RET Fusion Inhibitor Active Beyond Lung, Thyroid Cancers

The RET inhibitor selpercatinib (Retevmo) exhibited clinical activity in almost half of patients with non-lung/non-thyroid cancers associated with RET gene fusions, according to a subgroup analysis of a randomized trial.

Objective responses occurred in 15 of 32 (47%) patients with RET fusion-positive tumors representing nine different types of cancer. Responses (two complete) occurred in colon, pancreatic, carcinoid, small intestine, salivary, breast, and ovarian cancers, as well as xanthogranuloma and sarcoma. Ten other patients had stable disease for at least 16 weeks, resulting in a disease control rate (response plus stable disease) of 72%.

Median duration of response had yet to be reached after a median follow-up of 13 months, but 11 (73%) responses were ongoing at data cutoff, reported Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center in Houston, during the virtual American Association for Cancer Research (AACR) meeting.

“RET fusions in tumors other than non-small cell lung cancer (NSCLC) and thyroid cancer are uncommon but potentially actionable,” Subbiah concluded. “Selpercatinib demonstrates promising activity across a variety of non-lung/non-thyroid RET fusion-positive advanced solid tumors, including multiple treatment-refractory gastrointestinal malignancies. Selpercatinib is well tolerated in these patients, with a safety profile consistent with the overall safety patient population.”

“Broad-based genomic profiling is essential to identify actionable oncogenic drivers, including RET fusions,” he added.

RET fusions occur in 2% of NSCLC and 10% to 20% of thyroid cancers. They are rarer but recurrent events in many other types of cancer, said Subbiah. The LIBRETTO-001 trial evaluated selpercatinib in 479 patients with advanced, pretreated RET fusion-positive cancer, primarily NSCLC (n=356), but also thyroid (n=47) and multiple other types of cancer (n=38). The trial provided the basis for FDA approval of selpercatinib for NSCLC and thyroid cancer associated with RET gene fusions.

As previously reported, single-agent selpercatinib led to objective responses in 64% of patients with pretreated NSCLC and 85% of those with no prior treatment. In the thyroid cancer cohort of LIBRETTO-001, the overall response rate was 79% in heavily pretreated patients and 100% in those who received selpercatinib as initial therapy.

The therapeutic relevance of RET fusions outside of NSCLC and thyroid cancer remained unclear, Subbiah noted. The small non-lung/non-thyroid subgroup of LIBRETTO-001 afforded an opportunity to evaluate the issue. Of the 38 patients in the subgroup, 32 had complete data.

The most common cancer types represented in the subgroup were pancreatic (28.1%); colon (28.1%); and breast, salivary, sarcoma, and unknown primary (6.3% each). The patients had a median age of 48, and a systemic treatment history of two prior lines (including chemotherapy in 27 of 32). Three patients had received no prior systemic therapy. The most common fusion partners were NCOA4 (41%), CCDC6 (16%), and KIF5B (9%).

Objective responses and stable disease occurred across a broad range of fusion partners, as well as tumor types, Subbiah noted. Five patients had progressive disease as best response.

The median time to response was 1.9 months, and response duration ranged from 2 to 33 months.

No new or unexpected safety signals emerged in the non-lung/non-thyroid subgroup, said Subbiah. The most common (≥20 of patients) treatment-emergent adverse events (TEAEs) were dry mouth, diarrhea, hypertension, liver enzyme increase (ALT and AST), fatigue, nausea, and abdominal pain. No patients in the cohort discontinued treatment because of TEAEs.

Investigators in LIBRETTO-001 continue to enroll patients with RET fusion-positive non-lung cancers.

AACR invited discussant Ezra Cohen, MD, of the University of California San Diego Moores Cancer Center, focused on “rules of targeted therapy” in summarizing his impressions from studies reported by Subbiah and others during the same session. To ensure optimal use and benefit from targeted therapy, molecular profiling of cancers must become universally available and applied. Selective inhibitors appear to have greater activity as compared with multitargeted “promiscuous” agents.

Resistance inevitably emerges, he continued. Preclinical modeling may provide answers that will facilitate development of proactive approaches to treatment resistance.

Toxicity profiles are unique to each class of targeted agents, making education of providers a critical issue for limiting and managing toxicity, he concluded.

Last Updated May 21, 2021