Retevmo (selpercatinib) phase III results in RET fusion-positive NSCLC and RET-mutant medullary thyroid cancer are both published in the New England Journal of Medicine and presented in a presidential symposium at ESMO Congress 2023.- Eli Lilly

In both clinical studies, results were based on pre-specified interim efficacy analyses conducted by independent data monitoring committees (IDMC). Results from the LIBRETTO-431 and LIBRETTO-531 Phase III trials were presented in a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2023 and simultaneously published in the New England Journal of Medicine.

"These results from LIBRETTO-431 and LIBRETTO-531 are striking and provide critical evidence supporting the importance of optimizing initial therapy for patients with RET-driven cancers," said David Hyman, M.D., chief medical officer, Lilly. "We are excited to be sharing these data with the clinical community in both NEJM and at ESMO. It is our hope that these data lead to further adoption of biomarker testing in the initial treatment journey for people with NSCLC and MTC and help make Retevmo a standard initial treatment option for all appropriate patients."

The labeling for Retevmo contains warnings and precautions for hepatotoxicity (evidence of liver dysfunction), interstitial lung disease (ILD)/pneumonitis, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, tumor lysis syndrome, risk of impaired wound healing, hypothyroidism, and embryo-fetal toxicity.

RET Fusion-Positive NSCLC: Data from LIBRETTO-431 : LIBRETTO-431 is a Phase III, randomized, open-label trial that evaluated Retevmo in patients with advanced or metastatic, treatment-naïve RET fusion-positive NSCLC. In the study, patients were randomly assigned to receive Retevmo, or pemetrexed and the investigator's choice of platinum-based chemotherapy (cisplatin or carboplatin) with or without pembrolizumab — which is a current first-line standard of care treatment option. LIBRETTO-431 is the first randomized trial that compared the safety and effectiveness of a targeted therapy to a PD-1 inhibitor plus chemotherapy in a biomarker-selected NSCLC patient population. The primary endpoint was tested first in patients stratified by intent-to-treat (ITT) with pembrolizumab if assigned to the control arm (ITT-pembrolizumab), then tested in the ITT population if deemed positive.

"These data provide clear evidence that Retevmo offers highly meaningful clinical impact for patients diagnosed with RET fusion-positive NSCLC and it should be considered as the first treatment option for these patients," said Caicun Zhou, M.D., Ph.D., director and professor at the Cancer Institute of Tongji University School of Medicine and Shanghai Pulmonary Hospital, and LIBRETTO-431 primary investigator. "While there is often urgency to treat, these results further highlight the importance of incorporating routine biomarker testing into a patient's care plan to direct early clinical decision-making towards the most effective therapies."

Results :A total of 256 patients received at least one dose of study treatment (Retevmo, 158; control arm, 98). Of the 261 patients in the ITT population, 159 were randomly assigned to Retevmo and 102 to the control arm. Of the 212 patients in the ITT-pembrolizumab population, 129 were randomly assigned to Retevmo and 83 to pembrolizumab with chemotherapy. Patients randomized to the control arm who had disease progression confirmed by blinded independent central review (BICR) were eligible for optional crossover to Retevmo. In the ITT-pembrolizumab population, the median PFS by BICR was 24.8 months (95% CI: 16.9, not estimable [NE]) with Retevmo versus 11.2 months (95% CI: 8.8, 16.8) in the control arm, corresponding to a hazard ratio (HR) of 0.465 (95% CI: 0.309, 0.699; p<0.001). pfs was longer with retevmo than in the control arm across all pre-specified subgroups. the overall response rate (orr) by bicr with retevmo was 83.7% (95% ci: 76.2, 89.6) compared to 65.1% (95% ci: 53.8, 75.2) in the control arm. similar results were observed in the itt population in both bicr and investigator-assessed endpoints and across all pre-specified subgroups. retevmo demonstrated superior pfs with an hr of 0.482 (95% ci: 0.331, 0.700; p><0.001) and an increase of more than 13 months in median pfs by bicr, showing 24.8 months (95% ci: 17.3, ne) with retevmo versus 11.2 months (95% ci: 8.8, 16.8) with control. overall survival (os) results remain immature with a censoring rate of approximately 80% (hr 0.961, 95% ci: 0.503, 1.835) in the itt-pembrolizumab arm.></0.001)></0.001).>

Intracranial baseline assessments were available for evaluation by neuroradiologic BICR for 192 patients in the central nervous system (CNS)-pembrolizumab population (Retevmo, 120; control arm, 72). Time to CNS progression was longer with Retevmo than in the control arm (cause-specific HR: 0.28; 95% CI: 0.12, 0.68), with eight patients (6.7%) on Retevmo having a first event of CNS progression compared to 13 patients (18.1%) in the control arm. Forty-two of the 192 patients (21.9%) were confirmed to have brain metastases at baseline, of which 29 were measurable (Retevmo, 17; control arm, 12). In the patients with measurable baseline brain metastases, the intracranial response rate for those who received Retevmo was 82.4% (95% CI: 56.6, 96.2) versus 58.3% (95% CI: 27.7, 84.8) in the control arm. Complete responses were observed in 35.3% of patients with Retevmo versus 16.7% in the control arm. Median intracranial response duration was not yet mature, but at 12 months, 76.0% of patients remained in response with Retevmo versus 62.5% in the control arm.

