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'Dirtier' Drugs Step Aside in RET-Positive NSCLC

— Over two-thirds of patients respond to selective RET inhibitor

Last Updated November 6, 2019
MedpageToday

BARCELONA -- Selpercatinib was highly active and induced durable responses in heavily pretreated patients with RET fusion-positive non-small cell lung cancer (NSCLC), and with a favorable safety profile, results of the trial indicated.

Among the first 105 patients enrolled in the phase I/II study, all of whom had advanced disease and had previously been treated with platinum-based chemotherapy, 68% responded to the investigational agent, Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York City, reported here.

Two patients with brain metastases had complete responses. Additionally, stable disease was achieved in 26% of the cohort and responses were seen regardless of prior therapy -- about half had been treated with targeted agents or PD-1/PD-L1 checkpoint inhibitors.

At data cutoff, the median duration of response was 20.3 months, while median progression-free survival (PFS) was 18.4 months, and the majority remained in response or were progression-free, according to data presented here at the (WCLC).

During a press briefing, Drilon explained that RET fusions are "bona fide drivers" of NSCLC, and that patients with these gene fusions (about 2% of all NSCLC cases) represent an underserved population.

"We've really tried hard over the last couple of years to develop older, dirtier drugs for these patients -- these are the multikinase inhibitors -- but those clinical trials have been fraught with issues," he said, pointing to low rates of response and substantial toxicities.

"It's incredible in the 20 years of this meeting how we've seen targeted therapy evolve to such specific drugs," Roy Herbst, MD, PhD, of Yale Cancer Center in New Haven, Connecticut, commented during the press conference.

"From a society point of view, I'm wondering how we're going to find these patients," he said. "Because we'll only be able to use these drugs if we find these patients."

"Unfortunately, the testing question also comes with an economic question," said Drilon. "I think if you're asking about the best possible test, we've shown that if you use comprehensive next-generation sequencing that has both DNA and RNA you're most likely to maximize picking up RET fusions -- not only that, but also picking up other clinically actionable alterations that you have drugs for."

Fluorescence in situ hybridization (FISH) or real-time PCR testing could be used in settings where next-generation sequencing isn't available, he said, but these methods might not detect every single RET fusion.

Study Details

Formerly called LOXO-292, selpercatinib is a highly active "cleaner" drug that selectively inhibits RET and thus reduces off-target side effects, and works against so-called "gatekeeper resistance" mutations, said Drilon. He highlighted one such patient -- a 42-year-old woman with a V804L gatekeeper mutation -- where selpercatinib resulted in a rapid clinical response that now approaches 1 year.

Similar to drugs such as osimertinib (Tagrisso) and alectinib (Alecensa) for EGFR-reliant and ALK-reliant cancers, selpercatinib was designed to penetrate the blood-brain barrier and has meaningful central nervous system activity.

"Those really check all of the boxes of favorable features that we like to see," Drilon said.

Among 11 patients with target brain metastases at baseline, 10 responded to selpercatinib (91%).

"That not only means that you can use this drug for patients who already have existing disease intracranially, but also as we've seen with other agents, you can use selpercatinib to potentially prevent that acquisition of brain metastases," said Drilon.

WCLC session discussant Robert Doebele, MD, PhD, of the University of Colorado Anschutz Medical Campus in Aurora, pointed to response rates in the 25% range in prior trials of older multikinase inhibitors for patients with RET fusion-positive NSCLC, and a median PFS in the range of 2-3 months.

Doebele also pointed out that mechanisms of resistance to selpercatinib and the other new selective RET inhibitor, pralsetinib (formerly BLU-667), will probably differ from those seen with older multikinase inhibitors, and thus will require special attention to discover.

"We don't have any data yet for either selpercatinib or pralsetinib," he said. "In an ideal world, we'd see cross sensitivity in these agents and perhaps the ability to go from one drug to the other if they cover different resistance mutations, but we just don't know yet."

Currently, there is no FDA-approved agent targeting RET fusion-related cancers, but the agency granted status to selpercatinib for metastatic RET fusion-positive NSCLC and thyroid cancer and to pralsetinib for metastatic RET fusion-positive NSCLC. Loxo Oncology, selpercatinib's developer, plans to submit the data on the 105 patients as part of an FDA marketing application later this year, said Drilon.

Data on 34 patients with treatment-naive disease were also presented at WCLC. In these, 85% responded to selpercatinib, including one complete response.

For the 105 patients included in the LIBRETTO-001 analysis, the median age was 61 and 59% were women. Patients had been treated with a median of three prior therapies -- 55% were exposed to PD-1/PD-L1 checkpoint inhibitors (most concurrently with chemotherapy) and 48% were exposed to one or more multikinase inhibitors. Following the phase I dose-escalation phase, a dose of 160 mg twice daily was settled on for the phase II portion of the trial.

RET fusion partners were led by KIF5B in 59% of patients, followed by CCDC6 in 22%.

Few patients discontinued selpercatinib due to treatment-related adverse events (AEs) -- just nine of 531 patients (1.7%) in the safety analysis of LIBRETTO-001. The most common treatment-emergent AEs of any grade were dry mouth (32%), diarrhea (31%), hypertension (29%), increased aspartate aminotransferase (AST; 28%) and alanine aminotransferase (ALT; 26%), fatigue (24%), constipation (22%), and headache (20%).

"Most of these side effects were grade 1 or 2 and very easily managed," said Drilon.

Grade 3/4 treatment-emergent AEs included diarrhea in 2%, hypertension in 15%, increased AST in 7% and ALT in 8%, and fatigue in 1%.

A randomized global phase III trial will test selpercatinib against platinum chemotherapy with or without PD-1/PD-L1 checkpoint inhibitors as first-line treatment for RET fusion-positive metastatic NSCLC.

Disclosures

Drilon disclosed relationships with Loxo Oncology, Bayer, Lilly, Pfizer, Genentech/Roche, Takeda, AstraZeneca, and others.

Primary Source

World Conference on Lung Cancer

Drilon A, et al "Registrational results of LIBRETTO-001: A phase 1/2 trial of LOXO-292 in patients with RET fusion-positive lung cancers" WCLC 2019; Abstract PL02.08.