You are here

New perspectives in the second-line treatment of non squamous NSCLC patients: Results from a large Italian Lung Cancer Working Group

Crit Rev Oncol Hematol. 2017;109:35–41


Lung cancer is still considered a big killer among cancer diseases, due to high incidence and mortality rates. The newer frontiers of therapeutic development regard the discovery of oncogene driven tumours: however, the majority of NSCLC patients are wild type and they cannot be treated with targeted based agents. The recent positive results obtained with immunotherapy and with the combination of angiogenesis inhibitors and docetaxel, changed the therapeutic scenario of the second line therapy of non squamous NSCLC without actionable mutations. A major issue is currently the lack of predictive biomarkers that could help the oncologists in the choice of the best second-line treatment. Aim of this project was to define an optimal therapeutic pathway for patients with non-squamous NSCLC, through a working group of a large number of Italian lung cancer oncologists. Panellists have identified and discussed the more significant criteria in the second-line setting for a therapeutic decision between the combination of angiogenesis inhibitors plus chemotherapy or immunotherapy. Finally, they expressed their preference on each criterion, building a proposal of a decision-making tree for a second-line treatment of non-squamous NSCLC.

Keywords: Non squamous NSCLC, Second line therapy, Nintedanib, Ramucirumab, Nivolumab, Pembrolizumab, Atezolizumab, Docetaxel, Therapeutic strategy.

1. Introduction

The improvement in the knowledge of the biology of non-small-cell lung cancer (NSCLC), the discovery of targetable oncogenic drivers, and the availability of new effective drugs also for actionable mutation patients has dramatically changed in recent years the therapeutic scenario of patients with lung cancer. In the first-line setting, the presence of EGFR-activating mutations and ALK rearrangements represents a key element for the choice of the treatment strategy, identifying specific patient subgroups (oncogene addicted), which need to be treated with biological targeted based drugs (Reck et al., 2014a). In case of non-squamous NSCLC without actionable mutation, the use of platinum-based combinations, preferably including pemetrexed or bevacizumab, should be considered as the first choice option (Reck et al., 2014a).

In the second line setting of non-squamous NSCLC, the standard therapeutic options included until to now docetaxel, pemetrexed or erlotinib, that showed an overall survival improvement in randomized clinical trials conducted more than ten years ago. On these bases, a second-line therapy has been generally offered to selected NSCLC patients with the main objective to improve lung cancer symptoms (Reck et al., 2014a). Recently, new active drugs with different mechanisms of action, including nintedanib, ramucirumab, nivolumab, pembrolizumab and atezolizumab have shown relevant overall survival improvement, modifying the landscape of the second line treatment for patients with non-squamous NSCLC that became more rich and complex. Currently, in consideration of the absence of defined predictive biomarkers that could help the oncologists in the choice of the best second-line treatment and of the increasing number of patients approaching a second-line therapy, it is important to define a correct “treatment pathway” for patients with advanced non-squamous NSCLC, where all the available options can be exploited in the different lines of treatment, in order to guarantee the best clinical results.

2. Literature overview of second-line treatment of NSCLC

In 2000 docetaxel was approved for the second-line treatment of patients with advanced non-squamous NSCLC (Table 1) (Shepherd et al, 2000 and Fossella et al, 2000). In 2004 pemetrexed demonstrated a similar efficacy with a better safety profile than docetaxel as final results of the phase III randomized study JMEI (Hanna et al., 2004). A meta-analysis of Di Maio M et al. demonstrated subsequently that the weekly schedule of docetaxel has an equivalent therapeutic effect in terms of OS, but lower toxicity compared with the three-weekly docetaxel schedule (Di Maio et al., 2007). The third drug approved for second-line treatment was erlotinib, which was evaluated in the double blind phase III randomized BR21 study (Shepherd et al., 2005). Erlotinib 150 mg/day was more effective than placebo and showed a significant improvement in the quality of life in term of cough, dyspnea and pain.

