Table of Contents  

Tiut and Zielinski: Novel systemic therapy in advanced non-small-cell lung cancer

Introduction

Lung cancer remains the most common cause of cancer-related death among both men and women worldwide. In 2015, lung and bronchial cancer was estimated to be responsible for 221 200 new cases and 158 040 deaths in the USA.1 Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases, and can be divided into two major types: non-squamous carcinoma (including adenocarcinoma, large-cell carcinoma and other cell types) and squamous cell (epidermoid) carcinoma. Adenocarcinoma is the most common type of lung cancer.2

The last few years have seen spectacular advances in therapeutic options for the treatment of NSCLC. Histological subtyping and the molecular testing (of selected patients) have become highly important, as several therapeutic options are approved for only specific histological subtypes or specific genetic aberrations. The selection of tumours for molecular testing is partially based on tumour histology.3 In 2015, the World Health Organization (WHO) published the fourth edition of the WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. There are some important changes compared with the 2004 classification, namely the use of immunohistochemistry throughout the classification, reclassifying of squamous cell carcinomas and the integration of molecular testing in order to help personalised therapy.4

This review presents the current options for the systemic therapy of advanced/metastatic NSCLC.

Treatment options for advanced/metastatic non-small-cell lung cancer

Standard chemotherapy (platinum-based combinations) has reached its limits, but targeted therapy for the treatment of advanced NSCLC has become available over the last few years. Although targeted therapy has made remarkable progress, there is great hope for the use of immune checkpoint inhibitors, which specifically enhance the immune response directed against the tumour.

Therapy should be chosen based on histology, the results of molecular testing, the age of the patient, performance status, comorbidities and patient preference.5

Based on the response to first-line systemic therapy, the treatment options include maintenance therapy or subsequent therapy. Maintenance therapy is a treatment strategy used for patients with advanced NSCLC, but only if they have responded or have stable disease after completing first-line chemotherapy, have a good performance status [0–1 Eastern Cooperative Oncology Group (ECOG) performance status] and do not have persistent chemotherapy-induced toxicity.6 Continuation maintenance therapy is the continuation of one or more drugs used in first-line therapy. Switch maintenance therapy consists of switching to a new and non-cross-resistant agent on completion of first-line chemotherapy. Both types of maintenance therapy can be continued until disease progression.7,8 Subsequent therapy (second- and third-line therapies) involves systemic therapy for patients with disease progression during or after first-line therapy.

Standard chemotherapy

Chemotherapy agents include platinum agents (cisplatin, carboplatin), taxanes (docetaxel, paclitaxel, albumin-bound paclitaxel), gemcitabine, pemetrexed, vinorelbine and etoposide (Table 1). Combination chemotherapy using these drugs is superior to single-agent chemotherapy.911

TABLE 1

Chemotherapy regimens

Platinum-based doublets
Cisplatin 75 mg/m2 i.v., day 1, paclitaxel 175 mg/m2 i.v., day 1, every 3 weeks13,16
Cisplatin 75 mg/m2 i.v., day 1, docetaxel 75 mg/m2 i.v., day 1, every 3 weeks13,17,18
Cisplatin 75 mg/m2 i.v., day 1, pemetrexed 500 mg/m2 i.v., day 1, every 3 weeks1922 – non-squamous histology
Cisplatin 75 mg/m2 i.v., day 1, gemcitabine 1250 mg/m2 i.v., days 1 and 8, every 3 weeks1820,23
Cisplatin 100 mg/m2 i.v., day 1, vinorelbine 25 mg/m2 i.v., days 1, 8, 15 and 22, every 4 weeks17,24
Carboplatin AUC 6 i.v., day 1, paclitaxel 175–225 mg/m2 i.v., day 1, every 3 weeks13,2528
Carboplatin AUC 6 i.v., day 1, paclitaxel 90 mg/m2 i.v., days 1, 8 and 15, every 4 weeks29
Carboplatin AUC 6 i.v. day 1, albumin-bound paclitaxel 100 mg/m2 i.v., days 1, 8 and 15, every 3 weeks25
Carboplatin AUC 6 i.v., day 1, docetaxel 75 mg/m2 i.v., day 1, every 3 weeks18,20,30
Carboplatin AUC 5–6 i.v., day 1, pemetrexed 500 mg/m2 i.v., day 1, every 3 weeks22,31,32 – non-squamous histology
Carboplatin AUC 5 i.v., day 1, gemcitabine 1250 mg/m2 i.v., days 1 and 8, every 3 weeks33,34
Carboplatin AUC 5 i.v., day 1, vinorelbine 30 mg/m2 i.v., days 1 and 8, every 3 weeks35
Non-platinum-based combination chemotherapy
Gemcitabine 1000 mg/m2 i.v., days 1 and 8, docetaxel 85 mg/m2 i.v., day 8, every 3 weeks36
Gemcitabine 1000 mg/m2 i.v., days 1 and 8, vinorelbine 25 mg/m2 i.v., days 1 and 8, every 3 weeks35,37
Single-agent regimens
Paclitaxel 200 mg/m2 i.v., day 1, every 3 weeks38,39
Albumin-bound paclitaxel 125 mg/m2 i.v. days 1, 8 and 15, every 4 weeks40
Docetaxel 75 mg/m2 i.v., day 1, every 3 weeks41,42
Pemetrexed 500 mg/m2 i.v., day 1, every 3 weeks31,42 – non-squamous histology
Gemcitabine 1250 mg/m2 i.v., days 1 and 8, every 3 weeks33
Vinorelbine 25 mg/m2, weekly43

AUC, area under the curve (in mg/min/ml); i.v., intravenous.

