As the focus increases on treating cancer in a tissue-agnostic way based on molecular profile, the Comprehensive Genomic Profiling Plus (CGP+) platform "has put us in a pretty good spot," Caris Life Sciences Inc. chief scientific officer David Spetzler told BioWorld.

Caris, busy in the field for about 10 years, brings a vast suite of CGP+ panels and assays to the collaboration with the National Cancer Institute and Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, better known as ECOG-ACRIN, for the NCI-MATCH precision-medicine trial, in which Caris will notify physicians at more than 1,100 participating clinical sites when its assay identifies gene abnormalities that could make a patient eligible for one of several NCI-MATCH treatments.

Last week, Science published a clinical study showing that the molecular profile of tumor cells – microsatellite instable, or MSI – rather than a tumor-origin approach can drive therapeutic strategy. treating advanced cancer patients who measured MSI-high or with mismatch repair deficiency with Keytruda (pembrolizumab, Merck & Co. Inc.) resulted in 53 percent response rate and 21 percent complete response rate. Prevalence of the profile was evaluated across more than 30 tumor types.

"Typically you need both cancer tissue and normal tissue to be able to determine if a patient is MSI-high, which is the final result that would create an indication for Keytruda," Spetzler said. "We're able to make that determination without the normal tissue," because the Caris methodology is so comprehensive. "Obviously, the immunotherapies are most exciting, but even within particular lineages, it's still highly advantageous to look more broadly [at biomarkers]. Lung cancer is the obvious poster child, where you want to be looking at EGFR, ALK, ROS1, and PD-L1, really right from the beginning. Those are already [targets of] approved compounds. It gets more interesting if you start to look at things coming down the pipeline. Neurotrophic tyrosine kinase [NTRK] is certainly one that's getting some press right now. While it's a rare alteration, the patients that harbor that translocation respond incredibly [well] to targeted therapies."

The matter of tissue-agnostic trials became an especially lively topic of talk as Stamford, Conn.-based Loxo Oncology Inc. said it will ask for approval based on such work for larotrectinib (LOXO-101). Data were presented at this year's American Society of Clinical Oncology (ASCO) meeting in Chicago, and Loxo made known the strategy with FDA just weeks after Keytruda was cleared for use in MSI-H/dMMR tumors regardless of tumor histology. (See BioWorld Today, May 25, 2017, and June 7, 2017.)

FDA action last month with regard to Keytruda is "one of the most significant events to ever happen in oncology," Spetzler said. "You've got the approval of a drug across all solid tumors based on a genetic alteration. It's the first time that's ever happened. What we've seen from the FDA in terms of moving toward these approvals [based on tissue-agnostic trial findings] is going to be exceptionally important. I don't know which one will be next. It could be neurotrophic tyrosine kinase inhibitors [such as Loxo's larotrectinib], but I think the poly ADP ribose polymerase [PARP] inhibitors are probably on that list." PARPs already have been approved in breast and ovarian cancers, with fast-track status in prostate, he noted.

Irving, Texas-based Caris joined the ASCO Targeted Agent and Profiling Utilization Registry (TAPUR) study as one of the first laboratories that will produce test reports optimized for the trial. TAPUR is evaluating efficacy of treatments based on patients' tumor genetic profiles.

Specifically, the experiment is a non-randomized trial that aims to describe the performance, including both safety and efficacy, of commercially available, targeted anti-cancer drugs prescribed for treatment of patients with advanced cancer based on prospectively-defined and potentially actionable genomic variants. The study provides approved targeted therapies that are contributed to the program by collaborating pharmaceutical companies, catalogues the choice of genomic profiling test by clinical oncologists, and thereby hopes to learn about the utility of registry data to develop hypotheses for more trials.

TAPUR is "an exploratory trial at this point," Spetzler said. "There may be arms of it that become registrational but we really have to see the effect size. TAPUR is more about approved drugs in an off-lineage setting, whereas NCI-MATCH is looking more at new drugs. Each of [the trials] has its own niche in terms of looking at understanding the utility of profiling." Whether TAPUR will have registrational elements is "a challenge to answer, because every single arm is a little different in terms of the frequency of alteration that would enable a patient to get enrolled there," he said. "Some of the more rare components will cause the trial to last longer.

'The right thing to do'

Caris had a presence at the recent ASCO meeting, too, where one study demonstrated the ability of CGP+ for use in personalized medicine and drug discovery and development through results identifying the frequency of homologous recombination deficiencies from about 53,000 tumors. More data resulted from an analysis of the 7,000 tumor database with total mutational load status to identify cancers that could respond to immunotherapies.

"We're of the mindset that the tissue-agnostic approach is really the right thing for all cancers," Spetzler said. "Cancer is a disease of the molecular pathway more than it is a disease of the lineage. It's definitely true that certain pathways are more abundantly and commonly altered in various lineages, which is why we have grown up with that lineage-based approach. But there are always exceptions. Biology is nothing if not full of exceptions. As we begin to understand those exceptions, we're going to be changing our definitions. We can already see that coming. Staging next year is going to incorporate molecular information," so that not just morphology but also biomarkers will be included.

Two subjects raised in relation to tissue-agnostic testing and approvals have to do with the small trial sizes and the difficulty of deciding if such a compound should be used instead of another.

"What you really want to do is say, 'OK, what is the probability of the patient responding to that drug?'" Spetzler said. "Say we're looking at ovarian cancer and they've got a BRCA mutation and so would be eligible for a PARP inhibitor, but they're also MSI-high, so they would be available for [Keytruda]. There's no direct data to compare them, so you have to look at the overall toxicity profile and response profile for each compound and make a decision. Doctors do that every single day."

Regarding the smaller trials, Spetzler said "the key really comes down to the effect size. You don't need a lot of patients if the response is huge. You've nailed it. There's a significant gap between statistics and what people instinctually trust – that's just the nature of the complexity of what's going on. We're all well aware that you can manipulate statistics and you have to be careful there, [but] you don't need a lot of patients to know it's the right thing to do."