Selpercatinib Shows Superior Efficacy Vs Multikinase Inhibitors in Advanced RET+ MTC

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Patients who received the RET inhibitor selpercatinib (Retevmo) as therapy for advanced, multikinase inhibitor–naïve, RET-mutant medullary thyroid cancer (MTC) had significantly better progression-free survival (PFS) and overall response rate (ORR) vs cabozantinib (Cabometyx) or vandetanib (Caprelsa), based on interim results from the phase 3 LIBRETTO-531 trial (NCT04211337) presented during the 2023 ESMO Congress.^1,2

At a median follow-up of 12 months, the median PFS by blinded independent central review (BICR) was not reached with selpercatinib (95% CI, not estimable [NE]-NE) whereas the median PFS was 16.8 months (95% CI, 12.2-25.1) in the kinase inhibitor arm, translating to a 72% reduction in the risk of disease progression or death (HR, 0.280; 95% CI, 0.165-0.475; P < .0001).

“Selpercatinib, a selective RET inhibitor, provides prolonged PFS, prolonged treatment failure-free survival, higher ORR, and a favorable safety profile as compared with multikinase inhibitors for the first-line treatment of patients with RET-mutant medullary thyroid carcinoma,” Julien Hadoux, MD, PhD, lead study author, medical oncologist, and attending physician at Gustave Roussy in Villejuif, France, said in a presentation during the meeting. “These results, therefore, support selpercatinib as the first-line standard of care for patients with advanced RET-mutant [MTC].”

Cabozantinib and vandetanib are both standard frontline treatment options in the advanced MTC setting, but Hadoux underscored their limitations, such as suboptimal RET inhibition, toxicity, and long pharmacologic half-lives “that complicate management.”

In May 2020, the FDA granted an accelerated approval to selpercatinib for the treatment of adult patients with metastatic RET fusion–positive non-small cell lung cancer (NSCLC);³ it received regular approval for this population in September 2022.⁴ The agent is also indicated for adult and pediatric patients at least 12 years old with advanced or metastatic RET-mutant MTC who need systemic treatment and adult and pediatric patients at least 12 years old with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory, if radioactive iodine is appropriate.³

Selpercatinib received a second accelerated approval in September 2022 for adult patients with locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic therapy or who have no satisfactory alternative treatment options.⁴ Both regulatory decisions were based on findings from the multicohort LIBRETTO-001 study (NCT03157128).⁵

In the phase 3 LIBRETTO-531 trial, investigators sought to define the optimal first-line regimen for patients with advanced RET-mutant MTC. To be eligible for enrollment, patients must have had unresectable locally advanced or metastatic RET-mutant MTC who had progressive disease via RECIST v1.1 criteria that was documented in the 14 months prior to study enrollment. Patients could not have previously received a kinase inhibitor.

A total of 291 patients with advanced RET-mutant MTC were randomized to receive selpercatinib at 160 mg twice daily (n = 193) or physician’s choice of cabozantinib at 140 mg daily or vandetanib at 300 mg daily (n = 98) in the first-line setting.

Stratification factors included mutational status (M918T vs other) and investigator’s choice of treatment if assigned to physician’s choice arm (cabozantinib vs vandetanib). Patients were permitted to cross over to receive selpercatinib if they met select criteria upon radiographic progression.

The primary end point was PFS per RECIST v1.1 criteria via BICR. Secondary end points were treatment failure-free survival (TFFS) by BICR and investigator, investigator-assessed PFS, overall survival (OS) by BICR and investigator assessment, and safety.

Patients were enrolled between February 2020 and March 2023 and were from 176 centers across 19 countries. A protocol-specified interim efficacy analysis occurred following 59 BICR PFS events. The data cutoff date was May 22, 2023. Hadoux reported that 18 patients discontinued selpercatinib vs 58 who discontinued cabozantinib or vandetanib. Twenty-four patients on the control arm crossed over to selpercatinib.

Baseline characteristics showed that the median age between both arms was 54.6 years (range, 12-84), with approximately one-fourth of patients at least 65 years old. Most patients were male (64.5%), White (68.7%), and had an ECOG performance status of 0 (59.7%). A total 62.5% of patients had a RET M918T mutation. The median time from diagnosis to study enrollment was 42.7 months (Q1-Q3, 15.2-98.9) and 61.6 months (Q1-Q3, 20.2-141.0) on the selpercatinib and control arms, respectively.