Platinum-based combination chemotherapy (four to six cycles) prolongs survival and improves the quality of life in patients with performance status 0 to 2.5 Numerous studies have compared different platinum-based doublet regimens. Survival and objective response rates have been similar in these trials; there were slight differences with regard to toxicity.1214 A meta-analysis compared cisplatin- versus carboplatin-based chemotherapy regimens in first-line treatment of advanced NSCLC. Carboplatin-based combinations were inferior to cisplatin-based combinations in terms of objective response rate. The cisplatin-based combinations were superior in terms of survival in two subgroups: patients treated with third-generation platinum-based regimens and patients with non-squamous histology.15 Cisplatin-based regimens are associated with more digestive toxicity, neurotoxicity and nephrotoxicity. Haematotoxicity is more common with carboplatin-based regimens.5

The most common first-line chemotherapy regimens are cisplatin or carboplatin plus pemetrexed, carboplatin plus paclitaxel for non-squamous NSCLC and cisplatin plus gemcitabine for squamous cell carcinoma.12,19,44,45

Pemetrexed should be used only for non-squamous NSCLC. Pemetrexed-based regimens may be preferable to taxanes-based regimens because of their lower toxicity.19,46 Pemetrexed can also be used as maintenance therapy (both continuation and switch) and as subsequent therapy in the case of non-squamous NSCLC.

In the phase III PARAMOUNT trial, patients with advanced non-squamous NSCLC received pemetrexed continuation maintenance therapy after four cycles of pemetrexed–cisplatin induction therapy. Pemetrexed continuation maintenance therapy was well tolerated and offered superior overall survival to placebo (median 13.9 months for pemetrexed vs. 11.0 months for placebo).47

The phase III JMEN trial investigated the use of pemetrexed as switch maintenance therapy in patients with advanced NSCLC who had received four cycles of platinum-based doublets (none of them included pemetrexed). Therapy with pemetrexed was well tolerated and offered improved progression-free survival (PFS) (4.3 months vs. 2.6 months) and overall survival (13.4 months vs. 10.6 months) compared with placebo.48

A phase III trial compared pemetrexed versus docetaxel in the second-line setting for advanced NSCLC. The response and clinical benefits were similar, but pemetrexed caused significantly fewer side-effects than docetaxel.46

Taxanes (paclitaxel, albumin-bound paclitaxel, docetaxel) can be used in combination with platinum agents as first-line therapy in both non-squamous and squamous carcinoma. Docetaxel may also be used as switch maintenance therapy and subsequent therapy.

Docetaxel as switch maintenance therapy was assessed in a phase III trial that compared immediate with delayed docetaxel administration after first-line therapy with gemcitabine plus carboplatin. The results showed a significant improvement in PFS when docetaxel was administered immediately after first-line therapy (median 5.7 months vs. 2.7 months).41

The use of docetaxel as second-line treatment was evaluated in two phase III trials. The first trial compared docetaxel with best supportive care in patients with advanced NSCLC, who had been previously treated with platinum-based chemotherapy; treatment with docetaxel was associated with significant prolongation of survival.49 The second trial compared docetaxel with vinorelbine or ifosfamide in patients with advanced NSCLC previously treated with platinum-containing chemotherapy; docetaxel 75 mg/m2 every 3 weeks showed clinical benefit in second-line treatment settings.50

A phase III trial comparing the albumin-bound paclitaxel–carboplatin combination with the solvent-based paclitaxel–carboplatin combination as first-line treatment in patients with advanced NSCLC found a significantly improved overall response rate for albumin-bound paclitaxel compared with solvent-based paclitaxel. The albumin-bound paclitaxel arm was associated with less neuropathy of grade 3 or higher, neutropenia, myalgia and arthralgia. There was an increased risk of thrombocytopenia and anaemia in the albumin-bound paclitaxel arm.25 Albumin-bound paclitaxel was well tolerated without premedication in a clinical trial.40 In 2012, the US Food and Drug Administration (FDA) approved albumin-bound paclitaxel for use in combination with carboplatin for the initial treatment of patients with locally advanced or metastatic NSCLC.51

Gemcitabine can be used in combination with platinum agents as first-line therapy in both non-squamous and squamous carcinoma. Gemcitabine was studied in a phase III randomised trial of continuation maintenance therapy versus best supportive care after an initial regimen of cisplatin–gemcitabine. The results showed a significantly longer time for disease progression using gemcitabine than with best supportive care in patients with advanced NSCLC.52 In a phase III study it was investigated whether continuation maintenance with gemcitabine or switch maintenance with erlotinib (Tarceva®, Roche, Basel, Switzerland) improves PFS compared with observation in patients with advanced NSCLC whose disease was controlled after cisplatin–gemcitabine first-line chemotherapy. The results showed that gemcitabine continuation maintenance or erlotinib switch maintenance significantly reduced disease progression, with a non-significant improvement in overall survival.53 Gemcitabine may also be used as subsequent systemic therapy for patients with advanced NSCLC.54

Non-platinum-based combination chemotherapy with third-generation agents is a therapeutic option only if platinum therapy is contraindicated. In clinical trials, the response rate was higher for platinum-based combinations than for non-platinum-based combinations, but a lower toxicity was observed for non-platinum regimens.5,36,55

For patients with performance status 2, the chemotherapy can be either single-agent (gemcitabine, vinorelbine, taxanes) or platinum-based combinations. The use of platinum-based combinations in patients with advanced NSCLC and ECOG performance status of 2 resulted in statistically significant improvements in overall survival compared with single-agent chemotherapy.11,31,56

