Selpercatinib

A phase I/II trial (LIBRETTO-001 [NCT03157128]) evaluated the safety and efficacy of selpercatinib in adolescent and adult patients with any solid tumor with an activating RET pathogenic variant. The primary end point was an objective response (complete response or partial response). Patients with RET fusion–positive thyroid cancer had radioiodine-refractory disease and received at least one previous systemic therapy other than radioiodine. Nineteen patients with RET fusion–positive thyroid cancer were enrolled; 13 patients had papillary thyroid cancer, 3 had poorly differentiated thyroid cancer, 1 had anaplastic thyroid cancer, and 1 had Hürthle cell thyroid cancer. Ninety-five percent of patients with RET fusion–positive thyroid cancer received the phase II dose of 160 mg twice daily.[36]

A phase I/II trial (LIBRETTO-001 [NCT03157128]) evaluated the safety and efficacy of selpercatinib in adolescent and adult patients with any solid tumor with an activating RET pathogenic variant. The primary end point was an objective response (complete response or partial response). Patients with RET fusion–positive thyroid cancer had radioiodine-refractory disease and received at least one previous systemic therapy other than radioiodine. Nineteen patients with RET fusion–positive thyroid cancer were enrolled; 13 patients had papillary thyroid cancer, 3 had poorly differentiated thyroid cancer, 1 had anaplastic thyroid cancer, and 1 had Hürthle cell thyroid cancer. Ninety-five percent of patients with RET fusion–positive thyroid cancer received the phase II dose of 160 mg twice daily.[36]

The objective response rate was 79% (95% CI, 54%−94%).[36][Level of evidence C2]

A phase I/II trial (LIBRETTO-001 [NCT03157128]) evaluated the safety and efficacy of selpercatinib in adolescent and adult patients with any solid tumor with an activating RET pathogenic variant. The primary end point was an objective response (complete response or partial response). Patients with RET fusion–positive thyroid cancer had radioiodine-refractory disease and received at least one previous systemic therapy other than radioiodine. Nineteen patients with RET fusion–positive thyroid cancer were enrolled; 13 patients had papillary thyroid cancer, 3 had poorly differentiated thyroid cancer, 1 had anaplastic thyroid cancer, and 1 had Hürthle cell thyroid cancer. Ninety-five percent of patients with RET fusion–positive thyroid cancer received the phase II dose of 160 mg twice daily.[36]

At 1 year, 71% of responses were ongoing (95% CI, 39%−88%) and 64% of patients were progression-free.

A phase I/II trial (LIBRETTO-001 [NCT03157128]) evaluated the safety and efficacy of selpercatinib in adolescent and adult patients with any solid tumor with an activating RET pathogenic variant. The primary end point was an objective response (complete response or partial response). Patients with RET fusion–positive thyroid cancer had radioiodine-refractory disease and received at least one previous systemic therapy other than radioiodine. Nineteen patients with RET fusion–positive thyroid cancer were enrolled; 13 patients had papillary thyroid cancer, 3 had poorly differentiated thyroid cancer, 1 had anaplastic thyroid cancer, and 1 had Hürthle cell thyroid cancer. Ninety-five percent of patients with RET fusion–positive thyroid cancer received the phase II dose of 160 mg twice daily.[36]

Treatment-related adverse events (any grade) occurred in 94% of patients.

A phase I/II trial (LIBRETTO-001 [NCT03157128]) evaluated the safety and efficacy of selpercatinib in adolescent and adult patients with any solid tumor with an activating RET pathogenic variant. The primary end point was an objective response (complete response or partial response). Patients with RET fusion–positive thyroid cancer had radioiodine-refractory disease and received at least one previous systemic therapy other than radioiodine. Nineteen patients with RET fusion–positive thyroid cancer were enrolled; 13 patients had papillary thyroid cancer, 3 had poorly differentiated thyroid cancer, 1 had anaplastic thyroid cancer, and 1 had Hürthle cell thyroid cancer. Ninety-five percent of patients with RET fusion–positive thyroid cancer received the phase II dose of 160 mg twice daily.[36] › Treatment-related adverse events (any grade) occurred in 94% of patients.

Grade 3 adverse events were observed in 28% of patients, and grade 4 adverse events were observed in 2% of patients.

