A phase II trial of mTORC1/2 inhibition in STK11 deficient non small cell lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Clinical Trials

Background:

• Non-small cell lung cancer (NSCLC) with STK11 deficiency lacks targeted therapies.
• STK11 loss drives metabolic reprogramming, including mTORC1 activation and increased glycolysis, presenting a potential therapeutic vulnerability.
• Targeting this metabolic vulnerability with mTORC1/2 inhibition is a novel therapeutic strategy.

Purpose of the Study:

• To evaluate the efficacy of vistusertib, an mTORC1/2 inhibitor, in patients with STK11-deficient NSCLC.
• To investigate potential resistance mechanisms to mTORC1/2 inhibition in this patient population.

Main Methods:

• A Phase II clinical trial (National Lung Matrix Trial, arm B2) involving 54 NSCLC patients, with 49 being STK11-deficient.
• Patients received vistusertib; efficacy was assessed by objective response (OR) and durable clinical benefit (DCB) rates using Bayesian analysis.
• Longitudinal circulating tumor DNA (ctDNA) analysis and in vitro studies were performed to explore resistance mechanisms.

Main Results:

• The estimated true OR rate in STK11-deficient NSCLC with KRAS mutation (B2D) was 9.8%.
• Estimated true DCB rates were 24.4% for B2D and 14.6% for STK11-deficient NSCLC without KRAS mutation (B2S).
• Longitudinal ctDNA revealed SMARCA4 mutation enrichment, and in vitro studies indicated adaptive resistance via AKT reactivation.

Conclusions:

• Vistusertib demonstrated limited clinical benefit in STK11-deficient NSCLC and cannot be recommended in this setting.
• Adaptive resistance mechanisms, including SMARCA4 mutations and AKT reactivation, limit the efficacy of mTORC1/2 inhibition.
• Further research is needed to overcome resistance and develop effective therapies for STK11-deficient NSCLC.