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Mixed results with genetics-guided cancer therapy

April 10, 2017

Molecular screening of different tumor types led to a matched targeted treatment strategy for a subset of patients with advanced, hard-to-treat cancers, although only a minority of those who were successfully screened and treated derived clinical benefit from the approach, a single-center, single-arm, open-label trial indicated.

Out of a cohort of 1,035 patients, a molecular portrait could be identified in 89% of them, among whom an actionable target was detected in almost half of the group at 49%, reported Fabrice Andre, MD, PhD, of Gustave Roussy Cancer Institute in Villejuif, France, and colleagues. This subsequently led to 199 patients actually receiving a treatment course matched to their specific genomic alternation.

And in this subgroup of patients, clinical benefit as reflected by the percentage of patients who achieved a progression-free survival (PFS) interval on matched therapy (PFS2) that was 1.3-fold longer than the PFS interval achieved on prior therapy (PFS1) was documented in one-third of them, 11% of them being objective responses.

“There are controversies about whether the use of high-throughput genomics could improve outcomes in patients with hard-to-treat cancers,” explained Andre and colleagues in Cancer Discovery. “In the present study, we have shown that tumor sequencing improves outcome in 33% of patients with advanced cancers,” they added. “Although these results are encouraging, only 7% of the successfully screened patients benefited from this approach.”

The Molecular Screening for Cancer Treatment Optimization (MOSCATO) 01 trial involved both adult and pediatric patients with a variety of tumor types. The most common tumors included digestive cancer followed by lung cancer, urological cancers, breast cancer, and head and neck cancer. The median number of prior lines of therapy was 4 and tumor biopsies were successfully taken in the majority of patients.

The approaches used to obtain molecular portraits for the 843 patients in whom such a portrait was identified included targeted sequencing and array comparative genomic hybridization analysis. As investigators noted, both RNA sequencing and whole-exome sequencing were added during the course of the study. “The vast majority of the patients received matched therapy in the context of phase I/II trials,” Andre noted. Complete responses were documented in two patients or 1% of those who received matched treatment.

There were also 20 partial responses, 10% of the treated cohort. Disease stabilized in 52% of the group and 17% had progressive disease. “The median follow-up for progression-free survival on matched therapy or PFS2 was 20 months,” researchers noted, “and median PFS2 was estimated at 2.3 months.” The estimated median overall survival was 11.9 months.

“There are several ways to further improve the efficacy of precision medicine,” Andre suggested. First, researchers need better ways with which to identify genomic alterations. For example, although both RNA and whole-exome sequencing were done in a large proportion of patients in the MOSCATO trial, “they were not useful to drive patients to therapy,” as he pointed out. Researchers also need to be able to more accurately identify which patients might gain from a genomics approach.

Lastly, scientists need to identify targeted combinations of therapies that might improve clinical outcomes, especially for patients who have more than one driver alteration.

Commenting on the study, Leif Ellisen, MD, PhD, of Massachusetts General Hospital Breast Cancer Center in Boston, felt that overall, the MOSCATO 01 trial was an encouraging study.

“There are a few things that you have to remember about this study in particular and the field in general,” Ellisen said. To some degree the “deck was stacked” against the study because patients who previously received standard therapy — including targeted agents against well-established actionable targets — were excluded from this trial.

“In other words, the study had already culled out known successes of genotype-driven therapy,” Ellisen emphasized.

He also pointed out that the median number of prior therapies was four, so investigators were pitted against advanced disease known to be more aggressive and resistant to treatment. “But the bigger picture is that systematically doing genotypic-directed therapy is really a means to a larger end and that larger end is allowing us to collect the data about the relationship between the genotype of a tumor and response to therapy that informs us how we should treat future patients.”

If physicians 30 years ago abandoned chemotherapy for patients with advanced cancer on the grounds that only a minority of them responded to it, “we would never have made any progress in oncology,” he added.

“This is really the same story — because only a minority of patients who benefit from this approach today does not mean that the data we are collecting and correlating with responses is not going to be the thing that allows us to make advances tomorrow as we refine our predictions and more patients can benefit in the future.”

The study was supported by Genentech and Sanofi.

Andre disclosed no relevant relationships with industry. One or more coauthors disclosed relationships with Roche/Genentech, AstraZeneca, Lilly, Servier, Merck, Pfizer, Eisai, Actelion, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Haliodx, Novartis, Sanofi, Pharmamar, and Pierre Fabre.

Ellisen disclosed no relevant relationships with industry.

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