Nationwide Genomic Screening Network Can Be Effective in Identifying Rare Targetable Genetic Alterations

Conference Correspondent

Gedatolisib, a highly potent dual inhibitor of PI3K and mTOR, is expected to have an effect for tumors with PI3K/AKT/mTOR pathway alterations. However, these pathway alterations are rare in patients with small-cell lung cancer (SCLC). Researchers used a nationwide genomic screening network in Japan, known as LC-SCRUM–Japan, to identify patients with relevant mutations, and conducted a phase 2 study of gedatolisib.

A multicenter, single-arm, phase 2 study was conducted to evaluate the efficacy and safety of gedatolisib in patients with advanced SCLC who had genetic alterations in the PI3K/AKT/mTOR pathway. Patients who enrolled had SCLC and targetable genetic alterations that were identified after reviewing data from 154 cancer centers and hospitals in Japan. The primary end point of the phase 2 study was objective response rate, and the planned sample size was 19.

From July 2015 to March 2020, 1035 patients with SCLC were screened. Targetable genetic alterations were identified in 263 patients (25%), including the MYC family (10%), PI3K/AKT/mTOR (7%), RAS (3%), and EGFR (2%).

A total of 15 patients with genetic alterations in the PI3K/AKT/mTOR pathway (2.5% PIK3CA, 3.7% PTEN, and 0.9% other mutations) enrolled in the phase 2 study and received gedatolisib. Their median age was 64 years (range, 52-84 years); 10 patients were male, and 6 patients had received ≥2 prior chemotherapy regimens.

The overall response rate associated with gedatolisib was 0%, and the disease control rate was 20%. Median progression-free survival was 0.9 months (95% confidence interval [CI], 0.4-3 months). Median overall survival was 5.8 months (95% CI, 1.2-15.6 months).

The safety profile of gedatolisib was similar to previous reports. Treatment-related grade 3 adverse events, including hypertension, hypoalbuminemia, oral mucositis, ALT increase, and creatinine increase, were observed in 4 patients. Only 1 patient with PTEN I8fs mutation had durable stable disease after treatment with gedatolisib: their progression-free survival was 6.7 months.

Researchers concluded that use of a large-scale nationwide genomic screening network can be an effective way to identify rare targetable genetic alterations, despite the fact that this phase 2 study did not demonstrate clinical benefit of gedatolisib for patients with advanced SCLC who had genetic alterations in the PI3K/AKT/mTOR pathway.


  • Udagawa H, Ikeda T, Umemura S, et al. Phase II study of gedatolisib for small-cell lung cancer patients with genetic alterations in PI3K/AKT/mTOR pathway based on a large-scale nationwide genomic screening network in Japan (EAGLE-PAT/LC-SCRUM-Japan). J Clin Oncol. 2020;38:suppl (abstract 9064).
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Last modified: November 5, 2020

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