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Molecular Profiling of Cancer Patients Uncovers Combination Treatments in I-PREDICT Study

NEW YORK (GenomeWeb) – Clinical trials in oncology may benefit from relying on personalized combination therapies rather than matching patients to monotherapies, according to a new analysis from the Investigation of Profile-Related Evidence Determining Individualized Cancer Therapy (I-PREDICT) team.

As part of the I-PREDICT study, the University of California, San Diego's Razelle Kurzrock and her colleagues molecularly profiled tumor samples from 149 individuals with stage IV metastatic cancers and used those profiles to suggest combination treatments for those patients. They suspected that personalized combination therapies might yield better outcomes in this patient population.

As they reported today in Nature Medicine, the researchers were able to identify personalized therapies for 88 percent of the patients who underwent treatment. They also calculated matching scores — reflecting the number of mutations in their tumors and the number of given — for these patients to find that a high score predicted both better progression-free and overall survival.

"Our findings suggest that the current clinical trial paradigm for precision oncology, which pairs one driver mutation with one drug, may be optimized by treating molecularly complex and heterogeneous cancers with combinations of customized agents," Kurzrock and her colleagues wrote in their paper.

The I-PREDICT team relied on a combination of genomic analysis using Foundation Medicine's FoundationOne and other tests and, when they could, programmed death-ligand 1 immunohistochemistry, tumor mutational burden, microsatellite instability status, and circulating tumor DNA analyses to profile the patients' tumors. Based on these results, a team of oncologists, pathologists, geneticists, and others devised possible multidrug combinations for each patient.

Eighty-three of the 149 consented patients underwent treatment. The untreated 66 patients deteriorated or died before treatment could begin.

What treatment the patients received was determined by their treating oncologists and was based not only on what the molecular tumor board suggested, but also the patient's preference, possible toxicities, payor coverage, and availability of investigational treatments. This, the researchers noted, reflects current clinical practice in the US.

Of the treated patients, 73 patients — or 88 percent — received a personalized therapy and those who did not received the standard of care. Overall, the researchers reported a matching rate of 49 percent, based on all 149 individuals consented to the study. Other precision oncology trials of predetermined monotherapies often have much lower matching rates in the range of 5 percent to 10 percent, the researchers noted.

As GenomeWeb reported last year from the American Society of Clinical Oncology's annual meeting this rate is even higher than 35 percent rate reported by the WINTHER study, conducted by the WIN Consortium. The researchers involved with WINTHER also reported new data this week regarding the use of transcriptomics to help personalize oncology treatments. 

In their new paper, the researchers suggested that this higher matching rate was due to the study's reliance on a large cancer gene panel and additional molecular markers as well as a short time from the receipt of results to the molecular tumor board meeting and the use of specialists to coordinate quick drug access.

For each patient, the researchers also calculated a matching score based on the number of mutations within their tumors that matched to the drugs they were given, divided by their total number of genomic alterations. High matching scores, the researchers reported, were independent predictors of increased disease control rate, progression-free survival, and overall survival. In particular, they found that progression-free survival could be extended by 30 percent or more when the majority of molecular alterations were targeted.

"Taken together, our findings underscore the safety, feasibility, and importance of designing precision oncology trials that emphasize personalized, individually tailored combination therapies, rather than scripted monotherapies, for patients with lethal cancers," the researchers wrote in their paper.

They noted that another I-PREDICT study group is evaluating such an approach in treatment-naïve patients with aggressive or metastatic disease.