Selpercatinib effective, safe in RET-altered thyroid cancer, NSCLC
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Selpercatinib appeared to be effective and safe for patients with RET-altered medullary thyroid cancer and RET fusion-positive non-small cell lung cancer, according to results of two studies published in The New England Journal of Medicine.
Based on these results, the FDA granted accelerated approval to selpercatinib (Retevmo, Eli Lilly) for adults with metastatic RET fusion-positive NSCLC; adults and children aged 12 years and older with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy; and adults and children aged 12 years and older with advanced or metastatic RET fusion-positive thyroid cancer that requires systemic therapy and has stopped responding to or is not appropriate for radioactive iodine therapy.
“Genome-driven precision oncology has changed the landscape of multiple solid-tumors,” Vivek Subbiah, MD, associate professor of investigational cancer therapeutics at The University of Texas MD Anderson Cancer Center and an author on both studies, told Healio. “Although we know RET as one of the earliest genes to be cloned, we didn’t have any specific RET-selective targeted treatment options for patients with NSCLC or thyroid cancer. The use of multitargeted kinase inhibitors with secondary RET activity resulted in only limited clinical benefit, because of dose-limiting off-target toxic effects that are associated with the concurrent inhibition of multiple non-RET kinases such as VEGFR2.”
In the phase 1/phase 2 LIBRETTO-001 trial, Subbiah and colleagues assessed the safety and efficacy of selpercatinib, a highly selective, small-molecule RET kinase inhibitor, among adolescents and adults with any solid tumor type that harbored an activating RET alteration. Patients enrolled in the phase 1 dose-escalation portion of the study received selpercatinib at doses ranging from 20 mg once daily to 240 mg twice daily. Patients in the phase 2 portion received the recommended dose of 160 mg twice daily.
RET fusion-positive NSCLC
RET fusions occur in 1% to 2% of patients with NSCLC and appear to be associated with a high risk for brain metastases.
Multitargeted kinase inhibitors designed to target other kinases but that provide some RET inhibition have not been shown to be very effective in treating patients with these fusions.
In the first study by Subbiah and colleagues, researchers reported results of selpercatinib among patients with RET fusion-positive NSCLC who had no prior treatment (n = 39; median age, 61 years; 56% women) or received at least platinum-based chemotherapy (n = 105; median age, 61 years; 59% women).
Objective response as determined by an independent review committee served as the primary endpoint. Duration of response, PFS and safety served as secondary endpoints.
Results among patients who had received platinum-based chemotherapy showed an objective response rate of 64% (95% CI, 54-73) with a median duration of response of 17.5 months (95% CI, 12-not evaluable). Sixty-three percent of responses remained ongoing at median follow-up of 12.1 months.
Among the previously untreated patients, 85% (95% CI, 70-94) achieved an objective response, with 90% of those responses continuing at 6 months.
Among 11 patients with measurable central nervous system metastasis at enrollment, 91% (95% CI, 59-100) achieved an objective intracranial response.
Common grade 3 or higher adverse events included hypertension (14%), increased alanine aminotransferase level (12%), increased aspartate aminotransferase level (10%), hyponatremia (6%) and lymphopenia (6%).
RET-altered thyroid cancer
Germline RET mutations result in hereditary multiple endocrine neoplasia 2A and multiple endocrine neoplasia 2B, leading to almost complete penetrance of medullary thyroid cancer in gene carriers, according to study background. These hereditary syndromes account for 25% of all medullary thyroid cancer cases. Among the other 75% of cases of sporadic medullary thyroid cancer, about 60% harbor somatic RET mutations, which are associated with more aggressive disease.
In the second study, Subbiah and colleagues reported results of selpercatinib among patients with RET-mutant medullary thyroid cancer who received prior treatment with (n = 55) or without (n = 88) the multikinase inhibitors vandetanib (Caprelsa, Sannofi Genzyme) and/or cabozantinib (Cometriq/Cabometyx, Exelixis), as well as among patients with previously treated RET fusion-positive thyroid cancer (n = 19).
Objective response rate as determined by an independent review committee served as the primary endpoint. Duration of response, PFS and safety served as secondary endpoints.
Results among patients previously treated with vandetanib and/or cabozantinib showed an ORR of 69% (95% CI, 55-81), with a 1-year PFS rate of 82% (95% CI, 69-90).
Among the patients who did not previously receive vandetanib or cabozantinib, 73% (95% CI, 62-82) achieved an objective response, with a 1-year PFS rate of 92% (95% CI, 82-97).
Among the patients with previously treated RET fusion-positive thyroid cancer, researchers reported an ORR of 79% (95% CI, 54-94) and a 1-year PFS rate of 64% (95% CI, 37-82).
Common grade 3 or higher adverse events included hypertension (21%), increased alanine aminotransferase level (11%), increased aspartate aminotransferase level (9%), hyponatremia (8%) and diarrhea (6%).
Twelve of the 531 patients who received selpercatinib in the overall trial discontinued treatment because of drug-related adverse events.
“Our next step is to identify these RET-altered patients, because they are rare,” Subbiah said. “The continued implementation of comprehensive next-generation sequencing molecular screening strategies that include the ability to detect RET fusions and RET mutations will be critical for identifying patients with NSCLC or thyroid cancer who may benefit from selpercatinib.”
RET abnormalities now join other genomic alterations— such as NTRK fusions, tumor mutational burden, deficient mismatch repair genes across cancers, and ALK, BRAF, EGFR, MET and ROS1 alterations in NSCLC —that warrant molecular screening strategies, Razelle Kurzrock, MD, director of the Center for Personalized Cancer Therapy and senior deputy director for clinical science at Moores Cancer Center, and chief of the division of hematology-oncology in the department of medicine at UC San Diego Health, wrote in an accompanying editorial.
“Next steps may include introducing these agents earlier in the course of the disease, addressing genomic co-alterations with customized combination therapy strategies, and using additional techniques such as transcriptome analysis in order to fully understand the molecular landscape of cancer,” Kurzrock wrote.
References:
- Drilon A, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2005653.
- Kurzrock R. N Engl J Med. 2020;doi:10.1056/NEJMe2024831.
- Wirth LJ, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2005651.
For more information:
Vivek Subbiah, MD, can be reached at vsubbiah@mdanderson.org.
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