Selpercatinib Improves Responses Regardless of Prior Treatment in RET-Mutant Medullary Thyroid Cancer

Selpercatinib (Retevmo) improved overall response rates (ORRs) in most patients with RET­-mutatedmedullary thyroid cancer (MTC) irrespective of prior systemic therapy, according to findings that were presented in a poster during the 2021 virtual ASCO Annual Meeting.¹

Findings from an exploratory post-hoc longitudinal intrapatient analysis of the ongoing phase 1/2 LIBRETTO-001 trial (NCT03157128). The ORR with selpercatinib was 69% in this patient population, which was significantly higher compared with the 10% ORR observed with immediate prior therapies received before patient enrollment to LIBRETTO-001.

ORR benefit was observed regardless of responses to immediate prior therapy before study enrollment. Patients who received cabozantinib (Cabometyx) prior to selpercatinib achieved a 14% ORR compared with 66% with selpercatinib. Patients who received vandetanib (Caprelsa) prior to selpercatinib achieved a 12% ORR compared with 71% with selpercatinib.

“Patients with no overall response to either cabozantinib or vandetanib may still derive benefit from subsequent selpercatinib treatment,” lead study author Lori Wirth, MD, medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School, and co-authors wrote in a virtual poster presentation of the data.

Selpercatinib is a first-in-class, highly selective RET kinase inhibitor. The agent was granted accelerated approval by the FDA in May 2020 for the treatment of patients with RET alteration–positive non–small cell lung cancer (NSCLC), MTC, and other thyroid cancers.

The regulatory decision was based on findings from the LIBRETTO-001 trial, in which selpercatinib demonstrated robust and durable antitumor activity in patients with RET mutation–positive MTC.

As a result, selpercatinib is being incorporated as a standard-of-care treatment option for patients with RET-mutant thyroid cancers in the United States, as well as other countries.

Some multitargeted kinase inhibitors, such as vandetanib and cabozantinib, are also approved to treat patients with metastatic thyroid cancer; however, the agents confer dose-limiting, off-target adverse effects.

Notably, findings from the LIBRETTO-001 trial revealed that patients benefitted from selpercatinib irrespective of prior vandetanib and/or cabozantinib treatment.

Because response rates tend to decline in subsequent lines of therapy, this post-hoc analysis evaluated the efficacy of selpercatinib based on immediate prior therapy before patient enrollment to the LIBRETTO-001 trial.

The analysis evaluated the integrated analysis set (n = 143) from the LIBRETTO-001 trial, which included patients with MTC who were enrolled in the study long enough to permit a minimum of 6 months of follow-up from the first dose of selpercatinib.

Immediate prior therapies included cabozantinib (31%), vandetanib (43%), other multitargeted kinase inhibitors (12%), such as sorafenib (Nexavar), lenvatinib (Lenvima), alectinib (Alecensa), pazopanib (Votrient), regorafenib (Stivarga), and sunitinib (Sutent), and other therapies (15%).

Patients were retrospectively analyzed for best overall response attained during therapy received immediately before enrollment. Responses were assessed per physician-reported best response in patients’ medical history and compared with the subsequent best overall response with selpercatinib per independent review committee RECIST version 1.1 criteria. As such, each patient served as their own control.

Patients with objective responses included those who achieved complete or partial responses. Patients without objective responses included those who experienced stable disease, progressive disease or were not evaluable/unknown.

In the overall population (n = 143), 62% (n = 89) of patients responded to selpercatinib but not to prior therapy; 7% (n = 10) of patients responded to selpercatinib and prior therapy; 3% (n = 4) of patients responded to prior therapy but not to selpercatinib, and 28% (n = 40) of patients did not respond to selpercatinib or prior therapy.

In patients whose immediate prior therapy was cabozantinib (n = 44), 57% (n = 25) of patients responded to selpercatinib but not to prior therapy, 9% (n = 4) responded to selpercatinib and prior therapy, 4% (n = 2) responded to prior therapy but not to selpercatinib, and 30% (n = 13) did not respond to selpercatinib or prior therapy.

In patients whose immediate prior therapy was vandetanib (n = 61), 61% (n = 37) of patients responded to selpercatinib but not to prior therapy, 10% (n = 6) responded to selpercatinib and prior therapy, 2% (n = 1) responded to prior therapy but not to selpercatinib, and 28% (n = 17) did not respond to selpercatinib or prior therapy.

In patients whose immediate prior therapy was other multitargeted kinase inhibitors (n = 17), 71% of patients (n = 12) responded to selpercatinib but not to prior therapy, 24% (n = 4) responded to selpercatinib and prior therapy, 6% (n = 1) responded to prior therapy but not to selpercatinib, and 0% (n = 0) did not respond to selpercatinib or prior therapy.

Further data indicated that the responses observed with immediate prior cabozantinib or vandetanib were lower compared with those noted in the phase 3 ZETA (NCT00410761) and EXAM (NCT00704730) trials, for which the FDA approvals for vandetanib and cabozantinib in MTC were based on, respectively. However, patients in the LIBRETTO-001 trial had received 1 to 8 prior lines of therapy.

“A limitation of this analysis was that immediate prior response assessment was based on physician-reported best response in patients’ medical history and may not follow RECIST criteria,” Wirth and co-authors wrote.

Another post-hoc intrapatient analysis from the LIBRETTO-001 trial demonstrated similar responses in NSCLC to the one conducted in MTC.2 Improvements in ORR were observed with selpercatinib irrespective of responses to immediate prior therapy.

Notably, the randomized phase 3 LIBRETTO-531 trial (NCT04211337) is ongoing to evaluate selpercatinib vs standard frontline therapy with cabozantinib or vandetanib in patients with RET-mutated MTC.

_References

1. _{Wirth L, Sherman E, Shah M, et al. Efficacy of selpercatinib after prior systemic therapy in patients with RET-mutant medullary thyroid cancer. J Clin Oncol. 2021;39(suppl 15):6074. doi:10.1200/JCO.2021.39.15_suppl.6074}
2. _{Drilon A, Gautschi O, Besse B, et al. Response to selpercatinib versus prior systemic therapy in patients with RET fusion-positive non-small-cell lung cancer (NSCLC): LIBRETTO-001 study. J Clin Oncol. 2021;39(suppl 15):9032. doi:10.1200/JCO.2021.39.15_suppl.9032}