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In LCMC Study, Longer Survival for Patients Receiving Genotype-guided Therapy

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NEW YORK (GenomeWeb) — Members of the Lung Cancer Mutation Consortium have reported that patients who received targeted therapy based on their molecular testing results had significantly improved survival compared to those who did not, in study of more than 1,000 lung cancers tested by the consortium for driver mutations over a period of four years.

The study, which appeared yesterday in the Journal of the American Medical Association, evaluated the molecular testing results and outcomes of approximately 1,000 lung adenocarcinoma patients tested by 14 participating LCMC centers between 2009 and 2012, under the consortium's effort to evaluate the feasibility and impact of genotyping to guide cancer therapy.

Comparing patients' outcomes, the study found that those who received genotype-driven therapy lived longer — 3.5 years on average — than those who had an oncogenic driver but did not get genotype-driven treatment, or those who tested negative for any driver mutations — a median survival of only 2.4 years and 2.1 years respectively.

Though only 28 percent of the cohort received therapy with a targeted agent based on their results, and their outcomes differed from those given standard therapy by only about a year, Marc Ladanyi, one of the study's co-authors told PGx Reporter that though the improvement offered by molecular profiling is small, it is worthwhile to both oncologists and patients.

"I'm not an oncologist but if you speak to oncologists I think they will tell you it's absolutely worth it. The survival curves are just one part of the story. The other part is that these [targeted] treatments are much better tolerated," he said. "Unfortunately, these patients are not getting long-term cures, but they do live longer and their quality of that longer life is better," he said.

Since its initiation, participant centers in the LCMC have adopted a variety of different testing tools, including mass spectrometry, Sanger sequencing, and multiplex hotspot panels, but all the approaches have focused on a set of 10 oncogenic drivers, including EGFR and KRAS mutation, ALK rearrangements, and other alterations.

These targets were chosen based on their frequency in the adenocarcinoma population, their ability to be tested in the context of a CLIA-certified lab, and the availability of associated targeted therapies — either approved agents or those in trials existing at the start of the study in 2009, the group wrote.

In their new study, the researchers described participating centers' results testing for EGFR mutations alone or for the full panel of 10 genes over a four-year period in about 1,000 patients. They then analyzed patient outcomes in light of whether they received or didn't receive genotype-directed therapy.

Amid growing use of genetic testing to guide therapy with select targeted agents, most frequently EGFR and ALK inhibitors, the LCMC study is the first, the authors wrote, to present data "from a prospective multi-institutional investigation supporting the concept that [targeted treatment] can be accomplished with more drivers and drugs with the potential to change the approach to lung cancer management."

According to the study authors, only about 70 percent of patients eligible for LCMC testing during the study period actually had adequate tissue to be enrolled in the study. And while 1,007 patients were successfully tested, only 733 were assessed for all 10 target genes, while the rest were tested only for EGFR mutations.

In this 733-patient subset, the researchers found that more than 60 percent had a potentially actionable oncogenic driver mutation, and of those, 275 patients received therapy with a targeted agent based on their genotype.

Including those who were tested only for EGFR mutations back into the analysis, the 275 patients who received genotype-directed therapy represented 28 percent of the overall 1,007-patient cohort and 44 percent of those with identified driver mutations.

A total of 146, or 83 percent, of 175 patients with EGFR(s) mutations were treated with erlotinib or another EGFR inhibitor either alone or in combination. Of another 35 patients with EGFR(o) mutations, 23 were treated with an EGFR inhibitor or another targeted agent, the authors reported.

Fifty-two of 80 patients with an ALK mutation got crizotinib, and about half of 23 patients with ERBB2-mutant lung cancer received an ERBB2-targeted agent. Nine percent, or 11, of 245 patients with KRAS mutations were treated with investigational targeted drugs.

Comparing patients' outcomes, the group found that the patients who received genotype-driven therapy lived the longest — 3.5 years on average versus 2.4 years for those who had an oncogenic driver but did not get genotype-driven treatment and only 2.1 years for patients for whom testing revealed no targetable mutation.

When the researchers reexamined outcomes excluding those patients with EGFR- and ALK-positive cancers, they found that for patients with other oncogenic drivers, survival was still clearly longer among those who received targeted therapy based on their genotype versus those who did not.

Overall, the authors wrote, KRAS mutations were the most frequently detected in the study cohort, found in 182 of the 466 mutation-positive patients. The consortium also detected 122 sensitizing EGFR mutations, 57 ALK rearrangements, as well as a number of other mutations in EGFR, ERBB2, BRAF, NRAS, MEK1, and MET.

According to the researchers, the percentage of patients the LCMC found to have potentially actionable mutations, as well as the number who were treated based on their results, matched well with results from studies by other centers.

Ladanyi said that previous randomized studies have also shown a survival benefit for those receiving genotype-directed therapy.

The consortium's study was not randomized, and thus is only a proof of concept that individuals who receive treatment matched to their cancer's driving mutations live longer than those who don't. But Ladanyi said the team found it promising that LCMC's results match closely with other teams' findings.

"This is more a study that looks at how this can work across many different centers and shows that you still see the survival advantage," he said. "The appeal of the study was to show that this paradigm of identifying mutations and selecting targeted therapies according to those mutations is something that really can be applied [across] many, many centers."

The authors also wrote that as multiplexed testing becomes more standard for lung cancer patients and as more targeted therapies enter clinical trials, the percentage of patients treated based on their genotype should grow.

Although some industry observers have identified the lack of targeted agents as a major hindrance to the advancement of personalized medicine, Ladanyi is not worried. "Drugs are coming," he said.

Moreover, he explained, another key aspect of the LCMC is that it allows the creation of cross-institutional clinical trials that can have a wider reach to recruit sufficient numbers of patients with much less frequent cancer driver mutations.

"There are some subsets of lung cancer patients whose cancers are driven by mutations that are not very common … So, it can be difficult for any single center to identify enough patients with that mutation eligible for a clinical trial," he said. "But obviously by having a consortium like this with high-quality analysis across multiple centers, you can start accruing numbers from those smaller subsets that can really become informative for clinical trials."

An editorial in the same issue of JAMA by Wake Forest University's Boris Pasche and Stefan Grant from the University of Alabama, Birmingham echoed this sentiment. "The approach presented in this study should be used as a starting point for the implementation of a new clinical trial model employing large multicenter clinical trials offering experimental treatment for multiple targets," the two wrote.

"At the same time, the research community must modify its clinical trial methodology," they added, "to incorporate the genomic features of tumors rather than simply using traditional histologic classification."

Moving forward, Ladanyi said that since the study period many of the consortium members have expanded their testing strategy to include additional oncogenes, and some, like Memorial Sloan Kettering Cancer Center, have adopted larger targeted next-gen sequencing panels into their clinical programs.

Currently, he said MSKCC still uses single-gene or limited multiplex testing as a first-line tool for many malignancies, including lung cancer and melanoma, but it also is offering a newer broad 341-gene NGS test for those patients for whom standard testing is negative or those with tumor types not served by simpler tests.

The LCMC has also expanded to include 16 centers, he said.

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