For patients without an epidermal growth factor receptor (EGFR)-activating mutation and poor performance status (3–4), the best supportive care should be offered.5

In elderly patients, chemotherapy can be either single-agent or platinum-based combinations. A phase III trial compared platinum-based combination chemotherapy with single-agent chemotherapy (vinorelbine or gemcitabine) in elderly patients (more than 70 years old) with advanced NSCLC and ECOG performance status 0–2. The platinum-based chemotherapy was associated with survival benefits compared with monotherapy (median overall survival 10.3 months vs. 6.2 months). Toxic effects were more frequent in the platinum-based arm.57

Targeted therapy

Targeted therapy has become part of the routine management of patients with advanced NSCLC. Targeted therapy consists of tyrosine kinase inhibitors (TKIs) against EGFR mutation-positive tumours or ALK (anaplastic lymphoma kinase)-rearranged tumours or antiangiogenic TKIs and monoclonal antibodies against vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR-2) or EGFR.

Extensive research in the field of molecular genetics identified key genetic aberrations (driver mutations) occurring in the oncogenes. These mutations determine the promoting of signalling pathways that lead to uncontrolled growth and proliferation. The rationale for the development of targeted therapies (small molecule inhibitors, monoclonal antibodies) is the inhibition of these up-regulated signalling pathways. The genetic aberrations identified in lung adenocarcinoma include EGFR mutations, ALK rearrangements, KRAS (Kirsten rat sarcoma viral oncogene homologue) mutations, MET (mesenchymal–epithelial transition factor) amplification, HER2 (human epidermal growth factor receptor 2) mutations, BRAF (v-Raf murine sarcoma viral oncogene homologue B) mutations, ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase) rearrangements, RET (rearranged during transfection) translocations and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) mutations. Fibroblast growth factor receptor 1 (FGFR1) gene amplification, discoidin domain receptor 2 (DDR2) gene mutation and PI3KCA mutations and amplifications were identified in squamous lung carcinoma.58,59

Epidermal growth factor receptor tyrosine kinase inhibitors

Epidermal growth factor receptor (also known as HER1 or ErbB1) is a member of the receptor tyrosine kinase family (HER or ErbB family). The other three members are HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). Improper activation of EGFR tyrosine kinase leads to increased cell proliferation, survival and metastasis. The main mechanisms involved in EGFR activation are increased expression of EGFR on malignant cells, enhanced ligand production by malignant cells and activating mutations of EGFR within malignant cells.59,60

Mutations in EGFR occur in about 50% of Asian patients with NSCLC and about 10–15% of patients with NSCLC in western countries. EGFR mutations are also observed more frequently in women, patients with no or minimal history of smoking and adenocarcinoma histology.6163 All NSCLC patients should be tested for the presence of EGFR mutations before starting first-line treatment.5

The two most common sensitizing EGFR mutations are deletions in exon 19 (approximately 45% of mutations) and L858R point mutation in exon 21 (approximately 40% of mutations), both conferring sensitivity to EGFR TKIs.58,60

First-generation (reversible) epidermal growth factor receptor tyrosine kinase inhibitors

The first available targeted therapies for advanced NSCLC were gefitinib (Iressa®, AstraZeneca, London, UK) and erlotinib. Erlotinib, in 2013, and gefitinib, in 2015, were approved by the FDA as first-line treatment for patients with metastatic NSCLC whose tumours express EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. Erlotinib was previously approved by the FDA for the treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen (in 2004) and as maintenance therapy after platinum-based first-line chemotherapy (in 2010).64,65 Several clinical trials compared EGFR TKIs with chemotherapy in terms of survival, response rate, PFS and quality of life for patients with advanced NSCLC and sensitising EGFR mutations.

A phase III study, carried out in Asia [Iressa Pan-Asia Study (IPASS)], compared gefitinib with carboplatin plus paclitaxel as first-line treatment in clinically selected patients who had advanced NSCLC. In this study, over 1200 patients (previously untreated never-smokers and light ex-smokers) were randomised. The results showed that the EGFR mutation was the strongest predictive biomarker for benefit of gefitinib over chemotherapy in terms of PFS and objective response rate. In the subgroup of patients with EGFR mutation, PFS was significantly longer for gefitinib than for carboplatin–paclitaxel (median 9.5 months vs. 6.3 months) and the objective response rate (ORR) was greater with gefitinib than with carboplatin–paclitaxel (71.2% vs. 47.3%). In the mutation-negative subgroup, carboplatin–paclitaxel was superior to gefitinib in terms of PFS and ORR.27 Overall survival was similar in patients receiving gefitinib or carboplatin–paclitaxel regardless of the presence or absence of EGFR mutation, presumably because patients who received chemotherapy in first-line treatment crossed over to subsequent therapies. Progression-free survival was significantly longer with gefitinib in patients whose tumours had both a high EGFR gene copy number and EGFR mutation, but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation, showing that EGFR mutations are the strongest predictive biomarker for PFS and tumour response to first-line gefitinib.66

The First-SIGNAL trial compared gefitinib with cisplatin plus gemcitabine in first-line treatment of advanced pulmonary adenocarcinoma in never-smokers. Overall survival was not significantly different between the two treatment arms; the therapy with an EGFR TKI after study discontinuation of patients from the chemotherapy arm was considered as the most likely reason for this result. Among patients who received gefitinib treatment, the EGFR mutation-positive status was predictive for higher objective response rate and longer PFS.67