Table 1

Drugs approved for the second-line treatment of patients with advanced non-squamous NSCLC.


Author, year Patients Regimen Response TTP/PFS (weeks) Median OS (months) p
Shepherd et al. (2000) 204 Docetaxel vs BSC 7.1% vs 0 10.6 vs 6.7 7.0 vs 4.6 0.047
Fossella et al. (2000) 373 Docetaxel 100 mg/m2 vs Docetaxel 75 mg/m2 vs Vinorelbine/Ifosfamide 10.8% vs 6.7% vs 0.8% 8.4 vs 8.5 vs 7.9 5.5 vs 5.7 vs 5.6 n.s
Hanna et al. (2004) 571 Pemetrexed vs docetaxel 9.1 vs 8.8% 11.6 vs 11.6 8.3 vs 7.9 n.s.
Shepherd et al. (2005) 731 Erlotinib vs BSC 8.9% vs <1% 8.8 vs 7.2 6.7 vs 4.7 <0.001

After ten years without significant progress, new effective therapeutic options are now available for the second-line treatment of non-oncogene-addicted patients with advanced NSCLC, including nintedanib, ramucirumab, nivolumab, pembrolizumab and atezolizumab (Table 2).

Table 2

New drugs for the second-line treatment of patients with advanced non-squamous NSCLC.


Author, year Patients Regimen Response PFS (months) Median OS (months) p
Reck et al. (2014c) 1314 Docetaxel + nintedanib vs docetaxel + placebo 4.7% vs 3.6% 4.0 vs 2.8 12.6 vs 10.3 0.0359
Garon et al. (2014 1253 Docetaxel + ramucirumab vs docetaxel + placebo 23% vs 14% 4.5 vs 3.0 10.5 vs 9.1 0.023
Borghaei et al. (2015) 582 Nivolumab vs docetaxel 19% vs 12% 2.3 vs 4.2 12.2 vs 9.4 0.002
Herbst et al. (2016) 1034 Pembrolizumab 2 mg/kg vs Pembrolizumab 10 mg/kg vs docetaxel 18% vs 18% vs 9% 3.9 vs 4.0 vs 4.0 10.4 vs12.7 vs 8.5 0.0008 < 0.0001
Fehrenbacher et al. (2016) 287 Atezolizumab vs docetaxel 15% vs 15% 2.7 vs 3.0 12.6 vs 9.7 0.04
Barlesi et al. (2016) 1225 Atezolizumab
vs docetaxel
14% vs 13% 2.8 vs 4.0 13.8 vs 9.6 0.0003

