March 2017, Vol. 6, No. 1
The Road MAP to Targeted Therapy in Squamous-Cell Carcinoma: Lung Cancer Master Protocol (SWOG S1400) OverviewLung Cancer
Lung cancer is the leading cause of cancer-related death worldwide. More than 85% of cases of the disease are classified as non–small-cell lung cancer (NSCLC), with a predicted 5-year survival rate of 16%.1 The battle against lung cancer entered a new era with the identification of actionable genomic aberrations in NSCLC. Molecularly targeted drugs for patients bearing activating mutations in epidermal growth factor receptor,2,3 anaplastic lymphoma kinase fusions,4,5 or ROS proto-oncogenes 1 receptor tyrosine kinase rearrangements6 have led to substantial clinical benefit in the respective subsets of patients with NSCLC. However, these targetable molecular alterations are largely limited to lung adenocarcinomas.
Although there has been limited progress in the targeted therapy arena for squamous-cell carcinoma (SCC), which accounts for 25% of NSCLC, recent advances in sequencing technologies have led to a deeper understanding of the molecular landscape of this subtype of the disease.7 Compared with other cancers, lung SCC has one of the highest rates of genetic aberrations,8 some of which could represent appealing therapeutic targets. The Cancer Genome Atlas (TCGA) study of lung SCC found a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumor.7 Multiple potential therapeutic targets were revealed, such as PIK3CA mutations; cell cycle gene amplifications or mutations/deletions; and fibroblast growth factor receptor (FGFR) gene mutations, fusions, and amplifications. The translation of this vast knowledge into routine patient care is a major clinical challenge. However, emerging evidence suggests that the complex genomic texture and the high mutational burden of lung SCC play a critical role in determining response to novel immunotherapy agents.9
In recent years, monoclonal antibodies targeting the programmed cell death protein-1 (PD-1) pathway have emerged as a new treatment paradigm in NSCLC, including lung SCC. The anti–PD-1/PD-L1 (PD-1 ligand 1) agents nivolumab,10 pembrolizumab,11 and atezolizumab12 recently received US Food and Drug Administration (FDA) approval for use in patients with previously treated metastatic NSCLC. A recent phase 3 study showed that in patients with untreated advanced NSCLC, pembrolizumab was associated with significantly longer progression-free survival and overall survival and a better toxicity profile than platinum-based chemotherapy.13 Based on these findings, the FDA has recently approved pembrolizumab for patients with treatment-naive advanced NSCLC expressing ≥50% PD-L1 on tumor cells.
Anti–PD-1/PD-L1 agents have shown greater activity in patients whose tumor expresses PD-L1 when tested using immunohistochemistry (IHC). However, durable responses are also seen in patients without PD-L1 expression. In addition, there is temporal and spatial heterogeneity of PD-L1 expression in NSCLC.14 Although IHC for PD-L1 can be performed on the small samples used in routine lung cancer diagnostics, there is a risk for significant sampling bias because of intratumor heterogeneity.15 These factors hamper the use of tumor PD-L1 expression as the sole predictive biomarker of response to anti–PD-1/PD-L1 agents.
The expression of PD-L1 on antigen-presenting cells and tumor-infiltrating immune cells has also been examined as a marker of response to anti–PD-1/PD-L1 agents with conflicting results.16,17 More recently, in a study of advanced melanoma and NSCLC, clonal neoantigens have been found to be associated with a favorable response to PD-1 inhibitors.18 In contrast, in poor responders, tumors with a high subclonal neoantigen burden were enriched. The use of neoantigens as biomarkers requires expensive techniques, such as whole exome sequencing, and is still in early stages of investigation. Taken together, currently available data confirm the lack of a single validated biomarker that can predict response to immunotherapy agents.
Despite advances in understanding the genomics of lung SCC, numerous challenges have slowed the translation of this knowledge into clinical practice. First, the conventional path toward regulatory approval of novel agents in oncology is a lengthy and expensive one. The time from initial drug discovery to clinical testing and regulatory review can take up to 15 years.19 Second, screening patients for biomarker-driven studies requires substantial time and technical facilities, with relatively high screen failures. The analysis of lung cancer tissue is particularly challenging, as primary lung tumors often show much lower tumor cellularity compared with other tumor types. The fraction of a given region containing tumor cells can often be less than 20% because of the high proportion of stromal cells, lymphocytic infiltration, and necrosis.15,20 Finally, all of these challenges are compounded when the biomarker of interest occurs at a low frequency. It is worth noting that only 3% to 5% of adult patients with cancer in the United States enroll in clinical trials,21 which underscores the difficulties of completing studies with the needed statistical power. Therefore, alternative clinical research strategies are needed to overcome these challenges.
