Improved Treatment Outcomes by Using Patient Specific Drug Combinations in Mammalian Target of Rapamycin Activated Advanced Metastatic Cancers

Timothy Crook; Darshana Patil; Andrew Gaya; Nicholas Plowman; Sewanti Limaye; Anantbhushan Ranade; Amit Bhatt; Raymond Page; Dadasaheb Akolkar

doi:10.3389/fphar.2021.631135

Improved Treatment Outcomes by Using Patient Specific Drug Combinations in Mammalian Target of Rapamycin Activated Advanced Metastatic Cancers

Front Pharmacol. 2021 Apr 16:12:631135. doi: 10.3389/fphar.2021.631135. eCollection 2021.

Authors

Timothy Crook¹, Darshana Patil², Andrew Gaya³, Nicholas Plowman⁴, Sewanti Limaye⁵, Anantbhushan Ranade⁶, Amit Bhatt⁶, Raymond Page⁷, Dadasaheb Akolkar²

Affiliations

¹ Broomfield Hospital, Chelmsford, United Kingdom.
² Datar Cancer Genetics, Nasik, India.
³ HCA Healthcare United Kingdom, London, United Kingdom.
⁴ St Bartholomew's Hospital, London, United Kingdom.
⁵ Kokilaben Dhirubhai Ambani Hospital, Mumbai, India.
⁶ Avinash Cancer Clinic, Pune, India.
⁷ Worcester Polytechnic Institute, Worcester, India.

Abstract

Background: Activation of the mTOR signaling pathway is ubiquitous in cancers and a favourable therapeutic target. However, presently approved mTOR inhibitor monotherapies have modest benefits in labeled indications while poor outcomes have been reported for mTOR inhibitor monotherapy when administered in a label-agnostic setting based on univariate molecular indications. The present study aimed to determine whether patient-specific combination regimens with mTOR inhibitors and other anticancer agents selected based on multi-analyte molecular and functional tumor interrogation (ETA: Encyclopedic Tumor Analysis) yields significant treatment response and survival benefits in advanced or refractory solid organ cancers. Methods: We evaluated treatment outcomes in 49 patients diagnosed with unresectable or metastatic solid organ cancers, of whom 3 were therapy naïve and 46 were pre-treated in whom the cancer had progressed on 2 or more prior systemic lines. All patients received mTOR inhibitor in combination with other targeted, endocrine or cytotoxic agents as guided by ETA. Patients were followed-up to determine Objective Response Rate (ORR), Progression Free Survival (PFS) and Overall Survival (OS). Results: The Objective Response Rate (ORR) was 57.1%, the disease Control rate (DCR) was 91.8%, median Progression Free Survival (mPFS) was 4.9 months and median Overall Survival (mOS) was 9.4 months. There were no Grade IV treatment related adverse events (AEs) or any treatment related deaths. Conclusion: Patient-specific combination regimens with mTOR inhibition and other anti-neoplastic agents, when selected based on multi-analyte molecular and functional profiling of the tumor can yield meaningful outcomes in advanced or refractory solid organ cancers. Trial Registration: Details of all trials are available at WHO-ICTRP: https://apps.who.int/trialsearch/. RESILIENT ID CTRI/2018/02/011808. ACTPRO ID CTRI/2018/05/014178. LIQUID IMPACT ID CTRI/2019/02/017548.

Keywords: Akt; ETA; PI3K; PIK3CA; encyclopedic tumor analysis; mTOR; mTOR inhibitor; rapalog.