In the last decade, the emergence of targeted therapies has changed the treatment paradigm for non-small cell lung cancer (NSCLC). The growing availability of therapies targeting specific genetic alterations, such as epidermal growth factor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, have led to changes in the guidelines to reflect the need for molecular profiling. More recently, immunotherapeutic approaches have been investigated in the treatment setting of NSCLC, and these may provide superior outcomes and have substantially better tolerability compared to chemotherapy. Immunotherapies currently available for NSCLC include the checkpoint inhibitors anti PD-1 antibodies nivolumab and pembrolizumab. Several other anti PD-L1 compounds such as atezolizumab, durvalumab and avelumab are also very advanced in clinical investigation, in monotherapy as well as in combination with immune priming phase activators anti-CTLA4 ipilimumab and tremelimumab, across all treatment lines. The challenge facing oncologists is identifying which therapy is best suited to the individual patient.
Non-small cell lung cancer, targeted therapy, checkpoint inhibitors, immunotherapy
Tu Nguyen-Ngoc is supported by the Leenaards Foundation. Martin Reck has received personal honoraria for lectures and consultancy from F. Hoffmann-La Roche, Lilly, BMS, MSD, AstraZeneca, Merck, Boehringer-Ingelheim, Pfizer, Novartis and Celgene. Daniel SW Tan has been an advisor and consultant to Novartis, Bayer, Boehringer-Ingelheim, Merrimack and Pfizer, received travel funding and honorarium from Merck, Pfizer, Novartis, AstraZeneca, Boehringer- Ingelheim and Ariad, and received research funding from Novartis, GSK, Bayer and AstraZeneca. Solange Peters has provided consultation, attended advisory boards and/or provided lectures for F. Hoffmann–La Roche, Eli Lilly and Company Oncology, AstraZeneca, Pfizer, Boehringer-Ingelheim, BMS, Daiichi-Sankyo, Morphotek, Merrimack, Merck Serono, Amgen, Clovis and Tesaro, for which she received honoraria. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
Medical writing assistance was provided by Kat Mountfort at Touch Medical Media, UK.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
September 05, 2016 Accepted:
November 19, 2016
Solange Peters, Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. E: firstname.lastname@example.org
The publication of this article was supported by Novartis. The views and opinions expressed are those of the authors and do not necessarily reflect those of Novartis. The authors provided Novartis with the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the author’s discretion.
Lung cancer is the leading cause of cancer mortality worldwide1 and remains one of the major therapeutic challenges in oncology. Traditionally, lung cancer is subdivided based on histology: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) have completely different molecular and therapeutic profiles. The most common class is NSCLC, accounting for 85% of all cases.2 The prognosis of NSCLC dramatically changed following the discovery of genetic alterations affecting oncogenes, called drivers, including epidermal growth factor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangement, ROS1 or RET rearrangements, MET mutations or amplification, as well as BRAF or HER2 mutations (see Figure 1). The ability to target tumours at the molecular level has led to a paradigm shift in the management of patients with these mutations.
The availability of new therapies with differing modes of action is potentially confusing, not only for primary care physicians but also for medical oncologists. Furthermore, unmet needs remain in the treatment of NSCLC, including the development of resistance to targeted therapies and the fact that not all molecular subtypes are actionable to date. Furthermore, a large group of patients does not suffer from tumours characterised by oncogenic alterations, with the vast majority deprived of any actionable genetic change. These patients are currently treated by chemotherapy. There is a need for new treatments for these patients, and immunotherapy represents a promising approach, but also confers a challenge: identifying patients who will benefit optimally from these treatments. This article aims to discuss the use of targeted therapies and immunotherapy in the setting of NSCLC.
Targeted therapies for non-small cell lung cancer
Standard-of-care molecular characterisation of advanced NSCLC is performed by analysis of activating mutations of EGFR (in exons 19 and 21) and detection of an ALK rearrangement.3 Such screening of NSCLC patients for driver mutations have been standardised and validated.4 However, mutations on the EGFR gene are seen in fewer than 10% of NSCLC patients in Western populations,5,6 although this is higher (up to 50%) in Asian populations.5,7 The mutation has been reported with a higher frequency in non-smokers, women, and presence of adenocarcinoma.6 Clinical trials of approved targeted therapies for NSCLC are summarised in Table 1. The use of EGFR tyrosine kinase inhibitors (TKIs) is recommended as first-line therapy
for patients with an EGFR driver mutation, following an accumulation of evidence of superiority compared with chemotherapy. The first EGFR TKI was gefitinib8–11 followed by erlotinib12–14 and the second-generation TKI afatinib.15,16 In addition, dacomitinib is being evaluated as first-line therapy.17 However, despite high response rates, resistance to EGFR inhibitors invariably ensues in the majority of patients. One of the most common mechanisms of EGFR TKI resistance has been attributed to a single recurrent missense mutation: T790M within the EGFR kinase domain, which occurs in around half of resistant cases.18,19 Other mutations exist, including EGFR point mutations, EGFR amplification, bypass tracks and 15–20% unknown mechanisms.20 Several other agents are in clinical development.
Second-generation irreversible pan-HER EGFR TKIs, such as afatinib,21 dacomitinib22 and neratinib,23 do not seem to be highly effective after progression on first-generation TKI. As a result, third-generation EFGR inhibitors have been developed that selectively target EGFR-activating mutations (del19 and L858R), preserving their affinity in the presence of the T790M resistance mutation, but relatively sparing of EGFR wild type (WT) kinase. The most advanced of these are osimertinib (AZD9291)24 and rociletinib (CO-1686).25 In a phase I study, osimertinib showed a response rate of 61% and a progression-free survival (PFS) of 9.6 months among 127 T790M-positive patients previously treated with EGFR TKIs.26 The latest data from the two phase II studies (AURA extension and AURA2) showed a consistent efficacy and tolerability profile.27 Osimertinib received approval from the US Food and Drug Administration (FDA) in November 2015 and the European Medicines Agency (EMA) in December 2015 for EGFR T790M-positive NSCLC progressing after prior therapy with an EGFR TKI. Results of the confirmatory AURA3 phase III study are pending.
Rociletinib has also shown high efficacy (objective response rate [ORR] 59%, PFS 13.1 months) in T790M-mutated patients in a phase I/II study.28 However, due to a high proportion of unconfirmed responses, rociletinib has not received FDA approval yet and development has been halted. Interestingly, osimertinib and rociletinib also seem active in T790Mnegative NSCLC with lower response rates than in T790M-positive NSCLC. Unfortunately, resistance to third-generation EGFR TKIs occurs and new mechanisms of resistance have been found,29,30 which may differ for osimertinib, rociletinib and other agents in development. Of note, a few cases of NSCLC progressing after rociletinib have been shown to respond to osimertinib.31 Osimertinib and rociletinib are currently being tested in the first-line setting against first-generation TKIs. The results of these trials are eagerly awaited, as osimertinib have shown promising high efficacy (ORR 75%, 72% of PFS at 12 months) in preliminary data of first-line cohorts.32,33 The right sequence of EGFR TKIs is thus a big challenge. The choice may be guided by response to brain metastases: osimertinib and rociletinib appear to have almost as high efficacy in patients with brain metastases than without.34,35 Other agents in clinical development include HM6171336 and EGF816.37
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