Efforts to overcome the limitations of developing targeted therapy in small patient populations include adopting an umbrella trial design. This approach transitions from the traditional trials design, described as “one drug–one test,”22 to a patient-centered molecular testing design that allows the treating physician to select the most suitable therapeutic opportunity for a particular patient from a predefined set of potential targets. Examples include the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2,23 the National Lung Matrix Trial,22 and the phase 2 adaptive randomization design Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) and BATTLE-2 in NSCLC.24
The Lung Cancer Master Protocol (Lung-MAP), an umbrella trial designed specifically for advanced SCC of the lung, builds on the experience acquired in the aforementioned studies. The protocol was conceptualized by SWOG with the collaboration of public and private groups, including the National Cancer Institute, Foundation for the National Institutes of Health, National Clinical Trials Network, pharmaceutical industry partners, and several lung cancer advocacy organizations, such as the Lung Cancer Foundation of America. The protocol incorporates genomic testing of lung SCC through a next-generation sequencing platform (Foundation Medicine). After genomic testing, patients are assigned to 1 of several substudies, each evaluating an experimental targeted therapy, based on identification of potential biomarkers associated with each substudy. The protocol is unique in that it offers patients targeted therapy and immunotherapy under 1 umbrella protocol. In this article, we review the candidate biomarkers in Lung-MAP and present an overview of the trial design.
Lung-MAP Biomarkers and Drugs
Candidate drugs are evaluated by a multidisciplinary selection committee using specific criteria, such as demonstrated biologic activity against the target associated with a proposed predictive biomarker(s), well-understood mechanism of activity against the target, evidence of clinical activity in cancer, and manageable toxicity.
Phosphoinositide 3-Kinase (PI3K) Pathway
The PI3K family, which constitutes a large family of lipid and serine/threonine kinases, includes a number of phosphatidylinositol kinases involved in tumor cell proliferation, survival, metabolism, and migration. Class 1A PI3Ks are composed of heterodimers of an inhibitory adaptor/regulatory (p85) subunit and a catalytic (p110) subunit.25 There are 3 known isoforms of Class 1A p110: p110α, p110β, and p110δ. The p110α isoform is encoded by the PIK3CA gene, a known oncogene that frequently is mutated in several solid tumors.25 Genetic screens in model organisms have identified protein kinase B (AKT) as the primary downstream mediator of the effects of PI3K.25 The PI3K/AKT pathway is negatively regulated by the tumor suppressor phosphatase and tensin homolog (PTEN) protein.25 The PI3K/AKT pathway is commonly activated in lung SCC by several mechanisms, including PIK3CA-activating mutations (16% of lung SCC in the TCGA), AKT3-activating mutations (16%), and PTEN-inactivating mutations.7 Lung-MAP investigators selected taselisib (GDC-0032) to be evaluated in patients with activated PI3K pathway. Taselisib is a potent, oral, selective inhibitor of the p110α isoform.26 Taselisib has an established safety profile in phase 1 studies, with clinical activity seen in patients with PIK3CA-mutant NSCLC.27
Fibroblast Growth Factor Receptor
The FGFRs are 4 single-pass, transmembrane, tyrosine kinase receptors (FGFR1-FGFR4), consisting of an extracellular portion, a transmembrane region, and an intracellular domain.28 Upon ligand-receptor binding, FGFR dimerizes and, ultimately, leads to the activation of different pathways. The main downstream signaling pathways are RAS/MAPK and PI3K/AKT cascades promoting cell survival, motility, invasiveness, and proliferation. Activating mechanisms of the FGFR family in NSCLC include gene amplification, fusions, and mutations.28 Amplification of the FGFR1 gene is a common, potentially actionable alteration in lung SCC, with a reported frequency of 15% to 22%.7,28-30 The overall frequency of somatic FGFR2 and FGFR3 mutations in lung SCC is 6.7%.28 Some of these mutations—notably those that occur in the kinase domain of FGFR2—have been shown to be transforming in preclinical models.31 FGFR132 and FGFR333 fusions occur in 2% to 4% of lung SCC.
