With the recognition that tumor molecular phenotypes may predict response to targeted therapies, a number of national multi-center umbrella and basket trials have been initiated in recent years. Umbrella trials enroll patients with a single tumor type, defined by primary anatomic site, and assign various treatments according to the molecular characterization of each case. Conversely, basket trials enroll patients with multiple tumor types, restricting eligibility according to biomarker status. Examples of both models abound, including the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis (I SPY) trials in breast cancer (1), Lung Master Protocol (Lung MAP) trial in advanced squamous lung cancer (2), Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) in surgically resected non-small cell lung cancer (NSCLC) (3), Lung Cancer Mutation Consortium (LCMC)-associated trials in advanced lung adenocarcinoma (4), the National Cancer Institute (NCI)-Molecular Analysis for Therapy Choice (NCI MATCH) Trial (5), and the Targeted Agent and Profiling Utilization Registry (TAPUR) (6), sponsored by the American Society of Clinical Oncology (ASCO) in previously treated advanced solid tumors.
These efforts require tremendous resources and coordination, and they would not be undertaken without an earlier generation of studies that demonstrated feasibility. Chief among these earlier trials is the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) program, a prospective, biopsy-mandated, biomarker-based, adaptive randomized clinical trial platform for patients with advanced NSCLC (7,8). Recognizing that archival tumor tissue from the time of diagnosis may not accurately reflect the current biomarker status of the tumor, the BATTLE trials pioneered the use of real-time biopsies and biomarker analysis to assign patients to specific treatment cohorts. Despite concerns over the willingness of patients with metastatic lung cancer to undergo yet another round of invasive procedures, as well as the associated risks, the BATTLE trials demonstrated this approach to be highly doable.
The BATTLE trials also pioneered the use of adaptive randomization, which permits efficient pairing of biomarkers and therapeutic agents and assigns patients to the treatment with the greatest potential benefit on the basis of cumulative data (9). For instance, in BATTLE-2, the first 70 patients underwent equal randomization to 1 of 4 treatment arms: (I) the epidermal growth factor receptor (EGFR) inhibitor erlotinib; (II) erlotinib plus the AKT inhibitor MK-2206; (III) the MEK inhibitor AZD6244 plus MK-2206; and (IV) the multi-targeted [RAF/MEK/ERK pathway, vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR)] kinase inhibitor sofafenib. Subsequently, adaptive randomization incorporating 8-week disease control status [previously shown to correlate with overall survival (10)], KRAS mutation status and treatment was used to calculate and continuously update the posterior probability of efficacy for each treatment arm. This process, in turn, was designed to allow more patients to be assigned to effective therapies and fewer patients to be assigned to less effective therapies.
BATTLE-2 capitalized on the experience and knowledge gained during and after BATTLE-1, including the promising clinical effect of sorafenib and preliminary efficacy of MEK and AKT inhibitors, including in mutant KRAS tumors (11-17). Despite these advantages, BATTLE-2 made only modest inroads into the thorny challenge of pre-treated advanced NSCLC. The 8-week disease control rate was 48%, comparable to that observed in BATTLE-1. Overall, there was no significant association between 8-week disease control rate and KRAS mutation status. As might be expected, performance status predicted outcomes. Consistent with results from earlier trials of EGFR inhibitors (18,19), patients with KRAS mutant tumors had significantly longer PFS if treated with therapy that did not contain erlotinib (P=0.04).
Ultimately, the trial failed to identify any new promising treatments or predictive biomarkers. The use of EGFR inhibitors remains largely confined to patients with tumors harboring classic activating EGFR mutations (20,21). The search for effective treatments for KRAS mutant tumors—the second most common genomic alteration in human cancer following p53 mutations—continues apace, with efforts focusing on inhibition of effector pathways, inhibition of post-translational modification, synthetic lethality, and development of direct KRAS G12C inhibitors (17,22,23).
That the BATTLE-2 trial already seems somewhat outdated is testament to the incredible, unprecedented pace of discovery and advances in lung cancer and other malignancies. Multiplex, next-generation sequencing now provides simultaneous analysis of hundreds of cancer-related genes using similar quantities of tissue, within a similar time frame, and at comparable cost as those of single-gene assays such as Sanger sequencing (24). Particularly for patients with lung cancer, for whom biopsy of the primary site requires an invasive procedure and conveys risk of pneumothorax, the emergence of blood- and urine-based tumor genomic assays represents a major advantage. These platforms analyze circulating or cell-free tumor DNA and provide a spectrum, sensitivity, and specificity of genomic analysis comparable to that of tissue testing (25). Finally, the emergence of immunotherapy-based regimens, which have improved efficacy and tolerability compared to conventional chemotherapy, has revolutionized the treatment of advanced NSCLC (26-29). How these new drugs are best integrated into precision medicine remains to be seen.
