Retevmo (selpercatinib)

Several multikinase blockers targeting RET have been approved by the FDA for the treatment of cancer: (i) vandetanib for medullary thyroid carcinoma and (ii) cabozantinib, lenvatinib, and sorafenib for differentiated thyroid cancer. Pralsetinib is a specific RET blocker that is FDA-approved for the treatment of medullary thyroid cancer, RET-fusion positive thyroid cancer and NSCLC. Selpercatinib is FDA-approved for the management of RET-mutant medullary thyroid cancer, RET-fusion-positive thyroid cancer, and other RET-fusion-positive solid tumors...Currently, the number of new cases of thyroid cancer bearing RET mutations or RET-fusion proteins is about 13,000 per year and the number of cases of RET-driven NSCLC range from about 2000-4000 per year in the United States. Inactivating RET mutations result in Hirschsprung disease, a congenital disorder leading to aganglionosis of the gastrointestinal tract.

The validation of the NMA results could be assessed for progression-free survival of selpercatinib versus pembrolizumab + pemetrexed + platinum-based chemotherapy. Enabling the earlier assessment of single-arm trials, via pseudo comparator arms, will provide payers with greater confidence in anticipated treatment effects. In light of the joint clinical assessment, incorporation of single-arm trials within NMA facilitates the reporting of predicted treatment effects relative to multiple relevant comparators, which is important when considering the use of interventions for the global market.

P=N/A, N=15, Completed, University of Pisa

Given oncologic necessity, selpercatinib was reintroduced at a reduced dose (40 mg daily) without recurrence of severe transaminitis. This case highlights that selpercatinib can cause clinically significant hepatocellular DILI and underscores the diagnostic value of liver biopsy in distinguishing DILI from autoimmune hepatitis, particularly when considering safe dose modification and rechallenge.

The results of Study LIBRETTO-431, an ex-US multiregional, open-label, randomized, active-controlled trial of selpercatinib versus platinum-based and pemetrexed chemotherapy with or without pembrolizumab in patients with treatment-naïve advanced rearranged during transfection fusion-positive non-small cell lung cancer, highlight the challenges of interpreting OS in trials with high crossover rates and variable postprogression therapies. Trial results demonstrated a large improvement in progression-free survival with an acceptable safety profile, but were accompanied by an immature OS analysis with a hazard ratio of 1.26, favoring the chemoimmunotherapy arm. Regardless of the position of OS in the end point hierarchy, it is critical that OS analyses include prespecified plans for data collection and analytical methods to account for the potential impact of postprogression therapies on the interpretation of study results.

Early multi-kinase inhibitors such as vandetanib and cabozantinib demonstrated modest efficacy with significant toxicity, whereas the selective RET inhibitors selpercatinib and pralsetinib have achieved improved response rates and tolerability...Nonetheless, resistance, driven by secondary mutations and bypass signaling, presents a major therapeutic challenge. Ongoing development of next-generation inhibitors and combination strategies aims to overcome resistance and improve patient outcomes.

Drug-induced IL occurs with selpercatinib or pralsetinib treatment. The frequency increases with longer drug exposure. Serial monitoring is essential and when necessary, dose modification. Most cases do not lead to treatment discontinuation.

Oncogenic RET gene rearrangements drive a subset of lung adenocarcinomas (LUAD) and the tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib are approved therapeutics. By contrast, upfront treatment with selpercatinib and crizotinib in orthotopic tumors yielded complete elimination of 7 of 9 TR.1 tumors and both deepened and prolonged the duration of response in TR.2 tumors. The findings provide new insight into mechanisms of acquired resistance through bypass signaling and highlight the therapeutic benefit of simultaneous upfront blockade of driver oncogenes and dominant resistance mechanisms in LUAD.

Given the current pricing, neither selpercatinib as a first-line therapy nor as a second-line therapy was deemed to be cost-effective compared with chemotherapy for advanced NSCLC patients with RET fusions. Further real-world studies of selpercatinib and development of health outcome estimate scales are needed to provide additional evidence for clinicians and health policy decision-makers.

Upon re-evaluation one year later, imaging revealed recurrent paratracheal, pulmonary, hepatic, and possible adrenal metastases, prompting re-initiation of selpercatinib at a reduced dose, which she tolerated and continues to this day with surveillance of symptoms, serial electrocardiograms, laboratory work, and imaging. This case illustrates the aggressive course of RET M918T-mutated MEN2B and underscores the importance of early genetic diagnosis, vigilant surveillance, and continuity of selective RET inhibitor therapy to optimize disease control.

These molecular changes were associated with higher cell motility of TPC-1-SelpRWT1-knockdown. Collectively, these findings suggest that WT1 is a critical regulator involved in tumor plasticity, thereby supporting selpercatinib resistance.

The therapeutic strategy involved an immediate switch from rivaroxaban to therapeutic low-molecular-weight heparin (LMWH) and the initiation of dual targeted therapy with selpercatinib and tepotinib. Upon diagnosis of NBTE, a rapid oncologic work-up is warranted, as ongoing tumor progression is highly likely. This case questions the appropriateness of direct oral anticoagulants in patients with NBTE and active, progressive malignancy.