AZD4547, a novel and selective FGFR1-FGFR3 inhibitor,34 was investigated both in FGFR1-amplified NSCLC cell lines and patient-derived tumor xenograft models. Its potent antitumor activity was shown in FGFR1-“addicted” NSCLCs and correlated with FGFR1 gene amplification and protein overexpression.34 A phase 1 expansion of AZD4547 in previously treated lung SCC included 14 evaluable patients.35 Partial response was observed in 1 patient with high FGFR1 amplification. Treatment with this agent was well tolerated with a manageable toxicity profile.
Homologous Recombination Repair (HRR) Pathway
HRR is a pathway critical for several cellular processes, including the repair of DNA double-strand breaks and the recovery of stalled DNA replication forks.36 Aberrant HRR results in genomic instability, which may cause or contribute to carcinogenesis.37 Somatic molecular alterations in HRR, resulting in homologous recombination-deficient (HRD) tumors, are found in approximately 51% of patients with SCC of the lung.7,38 Commonly observed somatic mutations in this pathway in lung SCC include the following genes: BRCA1 (6%), BRCA2 (6%), FANCA (3%), and PALB2 (3%). Gene amplifications are seen in FANCG, FANCL, and C19ORF40 (4% each). Importantly, such HRD tumors may be more sensitive to DNA-damaging chemotherapeutics such as cisplatin or poly-ADP ribose polymerase (PARP) inhibitors.37 Talazoparib (BMN 673) is a potent oral PARP1/2 inhibitor that has shown promising efficacy in the treatment of HRD ovarian, breast, and lung tumors.39,40
Cyclin-Dependent Kinases (CDKs)
Transition from one stage of the cell cycle to the next is controlled by the actions of CDKs, which are activated upon interaction with their partner cyclins.41 For instance, CDK4 and CDK6 interact with the cyclin D1 gene (CCND1) to phosphorylate the retinoblastoma (RB) tumor suppressor protein and promote G1 cell-cycle progression to S phase.42 Deregulated cell-cycle progression resulting in uncontrolled cell proliferation is one of the hallmarks of cancer. Therefore, targeting cell-cycle progression has been an attractive therapeutic strategy in preclinical and clinical studies.41 Lung SCC has been found to have CDK4/6, CCND1, CCND2, CCND3, and CCND4 amplifications and mutations.7
Palbociclib is an orally bioavailable small-molecule inhibitor of CDK4/6, with a high level of selectivity for CDK4/6 over other cyclin-dependent kinases.43 Palbociclib inhibits CDK4/6 in vitro, resulting in loss of RB1 phosphorylation. It has been granted FDA approval in hormone-positive metastatic breast cancer.43
Immune Checkpoint Inhibitors
As discussed in the introduction of this article, monoclonal antibodies targeting the PD-1 pathway have emerged as new treatment options for patients with metastatic lung SCC. Lung-MAP offers patients several approved and experimental immune checkpoint inhibitors. These include nivolumab, which is currently a standard-of-care option for patients with advanced lung SCC whose disease has progressed on or after platinum doublet chemotherapy.10 Lung-MAP also offers patients the combination of nivolumab plus ipilimumab, which inhibits the CTLA-4 immune checkpoint. This regimen has a manageable safety profile and exciting clinical activity in NSCLC, including lung SCC.44 Finally, the upcoming Lung-MAP design will offer patients whose tumors are refractory to immunotherapy a combination of durvalumab (anti–PD-L1) and tremelimumab (anti–CTLA-4). A phase 1 study has established the safety and clinical activity of this regimen.45
The ultimate aim of Lung-MAP is to establish a National Clinical Trials Network mechanism for genomically screening large but homogeneous cancer populations and subsequently assigning and accruing these patients simultaneously to a multisubstudy “master protocol.” Biomarker-driven substudies in Lung-MAP evaluate a targeted therapy based on designated therapeutic biomarker–drug combinations, with the ultimate goal being approval of new targeted therapies in this setting. In addition, the protocol includes at least one “non-match” therapy substudy, which includes all screened patients not eligible for any of the biomarker-driven substudies. This master protocol mechanism aims to yield definable and measurable efficiencies in terms of improving genomic screening of cancer patients for clinical trial entry as well as improved timelines for drug–biomarker testing, allowing for inclusion of the maximum number of otherwise eligible patients in comparison to currently employed “single screen–single trial” approaches.