Despite these seismic shifts in the lung cancer landscape, the BATTLE trials have not lost relevance. The willingness of patients to undergo additional testing and await results before treatment, the ability to perform complex biomarker testing with rapid result turnaround, and the coordination and conduct of trials with dynamic designs remain key concepts as we continue the war on cancer, one battle at a time.
The authors thank Ms. Dru Gray for assistance with manuscript preparation.
Funding: This work was supported by a National Cancer Institute (NCI) Midcareer Investigator Award in Patient-Oriented Research (K24CA201543-01; to DE Gerber).
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Carey LA, Winer EP. I-SPY 2—toward more rapid progress in breast cancer treatment. N Engl J Med 2016;375:83-4. [Crossref] [PubMed]
- Herbst RS, Gandara DR, Hirsch FR, et al. Lung Master Protocol (Lung-MAP)-a biomarker-driven protocol for accelerating development of therapies for squamous cell lung cancer: SWOG S1400. Clin Cancer Res 2015;21:1514-24. [Crossref] [PubMed]
- Gerber DE, Oxnard GR, Govindan R. ALCHEMIST: Bringing genomic discovery and targeted therapies to early-stage lung cancer. Clin Pharmacol Ther 2015;97:447-50. [Crossref] [PubMed]
- Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014;311:1998-2006. [Crossref] [PubMed]
- Colwell J. NCI-MATCH trial draws strong interest. Cancer Discov 2016;6:334. [Crossref] [PubMed]
- TAPUR: Testing the use of Food and Drug Administration (FDA) approved drugs that target a specific abnormality in a tumor gene in people with advanced stage cancer (TAPUR). NCT02693535. Available online: https://clinicaltrials.gov/ct2/show/NCT02693535
- Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov 2011;1:44-53. [Crossref] [PubMed]
- Papadimitrakopoulou V, Lee JJ, Wistuba II, et al. The BATTLE-2 study: a biomarker-integrated targeted therapy study in previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2016. [Epub ahead of print]. [Crossref] [PubMed]
- 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;5:181-93. [Crossref] [PubMed]
- Berry DA. Bayesian clinical trials. Nat Rev Drug Discov 2006;5:27-36. [Crossref] [PubMed]
- Dingemans AM, Mellema WW, Groen HJ, et al. A phase II study of sorafenib in patients with platinum-pretreated, advanced (Stage IIIb or IV) non-small cell lung cancer with a KRAS mutation. Clin Cancer Res 2013;19:743-51. [Crossref] [PubMed]
- Paz-Ares L, Hirsh V, Zhang L, et al. MISSION Trial—A phase III, multi-center, placebo-controlled trial of sorafenib in patients with relapsed or refractory predominantly non-squamous NSCLC after 2 or 3 previous treatment regimens. J Thorac Oncol 2015. [Epub ahead of print]. [PubMed]
- Wakelee HA, Lee JW, Hanna NH, et al. A double-blind randomized discontinuation phase-II study of sorafenib (BAY 43-9006) in previously treated non-small-cell lung cancer patients: eastern cooperative oncology group study E2501. J Thorac Oncol 2012;7:1574-82. [Crossref] [PubMed]
- Tolcher AW, Patnaik A, Papadopoulos KP, et al. Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Cancer Chemother Pharmacol 2015;75:183-9. [Crossref] [PubMed]
- Bedard PL, Tabernero J, Janku F, et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin Cancer Res 2015;21:730-8. [Crossref] [PubMed]
- Yap TA, Yan L, Patnaik A, et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol 2011;29:4688-95. [Crossref] [PubMed]
- Jänne PA, Shaw AT, Pereira JR, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 2013;14:38-47.
- Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008;372:1809-18. [Crossref] [PubMed]
- Liu G, Cheng D, Ding K, et al. Pharmacogenetic analysis of BR.21, a placebo-controlled randomized phase III clinical trial of erlotinib in advanced non-small cell lung cancer. J Thorac Oncol 2012;7:316-22. [Crossref] [PubMed]
- Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57. [Crossref] [PubMed]
- Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958-67. [Crossref] [PubMed]
- Lobell RB, Liu D, Buser CA, et al. Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I. Mol Cancer Ther 2002;1:747-58. [PubMed]
- Westcott PM, To MD. The genetics and biology of KRAS in lung cancer. Chin J Cancer 2013;32:63-70. [Crossref] [PubMed]
- Dietrich MF, Collins RH Jr, Gerber DE. Next-Generation Sequencing for the Identification of Targetable Molecular Alterations in Cancer. JAMA Oncol 2016;2:132-3. [Crossref] [PubMed]
- Oxnard GR, Paweletz CP, Sholl LM. Genomic analysis of plasma cell-free DNA in patients with cancer. JAMA Oncol 2016. [Epub ahead of print]. [Crossref] [PubMed]
- Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627-39. [Crossref] [PubMed]
- Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35. [Crossref] [PubMed]
- Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372:2018-28. [Crossref] [PubMed]
- Rizvi NA, Hellmann MD, Brahmer JR, et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 2016;34:2969-79. [Crossref] [PubMed]