A phase IV, single-arm study investigated the efficacy and safety of first-line gefitinib in Caucasian patients with stage IIIA/B/IV EGFR mutation-positive NSCLC. ORR was 69.8% based on investigator assessment and 50% as assessed by a central review.68 Based on these findings, and supported by the results of the IPASS study, in which PFS in a subgroup of patients (EGFR mutation-positive) was significantly longer with gefitinib than with chemotherapy, the FDA approved gefitinib for the first-line treatment of patients with metastatic NSCLC whose tumours harbour specific types of EGFR gene mutations, as detected by an FDA-approved test.65

The Chinese OPTIMAL trial compared efficacy and tolerability of erlotinib versus gemcitabine plus carboplatin in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC. Compared with standard chemotherapy, erlotinib conferred a significant PFS benefit (13.1 months for erlotinib vs. 4.6 months for chemotherapy) and was associated with more favourable tolerability.69 The final results showed that overall survival was similar in the erlotinib and gemcitabine plus carboplatin arms (22.8 months vs. 27.2 months) with no significant between-group differences in the overall population, the exon 19 deletion subpopulation or the exon 21 L858 mutation subpopulation.70

The EURTAC trial assessed the efficacy and safety of erlotinib compared with chemotherapy (cisplatin plus docetaxel or gemcitabine; carboplatin plus docetaxel or gemcitabine was permitted in patients unable to have cisplatin) for first-line treatment of European patients with advanced EGFR mutation-positive NSCLC. The erlotinib arm had an increased PFS (median 9.7 months vs. 5.2 months) and fewer severe adverse events than the chemotherapy arm.18

The combination of erlotinib with standard chemotherapy was investigated in the CALGB 30406 study, a randomised phase II trial of erlotinib alone or with carboplatin plus paclitaxel in patients with advanced lung adenocarcinoma who never smoked or who where former light smokers. Erlotinib and erlotinib plus chemotherapy had similar efficacy. In both arms of the study, PFS and the overall survival were significantly longer and the ORR was significantly higher in patients with EGFR mutation-positive tumours.71

The presence of KRAS point mutations defines a subgroup of patients with lung adenocarcinoma in whom the prognosis is very poor.7274 After an initial response, patients with NSCLC expressing EGFR mutations developed acquired resistance to EGFR TKI. The histological and genetic analyses of the tumours that acquired resistance to EGFR TKIs identified several mechanisms of acquired resistance, namely a mutation in exon 20 of EGFR (T790M) (approximately 50% of patients with secondary resistance), MET amplification (15–20%), PI3K mutations and transformation to small-cell lung cancer. The T790M mutation could also have been present prior to treatment with EGFR TKIs.7578

Second-generation (irreversible) epidermal growth factor receptor tyrosine kinase inhibitors

Afatinib (Giotrif®/Gilotrif®, Boehringer Ingelheim, Ingelheim, Germany) is an irreversible blocker of the ErbB family: EGFR (ErbB1), HER2 (ErbB2), ErbB4, with in vitro activity against T790M mutation.79

In 2013, the FDA approved afatinib as first-line treatment for patients with metastatic NSCLC whose tumours express EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.80

The phase III trial LUX-Lung 3 in patients with metastatic lung adenocarcinoma expressing EGFR mutations compared afatinib with cisplatin–pemetrexed in first-line treatment. The results showed that afatinib significantly prolonged the PFS (median 11.1 months vs. 6.9 months) compared with chemotherapy. The benefit of afatinib treatment in terms of PFS was even higher in patients with exon 19 deletions and L858R mutations (13.6 months). The response rates were significantly higher in the afatinib arm than in the chemotherapy arm (56% vs. 23%). The most frequent adverse events associated with afatinib were diarrhoea, rash, dryness or irritation of skin and mucosa.21

The phase III trial LUX-Lung 6 in Asian patients with EGFR mutation-positive advanced NSCLC compared afatinib with cisplatin–gemcitabine as first-line treatment. Afatinib significantly prolonged PFS (median 11.0 months for afatinib vs. 5.6 months for chemotherapy).81

The analysis of overall survival data from the LUX-Lung 3 and LUX-Lung 6 trials showed that afatinib did not improve overall survival in the whole population. In the LUX-Lung 3 trial, median overall survival was 28.2 months in the afatinib group and 28.2 months in the chemotherapy group. In the LUX-Lung 6 trial, median overall survival was 23.1 months in the afatinib group and 23.5 months in the chemotherapy group. Overall survival was improved for afatinib in patients with EGFR exon 19 deletions.82

Erlotinib, gefitinib and afatinib should be used as first-line therapy for patients with sensitizing EGFR mutations. These agents may also be used in patients with performance status 3–4.5 EGFR TKIs may be continued after disease progression to prevent symptomatic progression and increases in tumour size.83

Erlotinib may also be used as subsequent therapy and switch maintenance therapy after a previous chemotherapy regimen in patients with locally advanced or metastatic NSCLC.64

The phase III trial SATURN investigated erlotinib versus placebo as maintenance therapy in patients with advanced NSCLC and non-progressive disease after first-line platinum-doublet chemotherapy. PFS was significantly longer with erlotinib than with placebo (median 12.3 vs. 11.1 weeks), and also significantly longer with erlotinib in patients with tumours expressing EGFR mutations.84

A phase III trial (BR.21) compared erlotinib with a placebo in patients with NSCLC after the failure of first-line or second-line chemotherapy. The results showed that erlotinib prolonged survival and decreased symptoms compared with placebo. Median overall survival in the erlotinib group was 6.7 months, compared with 4.7 months in the placebo group. Patients who had never smoked, adenocarcinoma and EGFR expression were associated with responsiveness to erlotinib.85