Nintedanib is a multitarget TKI which blocks the Vascular Endothelial Growth Factor Receptors (VEGF-R), Platelet-derived Growth Factor Receptors (PDGF-R) and Fibroblast Growth Factor Receptors (FGF-R), flt-3 and src (Reck et al., 2014b). The efficacy and safety of second-line therapy with nintedanib in combination with docetaxel were assessed in the phase III randomized double blind study LUME-Lung 1, which enrolled over 1300 stage IIIB/IV NSCLC patients in 211 centers in 27 countries, stratified by ECOG performance status 0 and 1, previous treatment with bevacizumab, histological type and presence of cerebral metastasis (Reck et al., 2014c). The patients were randomized to receive docetaxel 75 mg/m2 on day 1 every three weeks plus nintedanib 200 mg every 12 h orally, or placebo, from day 2 to day 21, up to disease progression or unacceptable toxicity. The primary endpoint was PFS, assessed by an independent review committee; secondary endpoints were OS, clinical response percentage (ORR), safety and quality of life. After a median follow-up of 7.1 months, docetaxel plus nintedanib significantly increased PFS (3.4 vs 2.7 months, HR = 0.79; p = 0.0019), independently from histology with major effect in the adenocarcinoma patients (PFS: 4 vs 2.8 months, p = 0.0193). Pre-planified hierarchical analysis showed after a median follow-up of 31.7 months, significantly greater OS in adenocarcinoma patients treated with docetaxel plus nintedanib (12.6 months), than with those treated with docetaxel plus placebo (10.3 months, HR = 0.83; p = 0.0359), with a not negligible number of “long-surviving” patients (over 32 months). Moreover, in patients with adenocarcinoma and time since start of first line therapy less than 9 months (early progressor), the overall survival advantage was 3 months (10.9 vs 7.9 months, HR = 0.75, p = 0.0073), while in patients with adenocarcinoma refractory to first-line therapy, the overall survival advantage was 3.5 months (9.8 vs 6.3 months, HR = 0.62, p = 0.0246). Finally, the investigation of the interaction between treatment and tumor burden, showed that greater tumour burden was associated with a greater treatment effect for docetaxel and nintedanib. In addition, a significant improvement in disease control rate (DCR) (60.2% vs 44%) in favour of nintedanib plus docetaxel was observed in adenocarcinoma patients. Nintedanib showed a good tolerability profile: grade ≥ 3 adverse events, mainly increase in transaminases and astenia (12 vs 1% for ALT and 4 vs 1% for AST, 3 vs 1% for astenia, respectively), generally manageable with an appropriate support therapy, were more frequent in the docetaxel plus nintedanib arm than docetaxel plus placebo arm. The anti-angiogenesis-related adverse events (bleeding and hypertension) were not significantly different between treatment groups (Reck et al., 2014c). The health related quality of life data did not show relevant differences between the treatment arms and thus indicate that the addition of nintedanib to docetaxel does not result in a detrimental effect compared to the monotherapy with docetaxel (Novello et al., 2015).

Another anti-angiogenic drug, ramucirumab, a totally humanized IgG1 monoclonal antibody that specifically targets the extracellular domain of VEGFR2, preventing the binding of several VEGF isoforms, has been recently evaluated in a multicentre, double-blind, randomized phase 3 study (REVEL trial) in the second-line treatment of patients with squamous and non-squamous metastatic NSCLC, pre-treated with platinum-based chemotherapy (Garon et al., 2014). A total of 1253 patients were randomized to docetaxel 75 mg/m2 plus ramucirumab (10 mg/kg) or placebo (day 1 of each 21-day cycle) until disease progression, unacceptable toxicity, drug interruption or death. Median OS, the primary endpoint of the study, was 10.5 months in the patients treated with ramucirumab plus docetaxel and 9.1 months in those treated with placebo plus docetaxel (p = 0.023). Also in this case the OS curves separate early and remain so for the entire duration of the follow-up: this fact is even more interesting because both histotypes (squamous and non-squamous) were included in the ITT analysis. The ramucirumab-based combination was more affective also in terms of median PFS (4.5 versus 3.0 months, HR 0.76, 0.68-0.86; p < 0.0001) and ORR (22.9% vs 13.6%, p < 0.001). The anti-angiogenesis-related adverse events rate were higher in the group treated with the active combination, although the difference in terms of grade 3 toxicity was not significant and the events were manageable with an appropriate dose reduction and support therapy (Garon et al., 2014).

