RET fusions represent a rare mechanism of acquired resistance in EGFR-mutant NSCLC. Combined RET and EGFR inhibition may offer clinical benefit, particularly in patients with co-occurring alterations. Personalized ddPCR-based liquid biopsy is a promising tool for real-time, non-invasive monitoring of treatment response and resistance evolution.

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.

P1/2, N=456, Recruiting, Sunshine Lake Pharma Co., Ltd. | Trial primary completion date: Jul 2025 --> Dec 2026

P1, N=12, Not yet recruiting, M.D. Anderson Cancer Center

P4, N=25, Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

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.

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.