The phase III trial LUX-Lung 8 compared afatinib with erlotinib as second-line treatment in patients with advanced squamous cell carcinoma. At the time of the primary analysis of overall survival, the results showed that PFS was significantly longer in the afatinib group than in the erlotinib group (median 2.6 months vs. 1.9 months). Overall survival was also significantly longer in the afatinib group than in the erlotinib group (median 7.9 months vs. 6.8 months).86

Third-generation (mutant-selective) epidermal growth factor receptor tyrosine kinase inhibitors

Osimertinib (AZD9291) (Tagrisso™, AstraZeneca, London, UK), a third-generation TKI, is a potent, oral, irreversible EGFR TKI, selective for both EGFR TKI-sensitizing and T790M resistance mutations. In November 2015, the FDA granted accelerated approval for osimertinib in patients with advanced NSCLC with a specific EGFR mutation (T790M) and disease progression after treatment with other EGFR-blocking therapies. The approval was based on two single-arm trials [AURA study phase II extension cohort and AURA2 (phase II trial)] that investigated the efficacy and safety of osimertinib in patients with advanced NSCLC, EGFR mutation positive and T790M positive, that progressed on or after EGFR TKI treatment. The ORR (primary endpoint) was 58% in the first trial and 64% in the second trial. The most common side-effects were diarrhoea, dry skin, rash and infection. The ongoing phase III AURA3 trial compares osimertinib with platinum-based doublet chemotherapy in patients with locally advanced or metastatic NSCLC, whose disease progressed with previous EGFR TKI therapy and whose tumours express a T790M mutation within the EGFR gene (ClinicalTrials.gov Identifier: NCT02151981).8789

Anaplastic lymphoma kinase inhibitors

In 2007, Japanese researchers discovered a small inversion in chromosome 2p that results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK gene in NSCLC cells. The fusion between EML4 and ALK results in an aberrant form of ALK tyrosine kinase protein that drives tumour growth.90 The frequency of ALK gene rearrangements in patients with NSCLC is about 3–5%.3 ALK fluorescence in situ hybridization (FISH) assay should be used for selecting patients for ALK TKI therapy; ALK immunohistochemistry, if carefully validated, may be considered as a screening methodology to select specimens for ALK FISH testing.91ALK-rearranged tumours are associated with younger age, never- or light-smoking status and adenocarcinoma histology. ALK rearrangements are infrequent in squamous cell carcinoma and mixed squamous cell histology can be found rarely. EGFR-sensitizing mutations, KRAS mutations and ALK rearrangements are generally mutually exclusive.92,93

First-generation anaplastic lymphoma kinase inhibitors

Crizotinib (Xalkori®, Pfizer, New York, NY, USA) is an oral small-molecule TKI targeting ALK, MET and ROS1 tyrosine kinase. In 2011, crizotinib received accelerated approval from the FDA for the treatment of patients with locally advanced or metastatic NSCLC who are positive for the ALK gene rearrangement; regular approval was received in 2013.94

The regular approval was based on the results of PROFILE 1007, a phase III trial that compared crizotinib with standard chemotherapy (docetaxel or pemetrexed) in previously treated patients with advanced NSCLC, positive for ALK rearrangement. This study showed that crizotinib, compared with chemotherapy, prolonged PFS (7.7 months vs. 3.0 months), increased response rates (65% vs. 20%) and improved the quality of life. Overall survival was found to be similar in the crizotinib and chemotherapy groups.42

PROFILE 1014 is a phase III trial comparing crizotinib with chemotherapy (pemetrexed with cisplatin or carboplatin) as first-line treatment in previously untreated patients with advanced non-squamous NSCLC, positive for ALK rearrangement. PFS was significantly longer with crizotinib than with chemotherapy (median 10.9 months vs. 7.0 months) and ORR was higher for crizotinib than for chemotherapy (74% vs. 45%). Crizotinib was also associated with greater improvement in quality of life and reduction in cancer symptoms. The most common adverse events with crizotinib were vision disorders, diarrhoea, nausea and oedema. At the time of the PFS analysis, no significant difference in overall survival was observed between the crizotinib group and the chemotherapy group, most likely attributable to the confounding effects of crossover treatment.22

Most patients eventually acquire resistance to crizotinib, frequently within 1 year. Multiple mechanisms of acquired resistance to crizotinib have been reported, namely ALK secondary mutations (including L1196M), ALK amplification (a gain in ALK gene fusion copy number), loss of ALK fusion gene, appearance of new driver mutations [EGFR activation, KRAS mutation, insulin-like growth factor 1 receptor (IGF-1R) activation].95,96

Second-generation anaplastic lymphoma kinase inhibitors

Ceritinib (Zykadia®, Novartis, Basel, Switzerland) is an oral, small-molecule, TKI of ALK. In contrast to crizotinib, ceritinib does not inhibit the kinase activity of MET, but does inhibit IGF-1R.97

In 2014, the FDA granted accelerated approval to ceritinib for the treatment of patients with ALK-positive, metastatic NSCLC who have progressed on or are intolerant to crizotinib.98

A phase I trial in patients with ALK-positive advanced NSCLC investigated the safety, maximum tolerated dose, pharmacokinetic properties and antitumour activity of ceritinib. The majority of patients (83 of 122 patients) had previously received crizotinib. In the subgroup of patients previously treated with crizotinib the ORR was 56%; similar tumour responses were observed in the subgroup of patients who had not received crizotinib previously (ORR 62%). Median PFS was 7.0 months for the whole cohort, 6.9 months for patients previously treated with crizotinib and 10.4 months for patients not previously receiving crizotinib therapy. The most common adverse effects included nausea, diarrhoea, vomiting, fatigue and increased alanine aminotransferase levels.97

