Table 4: FDA Benefit-Risk Analysis.

Dimension	Evidence and Uncertainties	Conclusions and Reasons
Analysis of Condition	RET gene fusions are somatic alterations which lead to formation of distinct RET oncoproteins.1,22 RET fusions are observed in <1% of patients with solid tumors other than NSCLC and thyroid cancer.1,2,3 The rarity of these tumors limits knowledge of alteration-specific prognosis, but survival is poor for most patients with advanced solid tumors that have progressed on or following prior systemic treatment, with 5-year OS ranging from 3% to 40%.4	Advanced RET fusion-positive solid tumors are a rare group of life-threatening malignancies with poor survival.
Current Treatment Options	While selpercatinib and pralsetinib are selective oral RET inhibitors granted accelerated approval in 2020 for patients with RET fusion-positive NSCLC and thyroid cancer, there are no approved therapies for other RET fusion-positive solid tumors. Treatment options for patients with advanced RET fusion-positive solid tumors are the same as those used for patients without a specific driver mutation, although the effectiveness of these treatments has not specifically studied in this subpopulation. For advanced solid tumors, second-line or greater therapies per NCCN guidelines vary by tumor type, are generally chemotherapy-based, with ORRs < 30%.	There is an unmet medical need for patients with locally advanced or metastatic RET fusion-positive solid tumors that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. This conclusion is based on the observed ORRs, DORs, and overall survival (OS) reported for therapies currently used in clinical practice for the treatment of this patient population.
Benefit	Study LIBRETTO-001 is an international, single-arm, dose-escalation and expansion study of selpercatinib in patients with advanced solid tumors harboring RET alterations. The primary efficacy population included 41 patients with locally advanced or metastatic RET fusion-positive solid tumors other than NSCLC and thyroid cancer that had progressed on or following prior systemic treatment or who had no satisfactory alternative treatment options. Patients with 10 of 14 tumor types with a variety of fusion partners had objective responses by BICR, and the overall confirmed ORR per RECIST 1.1 as determined by BICR was 44% (95% CI 28, 60) with median DOR 24.5 months (95% CI 9.2, NE).	The observed ORR and DOR, in the setting of a genetically-based biologic rationale and the existing approvals in advanced RET fusion-positive NSCLC and thyroid cancer, are clinically meaningful in the context of the poor prognosis of the disease and the limited available approved therapies. The Applicant will submit data from an ongoing clinical trial to further characterize ORR and DOR in additional patients with advanced RET fusion-positive solid tumors as a post-marketing requirement for accelerated approval.
Risk and Risk Management	The primary safety population included 796 patients treated with selpercatinib in Study LIBRETTO-001. The most common (≥25%) treatment-emergent adverse events (TEAEs) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache.	The observed safety profile is acceptable in the context of the treatment of a life-threatening disease and is overall consistent with the known adverse effects of selpercatinib. Although selpercatinib can cause serious toxicities, these safety concerns are adequately addressed by information in the product labeling.

Source: Adapted from U.S. Food and Drug Administration, sNDA Multi-disciplinary Review and Evaluation and Approval Package: RETEVMO (selpercatinib).¹⁹