RET-Mutant MTC (medullary thyroid cancer): Data from LIBRETTO-531; LIBRETTO-531 is a Phase III, randomized, open-label trial that evaluated Retevmo versus physician's choice of MKIs cabozantinib or vandetanib, which are currently approved first-line options for patients with advanced or metastatic, kinase inhibitor-naïve RET-mutant MTC. It is the first randomized trial that compared the safety and effectiveness of a highly selective RET-kinase inhibitor versus MKIs in this population.

"The magnitude of benefit observed in patients treated with Retevmo makes clear that it should become the standard of care for the initial systemic treatment of patients with progressive advanced RET-mutant MTC," said Julien Hadoux, M.D., Ph.D., medical oncologist at the Gustave Roussy Cancer Center and LIBRETTO-531 investigator. "These data should prove to be practice-changing for clinicians caring for patients with MTC and lead to routine biomarker testing."

A total of 291 patients with progressive RET-mutant MTC and no prior history of MKI therapy for advanced or metastatic disease were randomized in the study. One hundred and ninety-three patients were randomized to the Retevmo arm and 98 to the control arm to receive investigator's choice of cabozantinib (73) or vandetanib (25). Patients randomized to the control arm who experienced disease progression confirmed by BICR were eligible to cross over to Retevmo.

Results : At the interim analysis, the study had met the criteria for positive PFS. At a median follow-up of approximately 12 months, the BICR-assessed median PFS in the Retevmo arm was not reached and remained inestimable (95% CI, NE to NE), whereas the BICR-assessed median PFS in the control arm was 16.8 months (95% CI: 12.2, 25.1). This corresponded to a HR of 0.280 (95% CI: 0.165, 0.475; p<0.0001). investigator-assessed pfs yielded similar results with an hr of 0.187 (95% ci: 0.109, 0.321; p><0.0001). both bicr and investigator-assessed pfs were longer with retevmo across all pre-planned subgroups. treatment with retevmo resulted in a significant improvement in treatment failure-free survival (tffs) with an hr of 0.254 (95% ci: 0.153, 0.423; p><0.001). the orr with retevmo was 69.4% (95% ci: 62.4, 75.8) compared to 38.8% (95% ci: 29.1, 49.2) in the control arm (95% ci: 2.2, 6.3). os results remain immature with a censoring rate of more than 90%, although a favorable trend was observed (hr 0.374, 95% ci: 0.147, 0.949). the safety profile observed for retevmo in both studies was generally consistent with those identified across the previously reported retevmo development program (libretto-001, libretto-121, libretto-321).></0.001).></0.0001).></0.0001).>

About RET-Driven Cancers : Genomic alterations in the RET kinase, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth. RET fusions have been identified in approximately 1% to 2% of all NSCLC cases. NSCLC accounts for about 85% of all lung cancer diagnoses in the U.S., of which approximately 50% have actionable biomarkers. MTC accounts for 1% to 2% of thyroid cancers in the U.S. RET mutations are found in up to 50% of sporadic MTC and over 90% of hereditary MTC.

See- "First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion–Positive NSCLC".; Caicun Zhou, M.D., Ph.D., Benjamin Solomon, M.B., B.S., Ph.D., Herbert H. Loong, M.B., B.S., Keunchil Park, M.D., Ph.D., Maurice Pérol, M.D., Edurne Arriola, M.D., Ph.D., Silvia Novello, M.D., Ph.D., Baohui Han, M.D., Ph.D., Jianying Zhou, M.D., Andrea Ardizzoni, M.D., M. Perez Mak, M.D., Ph.D., Fernando C. Santini, M.D., et al., for the LIBRETTO-431 Trial Investigators. October 21, 2023 DOI: 10.1056/NEJMoa2309457/

See-"Phase III Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer"- Julien Hadoux, M.D., Ph.D., Rossella Elisei, M.D., Marcia S. Brose, M.D., Ph.D., Ana O. Hoff, M.D., et al., for the LIBRETTO-531 Trial Investigators. October 21, 2023 DOI: 10.1056/NEJMoa2309719.