Alectinib (Alecensa®, Roche) is an oral, small-molecule, adenosine triphosphate-competitive TKI of ALK. It does not inhibit the kinase activity of MET or ROS1, but it does inhibit RET. Alectinib is a potent and selective ALK inhibitor, with demonstrated ability to penetrate the tissue of the central nervous system (CNS).99

Alectinib was approved by the FDA in December 2015 for the treatment of patients with advanced (metastatic) ALK-positive NSCLC whose disease had worsened after treatment with crizotinib or who could not tolerate treatment with crizotinib.100

A phase II study investigated the efficacy and safety of alectinib in patients with crizotinib-refractory ALK-positive NSCLC. Most of the patients had also received at least one prior line of platinum-based chemotherapy in addition to crizotinib. Of the 138 patients treated, 61% had CNS metastases at baseline. Oral alectinib, 600 mg twice daily, demonstrated potent clinical activity. ORR was 50%, the median duration of response (DOR) was 11.2 months. Median PFS was 8.9 months. Alectinib determined the shrinkage of CNS metastases, with a CNS ORR of 57% in patients who had measurable CNS metastases; the median CNS DOR was 10.3 months.99 The most common side-effects of alectinib include fatigue, constipation, peripheral oedema and myalgia.100

Angiogenesis inhibitors

Angiogenesis is a crucial event in the process of tumour growth and metastasis. The key signalling pathways involved in angiogenesis include VEGF, fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF), along with their corresponding receptors (VEGFR, FGFR and PDGFR, respectively). One of the best-characterised proangiogenic pathways is the VEGF family, which comprises proangiogenic signalling factors (ligands) (VEGF-A, -B, -C, -D and -E, placenta growth factor) and three receptor tyrosine kinases (VEGFR-1, -2 and -3). Up-regulation of the VEGF pathway is associated with tumour progression and poor prognosis. The development of angiogenesis inhibitors involved two approaches: monoclonal antibodies that block the function of VEGF ligands or receptors and TKIs that inhibit VEGFRs and their signalling pathways. Many angiogenesis inhibitors have been assessed in clinical trials but generally without success.101,102

The only angiogenesis inhibitors that are currently approved for the treatment of NSCLC are two monoclonal antibodies, one directed against VEGF, bevacizumab (Avastin®, Roche), and the other against VEGFR-2, ramucirumab (Cyramza®, Eli Lilly & Co. Ltd, Surrey, UK).

Bevacizumab is a humanized anti-VEGF monoclonal IgG1 antibody that selectively binds circulating VEGF, which leads to the inhibition of VEGF binding to its cell surface receptors.103

In 2006, the FDA granted approval for bevacizumab administered in combination with carboplatin and paclitaxel for the initial treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, NSCLC.104

The primary trial supporting FDA approval was the ECOG 4599 trial, in which patients with recurrent or metastatic, non-squamous NSCLC who had not received chemotherapy were assigned to chemotherapy with paclitaxel and carboplatin alone or paclitaxel and carboplatin plus bevacizumab. The addition of bevacizumab to the platinum-based chemotherapy conferred a significant improvement in overall survival (median 12.3 months vs. 10.3 months), PFS (median 6.2 months versus 4.5 months) and response rate in patients with NSCLC and a good performance status. The addition of bevacizumab was associated with increased toxic effects, particularly febrile neutropenia and pulmonary haemorrhage.28

A subset analysis of the elderly patients (at least 70 years) enrolled in ECOG 4599 showed that bevacizumab administered in combination with carboplatin plus paclitaxel was associated with a higher degree of toxicity, but no obvious improvement in survival compared with carboplatin plus paclitaxel. The combination of bevacizumab with carboplatin plus paclitaxel demonstrated a superior response rate and a trend towards improved PFS.105

The phase III trial PointBreak compared pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab (PemCBev) versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab (PacCBev) in patients with advanced non-squamous NSCLC. The overall survival of patients in the PemCBev group was not superior to that of patients in the PacCBev group (median 12.6 months vs. 13.4 months). Median overall survival in the maintenance population was 17.7 months in the PemCBev arm and 15.7 months in the PacCBev arm. PFS was significantly longer in the PemCBev arm than in the PacCBev are (median 6.0 months vs. 5.6 months). Median PFS in the maintenance population was 8.6 months in the PemCBev arm and 6.9 months in the PacCBev arm. Significantly more drug-related grade ≥3 anaemia, thrombocytopenia and fatigue occurred with PemCBev; significantly more grade ≥3 neutropenia, febrile neutropenia, sensory neuropathy and alopecia occurred with PacCBev.106

In a secondary analysis, patient-level data from the ECOG 4599 and PointBreak trials were pooled to examine outcomes with bevacizumab and paclitaxel–carboplatin based on age. This analysis suggested that the survival benefits associated with paclitaxel–carboplatin plus bevacizumab extend to patient subgroups under 75 years. No benefit was observed for patients who were 75 years or older.107

The phase III trial AVAiL investigated cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for advanced non-squamous NSCLC. The therapeutic combination with bevacizumab significantly improved PFS and ORR but did not improve overall survival (13.1 months for the placebo group vs. 13.6 and 13.4 months in the bevacizumab 7.5 mg/kg and bevacizumab 15 mg/kg groups, respectively).108,109

