Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer

1. Progression-free survival was not reached in the selpercatinib group and was 16.8 months in the control group, with an HR of 0.28.

2. Adverse events grade ≥3 occurred in 52.8% in the selpercatinib group vs 76.3% in the control group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Medullary thyroid cancer is primarily caused by mutations in the RET, leading to constitutive activation of the RET kinase. Vandetanib and cabozantinib, multikinase inhibitors, are approved for treatment, but they have suboptimal RET inhibition and toxic effects. Selpercatinib, a selective and potent RET kinase inhibitor, demonstrated efficacy in nonrandomized studies. This phase 3 trial compared selpercatinib with vandetanib or cabozantinib in patients with progressive RET-mutant medullary thyroid cancer who hadn’t received kinase inhibitor treatment. The primary endpoint was progression-free survival (PFS) and secondary endpoints included treatment failure–free survival (TFFS), overall response rate (ORR), overall survival (OS), and safety. Median PFS was not reached in the selpercatinib group and was 16.8 months in the control group, with an HR of 0.28 (p<0.001). At 12 months, PFS was 86.8% in the selpercatinib group vs 65.7% in the control group. Similarly, median TFFS was not reached in the selpercatinib group and was 13.9 months in the control group, with an HR of 0.25 (p<0.001). ORR was 69.4% in the selpercatinib group vs 38.8%, with 11.9% vs 4.1% having a complete response, respectively. There was no OS data but estimates at 18 months were 95.5% in the selpercatinib group vs 92.8% in the control group. With regards to safety, adverse events grade ≥3 occurred in 52.8% in the selpercatinib group (hypertension 18.7%, increase in ALT 10.4%, increase in AST 4.7%, QT prolongation 4.7%) vs 76.3% in the control group (hypertension 17.5%, mucosal inflammation 13.4%, and palmar-plantar erythrodysesthesia syndrome 9.3%). The strengths of this study were the methodology and the limitations included the small sample size, and immature data.  Overall, this study found that selpercatinib showed improved outcomes in advanced RET-mutant medullary thyroid cancer than cabozantinib or vandetanib.

Click to read the study in NEJM

Relevant Reading: Efficacy of Selpercatinib in RET Fusion–Positive Non–Small-Cell Lung Cancer

In-Depth [randomized controlled trial]: This open-label phase 3 trial enrolled patients (>12 years) with pathologically confirmed, unresectable, locally advanced or metastatic medullary thyroid cancer with a RET mutation and prior use of kinase inhibitors and randomized (2:1) into selpercatinib (193 patients) vs physicians choice of cabozantinib (73) or vandetanib (25). Median PFS was not reached in the selpercatinib group and was 16.8 months (95%CI, 12.2-25.1) in the control group, with an HR of 0.28 (95%CI, 0.16-0.48, p<0.001). At 12 months, PFS was 86.8% (95%CI, 79.8-91.6) in the selpercatinib group vs 65.7% (95%CI, 51.9-76.4) in the control group. Similarly, median TFFS was not reached in the selpercatinib group and was 13.9 months (95%CI, 11.3-25.1) in the control group, with an HR 0.25 (95%CI, 0.15-0.42, p<0.001). ORR was 69.4% (95%CI, 62.4-75.8) in the selpercatinib group vs 38.8% (95%CI, 29.1-49.2), with 11.9% vs 4.1% having a complete response, respectively. There was no OS data but estimates at 18 months were 95.5% (95%CI, 90.1-98.0) in the selpercatinib group vs 92.8% (95%CI, 83.0-97.1) in the control group. With regards to safety, adverse events grade ≥3 occurred in 52.8% in the selpercatinib group (hypertension 18.7%, increase in ALT 10.4%, increase in AST 4.7%, QT prolongation 4.7%) vs 76.3% in the control group (hypertension 17.5%, mucosal inflammation 13.4%, and palmar–plantar erythrodysesthesia syndrome 9.3%). Overall, this study found that selpercatinib showed improved outcomes in advanced RET-mutant medullary thyroid cancer than cabozantinib or vandetanib.

Image: PD

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