1. Objective response rate was 43.9%. Patients treated with selpercatinib also experienced improved overall response and time on treatment than their previous respective therapies.

2. Most common adverse events of grades 3 or higher were hypertension, increased alanine aminotransferase and increased aspartate aminotransferase.

Evidence Rating Level: 2 (Good)

Study Rundown: Recently, there have been genome-driven oncology therapies that showed clinical benefit in the setting of specific biomarkers, regardless of the cancer type. Selpercatinib (a selective RET kinase inhibitor) has previously shown efficacy in RET fusion-positive thyroid and lung cancers. This study explored the efficacy and safety of selpercatinib in all other RET-positive cancer types and this is the 1st interim analysis. Tumour-agnostic patients with RET fusion-positive cancer were chosen, all of whom had disease progression after previous systemic therapies or had no satisfactory therapeutic options. Objective response rate (ORR), per independent review committee and investigator assessment, was 43.9% for both. At the time of the interim analysis, progression-free survival (PFS) and duration of response both had clinically meaningful improvements. The safety profile of selpercatinib was consistent with previous reports. The most common treatment-emergent adverse events (TEAEs) of grades 3 or higher were hypertension, increased alanine aminotransferase and increased aspartate aminotransferase. The strength of this interim study is that it highlights a potential therapeutic agent for tumour-agnostic populations, which currently only have 2 approved treatment options. Limitations to this interim study include a short follow-up, a small sample size, a non-randomized patient population, and no comparison group. Overall, selpercatinib is a promising treatment option for tumour-agnostic populations with RET fusion-positive tumours.

Click to read the study in The Lancet Oncology

Relevant Reading: Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes

In-Depth [prospective cohort]: This international phase 1/2 basket trial included 41 tumour-agnostic patients with RET fusion-positive cancers other than thyroid or lung cancers. These patients all had disease progression after previous systemic therapies or had no satisfactory therapeutic options. ORR, both by independent review committee and investigator assessment was 43.9% (95% confidence interval [CI], 28.5 to 60.3; 18 of 41 patients). From an exploratory ad-hoc intra-patient analysis of best overall response, responses to selpercatinib were seen in 46% of patients who previously received systemic therapy. Median PFS by independent review committee was 13.2 months (95% CI, 7.4 to 26.2) and 11.1 months (95% CI, 5.6 to 19.1) as per investigator assessment. Median duration of response was 24.5 months (95% CI, 9.2 to not evaluable) and 18.4 months (95% CI, 9.2 to not evaluable), respectively. The most common TEAEs of grades 3 or higher were hypertension (22% of patients), increased alanine aminotransferase (16%) and increased aspartate aminotransferase (13%). Overall, in this interim analysis, selpercatinib showed clinically meaningful activity in a tumour-agnostic cohort with RET fusion-positive tumours.

Image: PD

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