Precision medicine: Evolving trial design for targeted treatment

Physicians can now analyse tumours for the presence of multiple genes and proteins, but thereare currently no guidelines to determine which molecular assays are suitable for metastatic cancers.

Fabrice André, Institut Gustave Roussy

Fabrice André, Institut Gustave Roussy

Physicians can now analyse tumours for the presence of multiple genes and proteins, but thereare currently no guidelines to determine which molecular assays are suitable for metastatic cancers.

Last year, the first Molecular Analyses for Personalized (MAP) Medicine conference explored the use of genomics to help improve therapy selection in this setting.1 New technologies, including next-generation sequencing of tumours, have been validated but the conference concluded that precision medicine trials should be stratified according to the level of evidence available for the identified genomic alterations.1

A number of oncology trials have begun to address the complexities of tumour pathology by identifying drugs that may be highly effective in patients with particular mutations, regardless of their cancer type. Umbrella trials allow testing of multiple treatments targeted to specific tumour pathways in patients grouped according to an identified molecular alteration. Umbrella trials therefore eliminate the need for numerous regulatory and ethical approvals and give drug sponsors access to an existing network of study centres and/or a central pool of patients screened for specific mutations.

Like umbrella trials, basket trials treat by causative mutation, rather than tumour histology. Patients with identified tumour alterations, regardless of cancer type, are matched to a medication targeting that specific mutation or pathway, allowing investigation of multiple, often rare, tumour pathologies (Figure). Although basket trials have resulted in notable successes, including vemurafenib in BRAF V600E-mutated lung cancers, effectively blocking an identified mutation does not necessarily ensure clinical tumour response, and success in one cancer cannot be assumed across other tumour types, as illustrated by a lack of response to vemurafenib in BRAF V600E-mutated colorectal cancer.2 Combination treatment is a rational approach in precision medicine as tumours may exploit alternative biological pathways for survival, although in the aforementioned vemurafenib study, addition of the anti-EGFR antibody cetuximab did not improve outcomes in patients with colon cancer.2

The uncertainties of precision medicine were starkly emphasised in a presentation concerning olaparib in advanced gastric cancer given on Saturday by Dr Yung-Jue Bang of the Seoul National University Hospital, South Korea (Abstract LBA25). Originally, a basket trial of olaparib in patients with recurrent solid tumours who all had BRCA1/2 mutations showed encouraging results in ovarian cancer.3 This finding allowed more targeted investigation, and olaparib maintenance treatment was recently approved for patients with BRCA1/2-mutated ovarian cancer after responding to platinum-based second-line chemotherapy. A phase II trial of olaparib plus paclitaxel in metastatic/recurrent gastric cancer yielded a promising increase in overall survival versus paclitaxel alone, particularly in patients with low levels of ataxia-telangiectasia mutation (ATM), a key activator of DNA damage response,4 suggesting that precision medicine with olaparib may also be a possibility in gastric cancer. Despite these early signals, the phase III GOLD trial failed to show a significant increase in OS for patients with advanced gastric cancer treated with olaparib plus paclitaxel in either the total population or in ATM-negative patients. Pooling resources and patients using novel approaches, like umbrella trials, are vital in identifying new and effective anti-cancer drugs.

1. Swanton C, et al. Ann Oncol 2016;27:1443–8 2. Hyman DM, et al. N Engl J Med 2015;373:726–36 3. Kaufman B, et al. J Clin Oncol 2015;33:244–50 4. Bang YJ, et al. J Clin Oncol 2015;33:3858–65

This article appeared in the Monday edition of the Daily Reporter