Lung-MAP employs a hybrid master protocol in which the design for a given substudy is chosen from a limited number of clinical trial designs based on the expected biomarker prevalence and background data. The design options for the substudies include a phase 2/3 design and a single-arm phase 2 study followed by a randomized phase 3 study (under specified conditions). The protocol adapts a flexible framework in which new substudies can be added to the protocol at any time point whenever robust scientific rationale has become available.
Lung-MAP is a prospective, multisubstudy master registration protocol in which patients with advanced-stage previously treated SCC of the lung are assigned to a biomarker-driven targeted therapy phase 2 study, with the primary end point being objective response rate (ORR). If the ORR observed in the phase 2 study is judged sufficient, the study will proceed into a phase 3 trial, in which patients will be randomized to biomarker-driven targeted therapy or standard of care. A targeted therapy will be judged to have provided sufficient evidence to proceed to the phase 3 component if the ORR is at least 25%. Each substudy is defined by a genotypically defined alteration (biomarker) in the tumor and a drug that targets it. Each substudy will function autonomously and will open and close independently of the other substudies. The candidate drugs must have demonstrated biologic activity against the target associated with a proposed predictive biomarker(s).
Patient tumor specimens are submitted for central testing within 1 day after registration to the screening portion of the trial. Formalin-fixed and paraffin-embedded tissue from archival and/or fresh tumor biopsy must be available for biomarker testing. Biomarker analysis is performed using massive parallel DNA sequencing (Foundation Medicine) to detect potentially targetable genomic alterations in cancer-related genes. IHC assays can also be performed according to the biomarker being investigated. The tests are executed in Clinical Laboratory Improvement Amendments–certified laboratories. The turnaround time from tissue submission to reporting of results is ≤16 days. The current and the upcoming study’s schemas are shown in Figure 1A and Figure 1B, respectively. Substudy S1400C was closed in September 2016 because the investigational drug (palbociclib) failed to meet the predefined phase 2 end point (ORR ≥25%). The upcoming schema (Figure 1B) includes a new biomarker-driven substudy (S1400G) that will investigate talazoparib, a PARP inhibitor in patients with HRD-positive tumors. The current non-match substudy S1400I randomizes immunotherapy-naive patients to nivolumab with or without ipilimumab. To address the fastest growing segment of patients needing new therapeutic strategies, namely patients either refractory or relapsing after single-agent checkpoint inhibitor therapy, the new non-match study S1400F will consist of a single-arm trial exploring a combination of durvalumab (anti–PD-L1) and tremelimumab (anti–CTLA-4).
As of September 2016, 1003 patients were registered to S1400, with accruals from Alliance, ECOG-ACRIN, NRG, and the leading group SWOG; 723 patients were notified of their substudy assignment and 364 patients were registered to a substudy. Patients can either enter the trial at the time of progression on previous therapy or be prescreened while receiving frontline therapy and prior to progression, with the option to request study assignment at progression.
This study will provide a unique opportunity to establish a tissue/blood repository from patients with advanced SCC of the lung. The investigators will explore additional predictive tumor/blood biomarkers that may modify response or define resistance to the targeted therapy beyond the chosen biomarker for biomarker-driven substudies. Moreover, with the approval of anti–PD-1/PD-L1 agents in NSCLC, there is an urgent need to identify predictive biomarkers to allow better patient selection. The non-match substudy of Lung-MAP will be one of the largest systematic efforts to meet that need. Finally, this protocol will evaluate the screen success rate defined as the percentage of screened patients who register for a therapeutic substudy.
Challenges Associated with Lung-MAP
Lung-MAP faces a number of challenges. The study requires the enrollment of a large number of patients in a timely and efficient manner. Patients with lung SCC, especially in the second-line setting, are often in a compromised clinical condition as a result of their tumor as well as other comorbidities. This fact, in addition to the rarity of the chosen biomarkers, may make accrual a major obstacle. The investigators aim to overcome this by offering the trial to patients in hundreds of centers throughout the country. Naturally, coordinating the efforts of many investigators and institutes ranging from academia, regulatory bodies such as the FDA, and pharmaceutical partners represents a challenge in itself.