Ramucirumab is a fully humanized IgG1 monoclonal antibody that acts as an angiogenesis inhibitor by targeting the extracellular domain of VEGFR-2. It selectively inhibits human VEGFR-2 with a much greater affinity than its natural ligands.110,111 In 2014, the FDA approved ramucirumab for use in combination with docetaxel for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. The approval was based on a phase III trial (REVEL) that studied ramucirumab in combination with docetaxel versus docetaxel alone for patients with metastatic NSCLC as subsequent therapy after platinum-based therapy progression. Patients received docetaxel 75 mg/m2 and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, withdrawal or death. Patients who received ramucirumab in combination with docetaxel had an improved overall survival compared with the placebo plus docetaxel arm (median 10.5 months vs. 9.1 months). Median PFS was 4.5 months for the ramucirumab group, compared with 3.0 months for the control group. The most frequent (incidence ≥ 30%) adverse reactions in ramucirumab-treated patients were fatigue, neutropenia and diarrhoea.111,112 Based on these results, ramucirumab–docetaxel therapy is an option for subsequent therapy in patients with metastatic NSCLC.

Antiepidermal growth factor receptor monoclonal antibodies

Cetuximab (Erbitux®, Merck Serono, Darmstadt, Germany) is a chimeric human/murine monoclonal IgG1 antibody that blocks EGFR activation.113

The phase III trial FLEX (First-Line Erbitux in Lung Cancer) studied chemotherapy (cisplatin plus vinorelbine) plus cetuximab versus chemotherapy alone in chemo-naive patients with advanced EGFR-expressing NSCLC. Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group (median overall survival 11.3 months vs. 10.1 months). The survival benefit was seen across all major subgroups. The main cetuximab-related adverse event was acne-like rash (10% grade 3). First-cycle acne-like rash was associated with a better outcome in patients who received cetuximab (15.0 months vs. 8.8 months).114116

The phase III trial BMS099 investigated the efficacy of cetuximab plus chemotherapy (taxane/carboplatin) as first-line treatment of advanced NSCLC, without restrictions by histology or EGFR expression. The difference in PFS between study arms was not statistically significant (median 4.40 months for cetuximab plus chemotherapy vs. 4.24 months for chemotherapy). The response rate was higher in the cetuximab plus chemotherapy arm than in the chemotherapy-alone arm (25.7% vs. 17.2%). The difference in overall survival favoured cetuximab but did not reach statistical significance.117

A meta-analysis of four randomised phase II/III trials confirmed the survival benefit of cetuximab plus chemotherapy compared with chemotherapy alone (median overall survival 10.3 months vs. 9.4 months) as first-line therapy in patients with advanced NSCLC. The trial also demonstrated longer PFS and a higher response rate for cetuximab in combination with chemotherapy.118

Both the FDA and the European Medicines Agency rejected the approval of cetuximab in combination with chemotherapy for first-line therapy of advanced NSCLC.113

Necitumumab (Portrazza™, Eli Lilly & Co. Ltd) is a second-generation, recombinant, human IgG1 EGFR antibody. In November 2015, the FDA approved necitumumab in combination with combination chemotherapy (gemcitabine plus cisplatin) as first-line treatment for patients with advanced (metastatic) squamous NSCLC. The approval was based on the results of a phase III trial (SQUIRE) of necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous NSCLC. Overall survival was significantly longer in the necitumumab plus chemotherapy group than in the chemotherapy-alone group (median 11.5 months vs. 9.9 months). The number of patients with at least one adverse event of grade ≥3 was higher in the necitumumab group (72%) than in the chemotherapy-alone group (62%). The most common side-effects of necitumumab are skin rash and hypomagnesaemia.23,119

Targeted therapy – possible future solutions

The development of targeted agents is an ongoing process. Several TKIs and monoclonal antibodies addressed to molecular subgroups, other than EGFR mutations and ALK rearrangements, are currently under investigation: ROS1 rearrangements (crizotinib, foretinib), BRAF mutations (dabrafenib, vemurafenib, trametinib), MET amplification (crizotinib, tivantinib, cabozantinib, ficlatuzumab, rilotumumab), KRAS mutations, HER-2 mutations (afatinib, neratinib, dacomitinib, trastuzumab, pertuzumab), RET translocations (cabozantinib, vandetanib, ponatinib, sunitinib) and DDR2 mutations (dasatinib).58,59,120

Immunotherapy – checkpoint inhibitors

The immune system has a proven role in controlling and eradicating cancer. The response of the immune system against tumours involves several steps: recognition and elimination of the tumour cells by natural killer cells, capture of tumour antigens by antigen-presenting cells, activation of T cells in a regional lymph node, migration of T cells in the tumour tissue and recognition of specific tumour antigen, followed by activation and differentiation into effector T cells. T-cell activation is regulated by a balance of costimulatory and coinhibitory signals. The immune checkpoints are membrane receptors and ligands that mediate the inhibitory signals, protecting against autoimmunity and inflammation. The most extensively studied immune checkpoints in NSCLC are cytotoxic T lymphocyte antigen 4 (CTLA-4) receptor and programmed death 1 (PD-1) receptor. The CTLA-4 receptor is expressed exclusively on T cells and it regulates the early stages of T-cell activation. PD-1 is expressed by T cells, B cells and natural killer cells and it modulates the later stage of the immune response. The expression of immune checkpoint proteins can be dysregulated by tumours and is an important immune resistance mechanism, allowing the tumour to escape recognition and elimination by the immune system.121,122

Some immunotherapy options have been studied in NSCLC, namely non-specific immune stimulants (agonists of Toll-like receptors and talactoferrin alfa), vaccines (aiming to stimulate a cellular immune response to antigens differentially expressed in cancers) and checkpoint inhibitors. Several trials have so far failed to demonstrate efficacy of non-specific immune stimulants and vaccines in the overall trial populations.123

