A new tyrosine kinase inhibitor (TKI) afatinib (Giotrif) was approved for use in patients with EFGR mutations. Afatinib demonstrated an improved response rate and progression-free survival (PFS) compared with chemotherapy both in Caucasian¹ and Asian² patients. In addition, a meta-analysis of the pivotal trials showed for the first time an advantage in overall survival (OS), restricted to patients with exon 19 mutations, that was never demonstrated before with the two other TKIs gefitinib (Iressa) and erlotinib (Tarceva). Moreover, additional third-generation TKIs, such as AZD9291 and CO-1686, are presently being tested in randomized trials for patients with EGFR mutations who progress under a first-generation TKI and who harbor a T790M mutation causing drug resistance; very promising results have been observed in early development trials. EGFR testing in NSCLC patients should now be part of the initial work-up, and the European Medicines Agency recently approved blood–circulating free DNA as a source of material for EGFR testing, making it easier and faster than testing from biopsy material.

Crizotinib (Xalkori), presently used in second-line therapy, may be used to target ALK/EML4 translocation rather than conventional chemotherapy. The recently published PROFILE 1014 established the superiority of crizotinib over chemotherapy in first-line for response rate and PFS; however, OS results are not available and crossover was allowed.³ Based on the data, crizotinib should be approved shortly for first-line therapy. In addition, second-generation ALK TKIs (ceritinib, alectinib) have already been evaluated in crizotinib-resistant ALK-translocated patients and have showed impressive results in that setting, offering an additional targeted treatment choice. ALK/EML4 translocation should be part of the initial work-up of patients with NSCLC.

Immunotherapy in patients with NSCLC has been actively developing in 2014. Disappointing results from vaccine trials have been reported this year, either in the adjuvant setting with the MAGE-A3 vaccine in the MAGRIT trial or in the locally advanced setting with L-BLP25 vaccine in the START trial. Reasons for failure are not clear; however, a better understanding of the antitumor immune mechanisms allows the development of hypotheses considering the power of immune suppression through immune checkpoints that may prevent tumor–cell specific cytotoxic T lymphocytes from being active. More data have been presented in 2014 on immune system manipulations through immune checkpoint blockade by monoclonal antibodies directed at either CTLA4 or PD1 on lymphocytes from the tumor microenvironment and also at PDL-1 as a ligand on cancer cells.⁴ This immune suppression mechanism seems ubiquitous, and promising results have been obtained in numerous tumor types, including lung cancer. Initial results from phase I trials and expanded cohorts were mostly seen with anti-PD1, anti-PDL-1, and anti-CTLA4 monoclonal antibodies in all tumor types.⁵ Numerous antibodies from competing pharmaceutical companies are presently tested in randomized trials for metastatic lung cancers in first- and second-lines but also in locally advanced disease where radiation may potentiate their efficacy by favoring antigen release, as well as in resectable NSCLC.⁶ This new therapeutic approach is associated with potential immune-related toxicity.⁷

Response criteria are also expected to be better, like in the irRECIST, because initial treatment may induce an increase in tumor size associated with lymphocytic infiltration reflecting the local immune activation. In terms of individual profiles, present (preliminary) data seem to favor patients with a high expression of PDL-1 on their tumor; however, very little is known about the kinetics of PDL-1 expression. Further, PDL-1 has not always been tested on recent biopsy samples but more often from archived tissues, and responses have been documented in patients with low PDL-1 expression as has durable disease control. Smokers in limited series have had a higher response rate as well, possibly associated with a higher incidence of gene mutation. The field of lung cancer immunotherapy is rapidly expanding and will probably see a major breakthrough in the near future.