Innovative BATTLE Trials Pair Agents, Biomarkers in NSCLC

Anita T. Shaffer @Shaffer1
Published: Thursday, Feb 07, 2013
The data yielded a trove of information about interactions between biomarkers and targeted therapies. For instance, sorafenib demonstrated a 79% DCR among patients in the KRAS/BRAF marker group (11 of 14). Other effective pairings included erlotinib in the VEGF/VEGFR2 group and vandetanib in the EGFR group.

The study, however, was not designed to generate results that would translate immediately to the clinic. Instead, researchers said the trial is important because it established that real-time biopsies and biomarker analyses are feasible and safe for patients; that interactions between biomarkers and therapies can prospectively guide clinical trial design; and that the outcomes help elucidate the predictive value of the biomarkers for agents with related mechanisms of action.

BATTLE-2 Explores New Pathways

Now, the stage has been set for BATTLE-2, which aims to analyze biomarkers and therapies involving several pathways, including dual targeting of two different combinations.

The phase II trial, which is currently recruiting patients and has an estimated enrollment goal of 450 participants, begins with a baseline biopsy and tissue and blood analysis using several biomarker panels, including a mutation analysis, protein expression, and mRNA signatures.

Patients are being sorted into four arms in two stages, with the first cohort randomized adaptively by KRAS gene mutation status and the second group assigned through “refined adaptive randomization” based on discovery markers and signatures. Notably, patients whose tumors test positive for the EML4-ALK fusion gene or an EGFR mutation are excluded unless they previously failed treatment with an inhibitor aimed at those abnormalities.

The four treatment arms in the trial are: erlotinib, which inhibits EGFR; erlotinib plus MK-2206, for dual targeting of EGFR and the AKT pathways; selumetinib (AZD6244) and MK-2206, for a combination attack on MEK and Akt; and sorafenib, which impedes multiple kinases including Raf and VEGFR.

There is a strong rationale for targeting these pathways, Roy S. Herbst, MD, PhD, a principal investigator on BATTLE-2, said during a presentation at the 13th International Lung Cancer Congress, held in Huntington Beach, California, in July. Herbst, who co-chaired the conference, was one of the architects of the first BATTLE trial at MD Anderson and is now director of the Thoracic Oncology Research program at the Yale Comprehensive Cancer Center in New Haven, Connecticut.

He said the PI3K pathway, whose downstream activity includes Akt activation and mTOR phosphorylation, is an “early and reversible event in lung cancer” and that reactivation of the pathway is associated with acquired resistance to EGFR inhibitors. Thus, the pathway has emerged as a target of interest to pharmaceutical companies.

Likewise, the MEK protein is attracting considerable interest as an anticancer target. MEK plays an important role in the chain of activity in several pathways, including the Ras/Raf signaling channel. Herbst said attempts to target Ras directly in lung cancer have not proved effective, giving impetus to the strategy of dual inhibition of MEK and Akt in one arm of the BATTLE-2 trial.

More Battle Trials in the Works

While BATTLE and BATTLE-2 involve patients with stage IV refractory tumors, the BATTLE-FL trial seeks to relate biomarker status to therapies in patients with advanced NSCLC in the frontline setting. Participants are not candidates for curative treatment and have not received prior chemotherapy.

Depending on their biomarker analysis, patients are sorted into four arms. In one arm, patients receive the chemotherapy drugs carboplatin and pemetrexed, while in the other three arms participants will be treated with that chemotherapy combination plus either bevacizumab, cetuximab, or cixutumumab.

The trial, which began in May 2011, aims to enroll 300 patients and has a primary endpoint of PFS.

Another trial, BATTLE-Prevention, would focus on patients with stages I-III resected adenocarcinomas. The study, which is in the planning stages, would employ a “reverse migration” approach in which knowledge about biomarkers and targeted agents gained through studies in patients with metastatic disease would be used to evaluate therapies with a likelihood of preventing cancer onset or recurrence. Patients would be assigned to targeted therapies based on their biomarker profile.

While the original BATTLE trial has been hailed as a bold vision for the future of personalized medicine, the goals of investigators planning the prevention trial also are sweeping. Researchers envision a future in which customized options are available for patients whether they are current or former smokers at high risk of developing NSCLC, whether they have precancerous lesions, or whether they already have recurrent disease.

“An ideal prevention paradigm would select an intervention based on a personal risk profile that includes both clinical and molecular parameters. There would be a personalized approach for every patient,” Gold et al wrote in Cancer Prevention Research.

