Cancer Treatment Reviews xxx (2014) xxx–xxx Contents lists available at ScienceDirect Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv New Drugs Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors ⇑ Christian Rolfo a, , Elisa Giovannetti b, David S. Hong c, T. Bivona d, Luis E. Raez e, Giuseppe Bronte f, Lucio Buffoni g, Noemí Reguart h, Edgardo S. Santos i, Paul Germonpre j, Mìquel Taron k, Francesco Passiglia a,f, Jan P. Van Meerbeeck l, Antonio Russo f, Marc Peeters m, Ignacio Gil-Bazo n, Patrick Pauwels o, Rafael Rosell k a Phase I – Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA) Antwerp University Hospital, Edegem, Belgium b Department Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands c Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA d Hematology and Oncology Department, Hellen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA e Memorial Cancer Institute, Memorial Health Care System, Florida International University, Miami, FL, USA f Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy g San Giovanni Battista Molinette Hospital, Department of Medical Oncology, Turin, Italy h Medical Oncology Department, Hospital Clinic, Barcelona, Spain i Lynn Cancer Institute, Thoracic Oncology, Boca Raton, FL, USA j Department of Respiratory Medicine, AZ Maria Middelares, Kortrijksesteenweg 1026, 9000 Ghent, Belgium k Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain l Thoracic Oncology, Multidisciplinary Oncology Center Antwerp (MOCA) Antwerp University Hospital, Edegem, Belgium m Department of Medical Oncology, University Hospital Antwerpen, Wilrijkstraat 10, 2650 Edegem, Belgium n Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain o Molecular Pathology Unit, Pathology Department and Multidisciplinary Oncology Center Antwerp (MOCA) Antwerp University Hospital, Edegem, Belgium article info abstract Article history: Introduction: Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) Received 20 January 2014 yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring activating EGFR Received in revised form 23 April 2014 mutations. However, even in long-lasting responses, resistance to EGFR TKIs invariably occurs. Accepted 26 May 2014 Areas covered: This review examines resistance mechanisms to EGFR TKI treatment, which mainly arise Available online xxxx from secondary EGFR mutations. Other resistance-inducing processes include mesenchymal–epithelial transition factor (MET) amplification, epithelial–mesenchymal transformation, phenotypic change from Keywords: NSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeu- EGFR mutations tic strategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking of TKI inhibitors resistance NSCLC multiple members of the ErbB family. Several molecules which target multiple ErbB receptors are being New drugs investigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as daco- Novel therapeutic strategies mitinib and lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resis- tance (T790M) mutations, are currently under clinical development. Other therapeutic strategies include inhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 or Abbreviations: AEG-1, astrocyte elevated gene-1; ALK, anaplastic lymphoma kinase; ATP, adenosine triphosphate; BARD1, BRCA1-associated protein 1; BIM, B-cell lymphoma 2 interacting mediator of cell death; BRAF, v-raf murine sarcoma viral oncogene homolog B1; BRCA1, breast cancer 1, early onset; CNS, central nervous system; CRKL, crk-like protein; DCR, disease control rate; EGFR, epidermal growth factor receptor; EMT, epithelial–mesenchymal transformation; EphB4, ephrin type-B receptor 4; ER, oestrogen receptor; ERK, extracellular-signal-regulated kinases; HER, human epidermal growth factor receptor; HGF, hepatocyte growth factor; HSP90, heat shock protein 90; IGF-1R, insulin-like growth factor 1 receptor; KRAS, Kirsten rat sarcoma viral oncogene homologue; MBP-QP, mutation-biased PCR quenching probe; MEK, mitogen-activated protein kinase; MET, mesenchymal–epithelial transition factor; mRNA, messenger RNA; mTOR, mammalian target of rapamycin; NF-jB, nuclear factor kappa-light-chain- enhancer of activated B cells; NSCLC, non-small-cell lung cancer; ORR, overall response rate; OS, overall survival; PARP, poly (ADP-ribose) polymerase; PCR, polymerase chain reaction; PFS, progression free