New Breakthrough Therapy Designated for Thyroid Cancer and NSCLC

LOXO-292, which selectively targets RET and has demonstrated preclinical activity against activating RET fusions/mutations, holds promise.

The US Food and Drug Administration (FDA) recently granted a breakthrough therapy designation to LOXO-292 for the treatment of certain RET-altered cancers. LOXO-292 is indicated for the treatment of patients with RET-mutant medullary thyroid cancer (MTC) who require systemic therapy and progressed after previous treatment, and for refractory patients with metastatic RET–fusion-positive non–small-cell lung cancer (NSCLC) who require systemic therapy and progressed following anti–programmed death ligand 1 (PD-L1) therapy or platinum-based chemotherapy plus anti-PD-1 therapy.

“Multikinase inhibitors have limited activity in RET–fusion-positive and RET-mutant cancers, questioning the therapeutic potential of these targets,” wrote Alexander Drilon, MD, and colleagues in an abstract presented at the American Society of Clinical Oncology 2018 annual meeting. “LOXO-292 selectively targets RET and has preclinical activity against activating RET fusions/mutations, potential resistance mutations, and brain metastases.”

LOXO-292 is a small, highly selective RET inhibitor that has potent action against an ambit of RET alterations. Furthermore, the drug is well tolerated and highly bioavailable, with the ability to cross the blood-brain barrier.

RET gene fusions are found in about 10% of papillary thyroid cancers (PTCs), 2% of non–small-cell lung cancers (NSCLCs), and a small number of other malignancies. However, activating point mutations in RET exist in about 60% of medullary thyroid cancers (MTCs), including both hereditary and sporadic cases.

The FDA’s designation of LOXO-292 as a breakthrough therapy is based on the results of a phase I study conducted by Dr. Drillon and colleagues. The trial enrolled 57 patients with RET-altered cancers, including patients with RET–fusion-positive NSCLC and PTC, as well as RET-mutant MTC.

The researchers found that the overall response rate (ORR) in RET–fusion-positive patients was 69% (95% CI; 50%-84%). More specifically, the ORR was 65% in patients with NSCLC and 83% in those with PTC. Furthermore, 84% of patients had radiographic tumor reduction (range, -19% to -67%).

In RET–fusion-positive NSCLC, tumor regression occurred regardless of RET’s upstream partner. Of note, 3 NSCLC patients had initial brain metastases. The team observed tumor reduction in 79% of MTC patients, and 79% of MTC patients experienced a 50% or greater reduction in serum calcitonin.

Treatment with LOXO-292 was well tolerated, with only 2 patients sustaining severe adverse events. A total of 52 of 57 patients continued with treatment, and the median duration of response was not attained; all responses are ongoing, with the longest being greater than 6 months.

In an interview with Cancer Network, Ezra Cohen, MD, associate director of the Moores Cancer Center and a professor of medicine at the University of California San Diego, reflected on the importance of LOXO-292.

“This is a highly specific RET inhibitor that is quite effective,” stated Cohen. “Prior multi-kinase inhibitors that included RET as a target were less effective and accompanied by significant toxicity. LOXO-292 provides specificity with much less toxicity. This will become the first choice for RET-altered agents and the future in the field. It now also becomes imperative to test for RET alterations in cancer patients, especially those with thyroid and lung cancers.”

Nevertheless, Cohen sees drug resistance as a potential issue. “Unfortunately, we will have to eventually deal with resistance,” he said. “Despite the high response rates, some cancers are inherently resistant, and others will develop this [resistance]. It is incumbent upon us to begin to understand these mechanisms to extend the benefit of this drug and others in the class.”