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 cutoff date.

Loxo said its drug also “demonstrated robust reduction and clearance of RET alterations as detected in patients’ plasma cell free DNA (cfDNA).”

“The LOXO-292 Phase 1 data are striking,” said Alexander Drilon, M.D., clinical director in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center and presenting author. “The activity we reported is impressive and I am thrilled to see this promising efficacy with limited adverse events, especially in this heavily pre-treated patient population of RET fusion cancers, including those with brain metastases, and RET mutated MTC."

“We are very excited to share the initial LOXO-292 clinical experience with the oncology community at ASCO,” added Josh Bilenker, M.D., CEO at Loxo. “We have long believed that patients with RET fusion cancers and RET mutated MTC needed a purpose-built medicine tailored to their tumors. We hope that LOXO-292 continues to deliver on that premise.”

The primary endpoint of the trial assesses the maximum tolerated dose or recommended dose for further study. Secondary endpoints include safety, overall response rate and duration of response. Blueprint Medicines is also working on its experimental RET inhibitor, BLU-667, as both look to challenge existing RET products from Exelixis and Sanofi.

This comes a few days after Loxo said it was prepping for a November verdict from the FDA on its later stage effort, larotrectinib.

The Bayer-partnered drug has been awarded a priority review by the regulator for locally advanced or metastatic solid tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, with a target action date of Nov. 26.

Loxo's shares were up 12% premarket Monday morning after its weekend ASCO data presentation.

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