Another critical challenge is selecting the best possible drug. More than 100 candidate drugs were reviewed to identify the 5 in the first design of Lung-MAP.46 One of the unique challenges in the setting of lung SCC is that targetable genomic alterations occur in the context of a very complex genomic landscape, which may diminish the effectiveness of single-agent targeted therapy and require combination therapy or synthetic lethality approaches. In many cases, promising novel drugs do not have supporting clinical data. In addition, from the pharmaceutical companies’ point of view, the risk to the primary development paths for their drugs is not insignificant.
An additional obstacle is that the field of cancer genomics and therapeutics is rapidly evolving, particularly with the approval of immunotherapy in the first- and second-line settings for NSCLC. Lung-MAP has a flexible design, which aims to adapt quickly to emerging scientific data by closing current substudies or opening new ones.
Lung-MAP is a groundbreaking protocol that combines biomarker-driven targeted therapy studies under the umbrella of a single master protocol. It has a flexible framework that adapts to a rapidly evolving field. The study is a result of strong partnerships built between collaborative groups, patient advocacy, regulatory bodies, and pharmaceutical companies with the shared goal of setting a new model of rapid drug development and approval. It is hoped that this model will lead to improvement in the overall process of drug development, bringing safe and effective agents to patients, and ultimately, saving lives.
Dr Elamin is a member of the American Society of Clinical Oncology (ASCO) and the International Association for the Study of Lung Cancer (IASLC), and a recipient of the ASCO Young Investigator Award (YIA) and the Lung Cancer Research Foundation Award.
Dr Papadimitrakopoulou is nationally recognized for her leadershipand expertise in lung cancer treatment and research and is best knownfor her work in personalized therapy of non–small-cell lung cancer, in particular, the process of linking cancer biomarkers to novel therapies. She is a member of the American Association for Cancer Research, ASCO, and the Southwest Oncology Group’s Lung Committee, and serves on the membership and publications committees for IASLC. She has authored more than 150 peer-reviewed articles and has received awards from ASCO (YIA and Career Development Award), as well as grant funding from numerous sources, including the National Cancer Institute.
- Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11-30.
- Soria JC, Mok TS, Cappuzzo F, et al. EGFR-mutated oncogene-addicted non-small cell lung cancer: current trends and future prospects. Cancer Treat Rev. 2012;38:416-430.
- Hirsch FR, Jänne PA, Eberhardt WE, et al. Epidermal growth factor receptor inhibition in lung cancer: status 2012. J Thorac Oncol. 2013;8:373-378.
- Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small cell lung cancer. N Engl J Med. 2010;363:1693-1703.
- Shaw AT, Engelman JA. Ceritinib in ALK-rearranged non-small cell lung cancer. N Engl J Med. 2014;370:2537-2539.
- Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371:1963-1971.
- Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489:519-525.
- Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415-421.
- Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology: mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-128.
- 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;373:123-135.
- Garon EB, Rizvi NA, Hui R, et al; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018-2028.
- Fehrenbacher L, Spira A, Ballinger M, et al; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387:1837-1846.
- Reck M, Rodríguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823-1833.
- McLaughlin J, Han G, Schalper KA, et al. Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer. JAMA Oncol. 2016;2:46-54.
- Hiley CT, Le Quesne J, Santis G, et al. Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease. Lancet. 2016;388:1002-1011.
- Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20:5064-5074.
- Velcheti V, Schalper KA, Carvajal DE, et al. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest. 2014;94:107-116.
- McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351:1463-1469.
- Ferrarotto R, Redman MW, Gandara DR, et al. Lung-MAP—framework, overview, and design principles. Chin Clin Oncol. 2015;4:36.
- Jamal-Hanjani M, Hackshaw A, Ngai Y, et al. Tracking genomic cancer evolution for precision medicine: the lung TRACERx study. PLoS Biol. 2014;12:e1001906.
- Comis RL, Miller JD, Aldigé CR, et al. Public attitudes toward participation in cancer clinical trials. J Clin Oncol. 2003;21:830-835.