Programmed death 1/programmed death ligand 1 blockade

Programmed death protein 1, a type 1 transmembrane protein of the Ig superfamily, has two known immunosuppressive ligands, programmed death ligands 1 and 2 [PD-L1 (B7-H1) and PD-L2 (B7-DC)], which are expressed by tumour cells, stromal cells or both. Binding of PD-1 to PD-L1, which has an aberrant expression on tumour cells, results in intracellular responses that reduce T-cell activation. These findings determined the development of PD-1/PD-L1-directed cancer therapies. Antibodies blocking PD-1 or PD-L1 are in clinical development for the treatment of many types of cancer. Nivolumab (Opdivo®, Bristol-Myers Squibb), a genetically engineered, fully human IgG4 monoclonal antibody specific for human PD-1, and pembrolizumab (Keytruda®, Merck Sharp & Dohme, Kenilworth, NJ, USA), antibodies that block PD-1, are approved for the treatment of lung carcinoma.124128

In March 2015, nivolumab received FDA approval for the treatment of metastatic squamous NSCLC with progression during or after platinum-based chemotherapy.129 The approval was based on the results of a phase III trial (CheckMate-017 trial). Patients with stage IIIB or IV squamous cell NSCLC who experienced disease recurrence after one prior platinum-containing regimen were eligible for participation in this study. Patients were randomly assigned to receive either nivolumab, at a dose of 3 mg/kg every 2 weeks, or docetaxel, at a dose of 75 mg/m2 every 3 weeks. Superior overall survival was observed for nivolumab (median 9.2 months for nivolumab vs. 6.0 months for docetaxel), with a 1-year overall survival of 42% for nivolumab versus 24% for docetaxel and an ORR of 20% for nivolumab versus 9% for docetaxel. The efficacy of nivolumab was observed regardless of tumour PD-L1 expression levels; PD-L1 expression was neither prognostic nor predictive of efficacy. The safety profile of nivolumab was more favourable than that of docetaxel. The most common treatment-related adverse events in the nivolumab arm were fatigue, decreased appetite and asthenia.130

In October 2015, the FDA expanded the approval for using nivolumab to patients with non-squamous NSCLC whose disease progressed during or after platinum-based chemotherapy.131 The approval was based on the results of CheckMate-057, a phase III trial comparing nivolumab with docetaxel in previously treated patients with advanced non-squamous NSCLC. Patients were randomly assigned to receive either nivolumab, at a dose of 3 mg/kg every 2 weeks, or docetaxel, at a dose of 75 mg/m2 every 3 weeks. Overall survival was significantly longer with nivolumab than with docetaxel (median 12.2 months vs. 9.4 months), with a 1-year overall survival of 50.5% with nivolumab versus 39.0% with docetaxel. The response rate was 19% with nivolumab versus 12% with docetaxel. The safety profile of nivolumab was favourable in comparison with docetaxel, with most patients having adverse events of low severity. For patients whose tumours had PD-L1 staining of 1–10% or greater, nivolumab nearly doubled median overall survival compared with docetaxel. No meaningful differences in overall survival were noted between nivolumab and docetaxel among patients whose tumours did not express PD-L1.132

Pembrolizumab is a potent, highly selective, fully humanized IgG4-kappa monoclonal antibody against PD-1.133

In October 2015, the FDA granted accelerated approval for pembrolizumab for treating patients with advanced (metastatic) NSCLC, with tumours that express PD-L1, whose disease progressed after other treatments. Pembrolizumab is approved for use with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test (Dako, an Agilent Technologies Company, Glostrup, Denmark), the first test designed to detect PD-L1 expression in NSCLC.134

A phase I trial (KEYNOTE-001) evaluated the side-effects, safety and antitumour efficacy of pembrolizumab in patients with advanced NSCLC. Patients received intravenous pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks. The results showed that pembrolizumab had an ORR of 19.4% (based on a response rate of 18.0% in previously treated patients and 24.8% in previously untreated patients). Efficacy was correlated with smoking status; current or former smokers had a response rate of 22.5% in comparison with 10.3% among patients who had never smoked cigarettes. Median overall survival was 12.0 months overall: 9.3 months for previously treated patients, and 16.2 months for previously untreated patients. A proportion score of ≥ 50% (membranous PD-L1 expression ≥ 50% of tumour cells) was associated with a higher response rate and longer PFS and overall survival than a proportion score < 50% in both previously untreated patients and previously treated patients. Pembrolizumab showed an acceptable side-effect profile regardless of dose (10 mg/kg or 2 mg/kg). The most common treatment-related adverse events included fatigue, pruritus and decreased appetite. Adverse events of grade ≥ 3 were observed in less than 10% of patients. The overall incidence of pneumonitis was less than 4%.135

Other immune checkpoint inhibitors that are currently being investigated in lung cancer are PD-L1 inhibitors (MPDL3280A and MEDI4736) and CTLA-4 inhibitors (ipilimumab).136

Conclusion

Owing to the advances in the understanding of molecular genetics and identification of key genetic aberrations, NSCLC is seen as heterogeneous disease with different molecular subtypes. Tumour testing for identification of genetic aberrations leads to the personalising of therapy in advanced NSCLC. Although chemotherapy has improved survival over recent decades it is no longer the routine treatment in advanced NSCLC. The use of targeted therapy has led to a significant improvement in clinical outcomes. A new treatment approach using immune checkpoint inhibitors is demonstrating significant success and represents an important step forward in the treatment of advanced NSCLC.

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