Although a number of studies have reported that targeted therapy is superior to conventional chemotherapy when a tumor has a well-defined genomic variant or biomarker and the patient receives a drug that effectively inhibits that target, the evidence is not conclusive regarding whether matching treatments to the molecular or genomic profiles of patients truly leads to improved outcomes.
Dr. Richard L. Schilsky
“There are now a large number of ongoing or planned randomized controlled trials addressing this fundamental question,” said ASCO Chief Medical Officer Richard L. Schilsky, MD, FACP, FASCO, who was a discussant during the Clinical Science Symposium “New Diagnostics: When Actionable Is Objectionable” on Monday, June 1.
In addition to trials such as the National Cancer Institute (NCI) Molecular Analysis for Therapy Choice (MATCH) and the first ASCO-led trial, Targeted Agent and Profiling Utilization Registry (TAPUR), a number of phase II clinical trials are ongoing as part of the Novartis Signature program, which was the focus of this session. The Signature program began in 2013 with the goal of matching a patient’s genomic profile with pipeline compounds that target molecular abnormality. There are now eight trials at 179 sites across the United States, each of which is testing a different compound, such as buparlisib and dovitinib, in a range of tumor types and/or mutations.
“I’m hopeful that the Signature program, NCI MATCH, and TAPUR will help provide the answer” for whether matching treatments to molecular profiles is beneficial, Dr. Schilsky said.
A key feature of Signature is that it delivers the protocol to the patient, which expedites site initiation. Novartis works with any research-experienced site, including academic and community practices, that accepts their model. If a physician determines that a patient has an actionable mutation, regardless of their tissue type, the physician can contact Novartis to receive a Signature protocol package, which includes institutional review board–approved consent and protocol, allowing for expedited site initiation visits.
Dr. Sarina A. Piha-Paul
“The median start-up time across all of the sites was 4.9 weeks. When you compare this to an industry standard of about 41.0 weeks [to open a trial], this is pretty impressive,” said Sarina A. Piha-Paul, MD, of The University of Texas MD Anderson Cancer Center, who presented at the session (Abstract 106).
The most common tumor types in the Signature program are colorectal and non–small cell lung cancer adenoma, although some rare cancers have been accrued, including gallbladder and anal. Tumor types were excluded if key studies were planned or ongoing or there were data showing no benefit. The most common genetic alterations are RAS (17%) and PIK3CA (16%), although less frequent (< 1%) alterations have been detected.
The primary endpoint of the Signature program is stable disease at 16 weeks. There have been some interesting and exceptional responses, Dr. Piha-Paul said.
Of the 469 patients who received a compound, six achieved partial or complete remission, some which were long lasting (2.4% remission rate). Although this rate may seem disappointing, Dr. Schilsky pointed out that, “patients with tumors likely to benefit from the drugs in this protocol were a priori excluded from participation.”
Going forward, Novartis is interested in opening new Signature trials with combination therapy and applying the Signature trial model to other Novartis-sponsored trials, Dr. Piha-Paul said.
Watch the session: Visit the ASCO Virtual Meeting website.