Targeted Agents in BATTLE Studies

The original BATTLE study was supported by the US Department of Defense, while collaborators on subsequent trials include the National Cancer Institute and several pharmaceutical companies.

Bevacizumab
(Avastin)

Genentech
The recombinant humanized monoclonal IgG1 antibody inhibits activity of vascular endothelial growth factor (VEGF). Initially approved by the FDA in 2004, bevacizumab is indicated for nonsquamous, non-small cell lung cancer (NSCLC) with carboplatin and paclitaxel for first-line treatment of unresectable, locally advanced, recurrent, or metastatic disease. It also is approved in certain settings for metastatic colorectal cancer, glioblastoma, and metastatic renal cell carcinoma.
Bexarotene
(Targretin)

Eisai
This compound is a member of a subclass of retinoids that selectively activates retinoid X receptors (RXRs). The FDA initially approved the drug in capsule form in 1999 for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy.
Cetuximab
(Erbitux)

Eli Lilly and Company/Bristol-Myers Squibb
This agent is a monoclonal antibody that inhibits the epidermal growth factor receptor (EGFR). First approved in 2004, cetuximab is indicated in several settings for certain patients with advanced or recurrent squamous cell carcinoma of the head and neck, and in metastatic colorectal cancer.
Cixutumumab
(IMC-A12)

Eli Lilly and Company
This investigational molecule, also known as LY3012217, is a fully human IgG1 monoclonal antibody that inhibits insulinlike growth factor 1 receptor (IGF-1R) binding and signaling.
Erlotinib
(Tarceva)

Genentech/ Astellas Oncology
This compound inhibits phosphorylation of tyrosine kinases associated with EGFR. It is approved for treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen, and as maintenance treatment for patients with advanced NSCLC whose disease has not progressed after four cycles of first-line chemotherapy. Erlotinib, initially approved in 2004, also is indicated as firstline treatment in metastatic pancreatic cancer.
MK-2206
Merck/ AstraZeneca
This novel agent is an allosteric inhibitor of the Akt protein with the potential to disrupt aberrant activity in the PI3K/ AKT signaling pathway.
Selumetinib
(AZD6244)

Merck/AstraZeneca
This small molecule inhibits the mitogen-activated protein kinases MEK1 and 2, disrupting activity in the key MAPK pathway. Since MEK kinases are downstream from KRAS, the protein has emerged as a target for KRAS-mutated NSCLC. In December, results of a phase II trial published in The Lancet Oncology indicated that selumetinib improved survival in patients with KRAS-mutated NSCLC in combination with docetaxel versus docetaxel alone.
Sorafenib
(Nexavar)

Bayer HealthCare/Onyx Pharmaceuticals
This compound inhibits multiple kinases including BRAF, VEGFR1, 2, and 3, and RET. Initially approved in 2005, sorafenib is indicated for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma.
Vandetanib
(Caprelsa)

AstraZeneca
This agent, also known as ZD6474, inhibits multiple tyrosine kinases, including members of the EGFR, VEGFR, and RET families. It was approved in 2011 for patients with unresectable locally advanced or metastatic medullary thyroid cancer that is symptomatic or progressive.
Source note: Details on the designs of the BATTLE trials and agents under study used in this article and sidebar are available at www.ClinicalTrials.gov, NCT00409968, NCT01248247, NCT01263782.

Key Research

  • Gold KA, Kim ES, Lee JJ, et al. The BATTLE to personalize lung cancer through reverse migration. Cancer Prev Res. 2011;4(7):962-972.
  • Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer [published online ahead of print April 3, 2011]. Cancer Discov. 2011;1(1):44-53. doi:10.1158/2159-8274. CD-10-0010.
  • Rubin EH, Anderson KM, Gause CK. The BATTLE trial: a bold step toward improving the efficiency of biomarkerbased drug development [published online ahead of print April 3, 2011]. Cancer Discov. 2011;1(1):17-20. doi:10.1158/2159-8274.CD-11-0036.
  • Sequist LV, Muzikansky A, Engleman JA. A new BATTLE in the evolving war on cancer [published online ahead of print April 3, 2011]. Cancer Discov. 2011;1(1):14-16. doi:10.1158/2159-8274.CD-11-0044.
  • Wistuba I. The role of pathology/molecular diagnostics in personalized medicine. Presented at: 13th International Lung Cancer Congress; Huntington Beach, CA; July 19-22, 2012.
  • Zhou X, Liu S, Kim ES, et al. Bayesian adaptive design for targeted therapy development in lung cancer⎯a step toward personalized medicine. Clin Trials. 2008;5;181-193.



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