Additional efficacy findings showed that the PFS benefit with the highly selective, potent RET inhibitor was also observed via investigator assessment (HR, 0.187; 95% CI, 0.109-0.321; P <.0001). Selpercatinib also improved PFS across all prespecified subgroups, especially in those with a RET comutation beyond M918T (HR, 0.177; 95% CI, 0.075-0.422).

At a median 15 months of follow-up, 8 deaths occurred on the selpercatinib arm vs 10 on the control arm; 94.8% and 85.7% of patients on each arm are alive, respectively. Hadoux cautioned that the data are immature due to a censoring date of 90%, but highlighted that OS favored selpercatinib (HR, 0.374; 95% CI, 0.147-0.949; P = .0312). Of the 24 patients who crossed over to received selpercatinib, 19 remain on treatment as of the data cutoff date.

TFFS was defined as the time from randomization to the first occurrence of progressive disease assessed, discontinuation due to treatment-related adverse event (TRAE), both assessed by BICR, or death. The median TFFS by BICR was not reached with selpercatinib (95% CI, NE-NE) vs 13.9 months (95% CI, 11.3-25.1) with cabozantinib or vandetanib (HR, 0.254; 95% CI, 0.153-0.423; P <.0001), which was also reported to be statistically significant. When assessed via investigator, the TFFS benefit with selpercatinib was similar (HR, 0.157; 95% CI, 0.095-0.259; P <.0001).

The ORR via RECIST v1.1 criteria per BICR was 69.4% (95% CI, 62.4%-75.8%) with selpercatinib compared with 38.8% (95% CI, 29.1%-49.2%) with the kinase inhibitor group (OR, 3.7; 95% CI, 2.2-6.3; P <.0001). The complete response rate was 11.9% with selpercatinib vs 4.1% in the control group; partial response rates were 57.5% and 34.7%, respectively. The median duration of response was not reached with selpercatinib (95% CI, NE-NE) compared with 16.6 months (95% CI, 10.4-NE) with cabozantinib or vandetanib.

Regarding safety, grade 3 or higher common treatment-emergent adverse effects (TEAEs) occurred in 52.8% and 76.3% of patients on selpercatinib and cabozantinib/vandetanib, respectively; grade 3 or higher TEAEs occurred in 52.8% and 76.3% of patients, respectively. The most common grade 3 or higher TEAEs with selpercatinib were hypertension (19%), alanine aminotransferase increase (10%), aspartate aminotransferase increase (5%), fatigue (4%), and diarrhea (3%). In the control arm, these included hypertension (18%), mucosal inflammation (13%), palmar-plantar erythrodysesthesia syndrome (9%), and diarrhea (8%).

Dose reductions due to adverse events (AEs) occurred in 38.9%, 79.2%, and 71.0% of patients on selpercatinib, cabozantinib, and vandetanib, respectively; the discontinuation rates due to AEs occurred in 4.7% and 26.8% of patients, respectively. Four patients on selpercatinib died due to AEs vs 2 on the control arm.

The label for selpercatinib includes warnings and precautions regarding hepatotoxicity, interstitial lung disease or pneumonitis, QT interval prolongation, hypersensitivity, tumor lysis syndrome, hemorrhagic events, risk of hindered wound healing, hypothyroidism, and embryo-fetal toxicity.

_References

_{1. Hadoux J, Elisel R, Brose MS, et al. Randomized phase III study of selpercatinib versus cabozantinib or vandetanib in advanced, kinase inhibitor-naïve, RET-mutant medullary thyroid cancer. Ann Oncol. 2023;34(suppl 2):LBA3. doi:10.1016/j.annonc.2023.10.103}

_{2. Hadoux J, Elisel R, Brose MS, et al. Phase 3 trial of selpercatinib in advanced RET-mutant medullary thyroid cancer. N Engl J Med. Published October 21, 2023. doi:10.1056/NEJMoa2309719}

_{3. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. FDA. May 8, 2020. Accessed October 21, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-lung-and-thyroid-cancers-ret-gene-mutations-or-fusions}

_{4. FDA approves Lilly/s Retevmo (selpercatinib), the first and only RET inhibitor for adults with advanced or metastatic solid tumors with a RET gene fusion, regardless of type. News release. Eli Lilly and Company. September 21, 2022. Accessed October 21, 2023. https://www.prnewswire.com/news-releases/fda-approves-lillys-retevmo-selpercatinib-the-first-and-only-ret-inhibitor-for-adults-with-advanced-or-metastatic-solid-tumors-with-a-ret-gene-fusion-regardless-of-type-301630358.html}

_{5. Subbiah V, Wolf J, Konda B, et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol. 2022;23(10):P1261-1273. doi:10.1016/S1470-2045(22)00541-1}