A phase I/II trial (LIBRETTO-001 [NCT03157128]) evaluated the safety and efficacy of selpercatinib in adolescent and adult patients with any solid tumor with an activating RET pathogenic variant. The primary end point was an objective response (complete response or partial response). Patients with RET fusion–positive thyroid cancer had radioiodine-refractory disease and received at least one previous systemic therapy other than radioiodine. Nineteen patients with RET fusion–positive thyroid cancer were enrolled; 13 patients had papillary thyroid cancer, 3 had poorly differentiated thyroid cancer, 1 had anaplastic thyroid cancer, and 1 had Hürthle cell thyroid cancer. Ninety-five percent of patients with RET fusion–positive thyroid cancer received the phase II dose of 160 mg twice daily.[36] › Treatment-related adverse events (any grade) occurred in 94% of patients.

The most frequent adverse events were dry mouth (46%), hypertension (43%), diarrhea (38%), fatigue (38%), increased aspartate aminotransferase (AST) level (35%), nausea (35%), and constipation (35%).

A phase I/II trial (LIBRETTO-001 [NCT03157128]) evaluated the safety and efficacy of selpercatinib in adolescent and adult patients with any solid tumor with an activating RET pathogenic variant. The primary end point was an objective response (complete response or partial response). Patients with RET fusion–positive thyroid cancer had radioiodine-refractory disease and received at least one previous systemic therapy other than radioiodine. Nineteen patients with RET fusion–positive thyroid cancer were enrolled; 13 patients had papillary thyroid cancer, 3 had poorly differentiated thyroid cancer, 1 had anaplastic thyroid cancer, and 1 had Hürthle cell thyroid cancer. Ninety-five percent of patients with RET fusion–positive thyroid cancer received the phase II dose of 160 mg twice daily.[36] › Treatment-related adverse events (any grade) occurred in 94% of patients.

Thirty percent of patients had dose reductions because of treatment-related adverse events, and 2% of patients discontinued the drug because of adverse events.

A phase III randomized trial (NCT04211337) compared first-line selpercatinib with physician’s choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease within the 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was PFS, assessed by blinded independent central review. Patients in the control group with disease progression were permitted to cross over to the selpercatinib group. Treatment failure–free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if PFS was significant. Other secondary end points included overall response and safety.[37]

A phase III randomized trial (NCT04211337) compared first-line selpercatinib with physician’s choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease within the 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was PFS, assessed by blinded independent central review. Patients in the control group with disease progression were permitted to cross over to the selpercatinib group. Treatment failure–free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if PFS was significant. Other secondary end points included overall response and safety.[37]

At a median follow-up of 12 months, the median PFS was not reached in the selpercatinib group and was 16.8 months in the control group (95% CI, 12.2–25.1) (HRdisease progression or death, 0.28; 95% CI, 0.16–0.48; P < .001).[37][Level of evidence B1]

A phase III randomized trial (NCT04211337) compared first-line selpercatinib with physician’s choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease within the 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was PFS, assessed by blinded independent central review. Patients in the control group with disease progression were permitted to cross over to the selpercatinib group. Treatment failure–free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if PFS was significant. Other secondary end points included overall response and safety.[37]

The 12-month PFS rate was 86.8% (95% CI, 79.8%–91.6%) in the selpercatinib group and 65.7% (95% CI, 51.9%–76.4%) in the control group.

A phase III randomized trial (NCT04211337) compared first-line selpercatinib with physician’s choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease within the 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was PFS, assessed by blinded independent central review. Patients in the control group with disease progression were permitted to cross over to the selpercatinib group. Treatment failure–free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if PFS was significant. Other secondary end points included overall response and safety.[37]

The overall response rate was 69.4% (95% CI, 62.4%–75.8%) in the selpercatinib group and 38.8% (95% CI, 29.1%–49.2%) in the control group.

A phase III randomized trial (NCT04211337) compared first-line selpercatinib with physician’s choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease within the 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was PFS, assessed by blinded independent central review. Patients in the control group with disease progression were permitted to cross over to the selpercatinib group. Treatment failure–free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if PFS was significant. Other secondary end points included overall response and safety.[37]

Adverse events led to a dose reduction in 38.9% of patients in the selpercatinib group and 77.3% of patients in the control group. Adverse events led to treatment discontinuation in 4.7% of patients in the selpercatinib group and 26.8% of patients in the control group.