Retevmo (selpercatinib)

Real-world data showed selpercatinib to be effective in patients with RET fusion-positive NSCLC in Japan, with a favorable safety profile and no new safety concerns.

We also demonstrate that loss of KEAP1 reduces sensitivity of RET fusion-positive cells to selpercatinib, consistent with previous reports that these alterations promote drug resistance in other malignancies. In this study, we comprehensively profile KEAP1 mutations in thyroid tumors, showing that they are more prevalent and functionally significant than previously recognized. These findings position KEAP1 mutations as novel oncogenic variants in thyroid cancer and support the integration of KEAP1/NRF2 pathway profiling into future studies and clinical frameworks.

P2, N=1376, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2026 --> Jan 2027

Prevalence of secondary RET mutations after SRIs was low, underscoring greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide development of novel therapeutic strategies.

This case suggests that selpercatinib rechallenge may be effective in difficult-to-treat RET-positive NSCLC patients, including those with uncontrolled CNS disease.

Off-label combination therapy to treat targeted therapy resistance in advanced NSCLC is feasible in routine clinical practice. Additional real-world evidence is needed to clarify best practices with this emerging approach.

Our report indicates an association between selpercatinib plasma concentration and renal tubular damage, and emphasizes the importance of recognizing selpercatinib-induced tubular injury. This report also provides guidance for the management of these renal manifestations and for rechallenge guided by TDM, highlighting a potential role for TDM in dose determinations after selpercatinib-induced renal toxicity.

Selpercatinib was discontinued, and treatment with intravenous hydration, febuxostat, and furosemide was initiated. This case highlights that potent targeted therapy can trigger TLS even in the absence of conventional risk factors. Early recognition and aggressive management are essential to mitigate risk and allow continuation of effective treatment.

The immunotherapy was well tolerated, but did not have an impact on tumor growth rate at 6 months as measured by calcitonin kinetics.

P3, N=152, Active, not recruiting, Eli Lilly and Company | Trial primary completion date: Jan 2026 --> May 2026

A 67-year-old woman with EGFR exon 19-deleted adenocarcinoma received afatinib followed by long-term osimertinib. CSF liquid biopsy provided actionable, compartment-specific genotyping that outperformed cytology and guided effective retreatment. Incorporating CSF ctDNA into routine evaluation may improve therapeutic alignment across sanctuary sites; when feasible, maintaining EGFR blockade should be considered when CNS involvement is suspected in EGFR-mutated NSCLC in routine practice.