Innovative BATTLE Trials Pair Agents, Biomarkers in NSCLC

Pathways Targeted in BATTLE-2

Targeted agents under study are shown in blue boxes.

Adapted from Herbst RS. Targeting the PI3K/AKT axis: what lies ahead in lung cancer.

Presented at: 13th International Lung Cancer Congress; Huntington Beach, CA; July 19-22, 2012.

As therapy based on cell-signaling pathways has become a priority in cancer research, so has the concept of designing clinical trials that can better target patient populations more likely to benefit from a particular regimen.

In that arena, the phase II BATTLE clinical trial stands out as a groundbreaking effort to advance therapies for patients with non-small cell lung cancer (NSCLC) through an innovative design that allowed researchers to simultaneously analyze multiple agents based on “real-time” biomarker analyses of the individual participants. The BATTLE program is continuing with two ongoing trials, as well as plans for an additional study.

The need for new methods for tackling NSCLC is particularly pressing. Despite treatment advances, the five-year survival rate for all stages of NSCLC is only 17%, and drops as low as 1% for those diagnosed as stage IV, according to the American Cancer Society. Moreover, only 15% of lung cancers are detected when the disease is still localized and outcomes are better.

Targeted agents used in combination with chemotherapy often have faltered in phase III trials in unselected patients with NSCLC, and systemic chemotherapy has remained the mainstay for metastatic disease, with oncologists making treatment decisions based on such clinical factors as age, gender, or performance status.

Against this backdrop, researchers at The University of Texas MD Anderson Cancer Center in Houston led the planning for the first BATTLE trial in 2004. At the time, the molecular landscape for NSCLC was far less characterized than it is today, but the trial’s full name is indicative of its ambitious goals: Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination.

To test their hypotheses, researchers employed an adaptive trial design in which they used information collected early in the trial to assign patients to therapy based on the likelihood of success as the studies continued. The trial depended heavily on developing a biomarker profile for each patient.

Choosing Therapies for First Trial

“We felt the traditional way of testing drugs in combination with chemotherapy was not going to really help us move these drugs forward,” said principal investigator Edward S. Kim, MD, in an interview posted on MD Anderson’s website. Kim, now chair of the Department of Solid Tumor Oncology and Investigational Therapeutics at Carolinas HealthCare System’s Levine Cancer Institute, added, “We felt it was more important to really focus on the patient⎯finding what was unique about that patient’s tumor.”Four promising molecular targets were identified: endothelial growth factor receptor (EGFR), Ras/Raf, retinoid X receptor (RXR)/cyclin D1, and vascular endothelial growth factor (VEGF) or the angiogenesis cascade.

Investigators then selected four therapies to deploy against those signaling pathways: erlotinib (EGFR), vandetanib (VEGFR), erlotinib plus bexarotene (EGFR/ RXR), and sorafenib (KRAS/BRAF). Since no predominant biomarker had been identified yet in NSCLC, investigators used available research to match each patient’s molecular profile with the therapy most likely to benefit him or her.

In order to assess molecular tumor characteristics, the researchers recruited heavily pretreated patients with NSCLC and, during the course of the trial, performed two fresh core needle biopsies⎯with the challenging goal of completing biomarker analyses within 14 days.

In all, 255 of the 341 enrolled patients were randomized for treatment, with the first group of 97 patients randomized equally to the four treatment arms and the following 158 patients assigned through adaptive randomization to trial arms based on their biomarker status. The plan also allowed for patients who progressed to re-enter the trial and be randomized to another treatment, if appropriate.

The primary endpoint was the disease con trol rate (DCR) eight weeks after randomization, assessed through imaging studies, and many of the patients treated achieved that mark. Across all marker groups, 46% of those eligible for analysis (112 of 244 patients) exhibited disease control. In an analysis of 20 biomarker/treatment pairings (including a no-marker group), patients in eight groups exceeded the 0.8 historical probability of a DCR >30%.

For secondary endpoints, the overall median progression-free survival (PFS) was 1.9 months (95% CI, 1.8-2.4) and the median overall survival (OS) was 8.8 months (95% CI, 6.3-10.6). Median OS improved to 9.6 months for those who achieved a DCR at eight weeks, versus 7.5 months for those who did not.

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.

BATTLE-2 Explores New Pathways

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.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.

More Battle Trials in the Works

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.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.