survival; PI3K, phosphoinositide-3-kinase; PIK3CA, phosphoinositide-3-kinase, catalytic, alpha polypeptide; PTEN, phosphatase and tensin homologue; RECIST, Response Evaluation Criteria in Solid Tumours; RR, response rate; SCLC, small-cell lung cancer; TGF, transforming growth factor; TKI, tyrosine kinase inhibitors; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor. ⇑ Corresponding author. Address: Phase I – Early Clinical Trials Unit, Oncology Department University Hospital Antwerp UZA, Wilrijkstraat 10, 2650 Edegem, Belgium. Tel.: +32 3 821 36 46; fax: +32 3 825 15 92. E-mail address: [email protected] (C. Rolfo). http://dx.doi.org/10.1016/j.ctrv.2014.05.009 0305-7372/Ó 2014 Elsevier Ltd. All rights reserved. Please cite this article in press as: Rolfo C et al. Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.05.009 2 C. Rolfo et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx poly (ADP-ribose) polymerase in addition to mammalian target of rapamycin (mTOR), monoclonal anti- bodies against the insulin-like growth factor-1 receptor, and fulvestrant-mediated oestrogen receptor regulation. Conclusion: Improved understanding of mechanisms underlying resistance to EGFR TKIs emphasises the importance of a genotype-guided approach to therapy. Elucidation of resistance mechanisms is indeed crucial to target innovative therapeutic approaches and to improve the efficacy of anticancer regimes in NSCLC. Ó 2014 Elsevier Ltd. All rights reserved. Introduction tion, survival, migration and metastasis (Fig. 1). Targeting EGFR has become an essential strategy in the treatment of NSCLC [2]. Non-small cell lung cancer (NSCLC) is the most common form of Two reversible EGFR tyrosine kinase inhibitors (TKIs), gefitinib lung cancer, accounting for approximately 85% of cases. Disease and erlotinib, are currently commercially available for the treat- staging is essential in defining clinical management, and surgical ment of NSCLC. These agents were first investigated in unselected resection remains the best option in early stage disease. However, NSCLC patients with encouraging results [3–6] but subsequent tri- 70% of patients have locally advanced or metastatic disease at diag- als proved disappointing [7–9]. However, more recently clinical tri- nosis. To date first-line platinum-based chemotherapy has repre- als have shown clinical benefit of both gefitinib and erlotinib in a sented the standard treatment for these patients, achieving about specific population of NSCLC patients with tumours bearing EGFR 30% as response rates (RR) and an approximate 12-months median activating mutations [10–17]. The two most common EGFR muta- overall survival (OS). More recently, the molecular biology of lung tions, accounting for >85% of all EGFR alterations, are in-frame cancer has been shown to play an important part in its pathology. deletions in exon 19 (del19) or point mutations in exon 21 Genotyping for key mutations has become clinically relevant, guid- (L858R) [18] while exon 18 mutations are less frequent (approxi- ing the success of new therapies in NSCLC compared with tradi- mately 4%) [19,20]. The del19 and L858R mutations are present tional chemotherapy [1]. in 10% of Caucasian patients and 30–50% of Asian patients with NSCLC [21] and are sensitive to treatment with reversible EGFR Development of EGFR TKIs TKIs [22]. One particular area of research interest has focused on the ErbB Family, whose four members – epidermal growth factor receptor Resistance to EGFR TKIs (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ ErbB2), ErbB3 and ErbB4 – are central for the regulation of down- While most (>75%) NSCLC patients with somatic EGFR muta- stream signalling pathways important for tumour cell prolifera- tions show initial responses to treatment with the reversible TKIs Fig. 1. Receptors and signalling pathways involved in the development of NSCLC. Please cite this article in press as: Rolfo C et al. Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.05.009 C. Rolfo et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx 3 [21] they invariably develop or ‘acquire’ resistance to these agents specimens. For this reason the evaluation of studies assessing the [21,23]. There are also a number of patients who do not respond to clinical role of T790M should take into account the type of detec- initial treatment with reversible