- Middleton G, Crack LR, Popat S, et al. The National Lung Matrix Trial: translating the biology of stratification in advanced non-small-cell lung cancer. Ann Oncol. 2015;26:2464-2469.
- Barker AD, Sigman CC, Kelloff GJ, et al. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharm Ther. 2009;86:97-100.
- 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;34:3638-3647.
- Hennessy BT, Smith DL, Ram PT, et al. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4:988-1004.
- Lopez S, Schwab CL, Cocco E, et al. Taselisib, a selective inhibitor of PIK3CA, is highly effective on PIK3CA-mutated and HER2/neu amplified uterine serous carcinoma in vitro and in vivo. Gynecol Oncol. 2014;135:312-317.
- Jhaveri KL, Bedard PL, Cejalvo JM, et al. Phase I evaluation of the PI3 kinase (PI3K) inhibitor taselisib (GDC-0032) in multiple locally advanced or metastatic PIK3CA mutant solid tumor types. J Clin Oncol. 2016;34(suppl):Abstract TPS11621.
- Tiseo M, Gelsomino F, Alfieri R, et al. FGFR as potential target in the treatment of squamous non small cell lung cancer. Cancer Treat Rev. 2015;41:527-539.
- Jiang T, Gao G, Fan G, et al. FGFR1 amplification in lung squamous cell carcinoma: a systematic review with meta-analysis. Lung Cancer. 2015;87:1-7.
- Weiss J, Sos ML, Seidel D, et al. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med. 2010;2:62ra93.
- Liao RG, Jung J, Tchaicha J, et al. Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinoma. Cancer Res. 2013;73:5195-5205.
- Wu YM, Su F, Kalyana-Sundaram S, et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 2013;3:636-647.
- Capelletti M, Dodge ME, Ercan D, et al. Identification of recurrent FGFR3-TACC3 fusion oncogenes from lung adenocarcinoma. Clin Cancer Res. 2014;20:6551-6558.
- Gavine PR, Mooney L, Kilgour E, et al. AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res. 2012;72:2045-2056.
- Paik PK, Shen R, Ferry D, et al. A phase 1b open-label multicenter study of AZD4547 in patients with advanced squamous cell lung cancer: preliminary antitumor activity and pharmacodynamic data. J Clin Oncol. 2014;32(suppl 5s):Abstract 8035.
- Willers H, Pfäffle HN, Zou L. Targeting homologous recombination repair in cancer. In: Kelley MR, ed. DNA Repair in Cancer Therapy: Molecular Targets and Clinical Applications. 1st ed. San Diego, CA: Academic Press, Elsevier; 2012:119-160.
- Birkelbach M, Ferraiolo N, Gheorghiu L, et al. Detection of impaired homologous recombination repair in NSCLC cells and tissues. J Thorac Oncol. 2013;8:279-286.
- Waqar SN, Devarakonda SHK, Michel LS, et al. BRCAness in non-small cell lung cancer (NSCLC). J Clin Oncol. 2014;32(suppl):Abstract 11033.
- McLachlan J, George A, Banerjee S. The current status of PARP inhibitors in ovarian cancer. Tumori. 2016;102:433-440.
- Feng Y, Yu K, Cardnell R, et al. Talazoparib predictive biomarker analysis in human small cell lung cancer cells and PDX tumors. Mol Cancer Ther. 2015;14(12 suppl 2):Abstract A37.
- O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016;13:417-430.
- Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995;81:323-330.
- Turner NC, Ro J, André F, et al; PALOMA3 Study Group. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373:209-219.
- Hellmann MD, Gettinger SN, Goldman JW, et al: CheckMate 012: safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. J Clin Oncol. 2016;34(suppl):Abstract 3001.
- Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016;17:299-308.
- 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;21:1514-1524.
Dr Kaufman is the Chief Surgical Officer and Associate Director for Clinical Science at Rutgers Cancer Institute of New Jersey. He is a leading authority on tumor immunotherapy for the treatment of melanoma and has published more than 400 peer-reviewed scientific papers, books, review articles, and abstracts. He serves on [ Read More ]
Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma (NHL) after diffuse large B-cell lymphoma (DLBCL), with an estimated 16,000 new cases diagnosed annually in the United States.1,2 However, unlike DLBCL, which is a histologically aggressive lymphoma, FL has a long natural history, with 15% to 20% [ Read More ]