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BATTLE TrialBiopsy-Driven Therapies Feasible, Can Benefit LC

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BATTLE Trial: Biopsy-Driven Therapies Feasible, Can Benefit Lung Cancer Patients

Elsevier Global Medical News. 2010 Apr 19, JS MacNeil

Selecting targeted therapies based on biomarkers in individual tumor specimens led to improved outcomes for chemotherapy-refractory lung cancer patients in a prospective phase II clinical trial that promises to be a landmark in developing personalized medicine for lung cancer.

Disease control rates ranged from zero to 100% in five biomarker-based groups of patients, depending on how well a particular drug corresponded with a group's molecular features, lead researcher Dr. Edward S. Kim reported April 18 in a plenary session at the annual meeting of the American Association for Cancer Research in Washington.

The BATTLE I (Biomarker-integrated Approaches of Targeted Therapy for Lung cancer Elimination) trial was conducted by researchers at the University of Texas M.D. Anderson Cancer Center in Houston.

Notably, patients with KRAS mutations were more likely to be helped by sorafenib (Nexavar), while those with epidermal growth factor receptor (EGFR) mutations did better when treated with erlotinib (Tarceva) alone or in combination with bexarotene.

Although it has indications for renal and hepatocellular tumors, multi-targeted sorafenib is not approved for non-small cell lung cancer (NSCLC). Erlotinib, an EGFR inhibitor, is approved for second-line treatment of locally advanced or metastatic NSCLC.

"Certainly the study would indicate that sorafenib is worthy of further study," said Dr. Paul A. Bunn, Jr., a professor of oncology at the University of Colorado in Aurora, who discussed the BATTLE I trial at the plenary. Sorafenib had the best overall outcomes of all the drugs used in the study, he noted in an interview.

Perhaps even more important, BATTLE I showed that its unusual biopsy-driven trial design can be used in lung cancer, according to comments by Dr. Bunn and Dr. Deepa Subramaniam, interim chief of the Georgetown University Lombardi Cancer Center in Washington. At a press briefing, Dr. Subramaniam lauded the investigators for "accomplishing what was a major feasibility question."

The trial was too small with too many drugs and treatment groups to change clinical practice, Dr. Bunn explained in an interview. But more investigators will obtain tumor specimens, and use the trial's unusual design in a search for biomarkers that can help clinicians make treatment decisions.

"This is a trial that is going to help change the way trials are done," said Dr. Bunn, executive director of the International Association for the Study of Lung Cancer.

In what they said was a first in a lung cancer study, the investigators required core needle biopsies from more than 300 heavily pretreated patients enrolled in the BATTLE program. "We felt discomfort in asking them to undergo another biopsy," Dr. Kim said at the press briefing, recalling that not even the investigators were sure they could obtain fresh tumor specimens from these patients. Despite the concerns, pneumothorax incidence was 11.5%; only 6.5% of patients had treatment-related grade 3/4 toxicity.

Within two weeks of each biopsy, a thoracic research laboratory tested the specimens for 11 biomarkers, and the team used the results to randomize 255 patients in five groups based on signalling pathways. In the first phase of the trial, about 40% of participants were equally randomized among four treatments: erlotinib, sorafenib, vandetanib (Zactima, an experimental drug), or erlotinib with bexarotene.

The second phase built on the first phase results, using a "novel Bayesian randomization method," also called "adaptive randomization," so that the other 60% of patients were more likely to receive therapies that could benefit them based on their tumor's characteristics. Dr. Kim reported the proportion of patients achieving the trial's primary end point, disease control at 8 weeks, increased from 37% in phase I to 42% in phase II.

The investigators did not report complete or partial responses. Median overall survival reached 9 months for the population as a whole, and 39% of patients survived 1 year, according to the abstract.

Among the findings for the biomarker-based groups, Dr. Kim reported:

- Erlotinib produced better disease control in patients with an EGFR mutation (P = .04).

- Erlotinib plus bexarotene benefited patients who were positive for Cylin D1 by immunohistochemistry and those with EGFR amplification by fluorescence in situ hybridization (FISH) (P=.006).

- Sorafenib benefited patients with wild type EGFR (P = .012) or high polysomy (P = .048).

- Among patients with EGFR mutations and amplification by FISH, 100% of those treated with erlotinib achieved disease control, but no one did so if treated with sorafenib.

- Vandetanib produced improvement in patients whose vascular endothelial growth factor 2 receptor showed an increase with immunohistochemistry (P=.05).

A streamlined BATTLE II trial is under way, and BATTLE III is being planned, according to the investigators. While the search for biomarkers goes on, they are urging clinicians to start taking core biopsies in lung cancer patients. Dr. Kim said the group plans to publish data on where and how best to obtain tissue specimens, which can be difficult in previously treated patients.

Testing for EGFR mutation and rearrangement of the ALK gene, which is highly responsive to a novel drug, (PF-02341066) could be done now, even without formal recommendations relating these markers to treatments, Dr. Roy S. Herbst, second author, professor, and chair of thoracic medical oncology at M.D. Anderson, said during the press briefing.

"We need a good marker and a good drug," Dr. Herbst said of the goals of the ongoing investigation.

Support for the BATTLE trial came from a grant from the U.S. Department of Defense.

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