Nivolumab is a fully human IgG4 anti-PD-1 (programmed death 1) monoclonal antibody, able to block the signaling pathway mediated by the PD-1 and to restore anti-tumour immunity. The international randomized open-label phase 3 CheckMate 057 trial assessed the efficacy and safety nivolumab 3 mg/kg every 2 weeks, versus docetaxel 75 mg/m2 three-weekly in the second-line treatment of 582 patients with non-squamous stage IIIb/IV pre-treated NSCLC (Borghaei et al., 2015). The PD-L1 expression was assessed retrospectively by means of the correlative Dako/BMS automated immune-histochemical assay (Dako 28-8 antibody on tumour cells). The results showed a statistically significant OS advantage (HR 0.73; IC 95%, 0.59–0.89, p = 0.002) in favour of nivolumab: the median OS was 12.2 months (IC 95%, 9.7–15.0) in the 292 patients treated with nivolumab and 9.4 months (IC 95%, 8.1–10.7) in the 290 patients treated with docetaxel. The 1-year and 18 months OS were 51% and 39% versus 39% and 23% with nivolumab and docetaxel, respectively. In this case, a particular trend of the OS curve can be observed: during the first 3 months the OS was better for docetaxel, while subsequently it is significantly in favour of nivolumab; this phenomenon could be probably attributed to the different benefit of two not yet clearly identifiable sub-populations of patients with poor prognostic factors and/or more aggressive disease combined with low or no tumour PD-L1 expression (European Medicines Agency, 2016). A significant correlation between PD-L1 expression, at any cut-off (1%, 5% or 10%) and the OS (≥1%: HR 0.59; ≥5%: HR 0.43; ≥10%: HR 0.40) was observed. The analysis of PD-L1 expression levels in tumour cells showed that the activity of nivolumab improved proportionally to the increase in the PD-L1 expression, although many issues due to different antibodies and cut-off employed, the spatial and temporal tumour heterogeneity, make these results not fully reproducible at the moment in clinical practice. Given the different characteristics of the two drugs, the phenomenon of “pseudo-progression” and the sometimes delayed response type, the mPFS was lower for nivolumab compared with docetaxel (2.9 vs 4.2 months HR 0.92 p = 0.39). The toxicity profile was better for nivolumab, with grade 3–4 adverse events observed in 10% of patients treated with nivolumab and in 54% of patients treated with docetaxel. Similar results were observed with other PD1/PDL1 inhibitors (pembrolizumab and atezolizumab) in advanced NSCLC patients (Herbst et al, 2016, Reck et al, 2016, Fehrenbacher et al, 2016, and Barlesi et al, 2016).

Pembrolizumab is a highly selective, humanised, IgG4 monoclonal antibody against PD-1. In the Keynote 010 study, 1034 patients with previously treated NSCLC with PD-L1 expression on at least 1% of tumour cells were randomized to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m2 every 3 weeks. Overall survival was significantly longer for pembrolizumab 2 mg/kg (10.4 months,) and for pembrolizumab 10 mg/kg (12.7 months) versus docetaxel (8.5 months; p = 0.0008 and p < 0.0001, respectively). Among patients with at least 50% of tumour cells expressing PD-L1 with Dako companion test (Dako 22C3 antibody on tumor cells), overall survival was significantly longer with pembrolizumab 2 mg/kg (median 14·9 months) and with pembrolizumab 10 mg/kg (17.3 months) than with docetaxel (8.2 months; p = 0.0002 and p < 0·0001, respectively). Grade 3–5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (Herbst et al., 2016). Recently, in Keynote 024 study 305 patients with previously untreated NSCLC and an expression of at least 50% of PD-L1 were randomized to receive pembrolizumab at a fixed dose of 200 mg every 3 weeks or platinum based treatment. This study showed that pembrolizumab had, also in first-line setting, a better median progression-free survival (10.3 vs 6.0 months) and response rate (44.8% vs. 27.8%) compared to chemotherapy. Moreover, The estimated overall survival rate at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group and, last but not least, pembrolizumab showed fewer adverse events (Reck et al., 2016).

Atezolizumab is an engineered, humanised IgG1 monoclonal antibody anti-PD-L1 that blocks PD-L1–PD-1 and PD-L1–B7.1 interactions. In the POPLAR study, 287 patients who progressed on post-platinum chemotherapy were randomized to atezolizumab 1200 mg or docetaxel 75 mg/m2 every three weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells and tumour infiltrating immune cells by Ventana companion test (Ventana SP142 antibody). Overall survival was 12.6 months for atezolizumab versus 9.7 months for docetaxel (p = 0.04). Increasing improvement in overall survival was associated with increasing PD-L1 expression, but also patients with PD-L1 negative status according to the prespecified score, have had advantage of immunotherapy over docetaxel (Fehrenbacher et al., 2016). These results were confirmed by the OAK study, a randomized phase 3 clinical study that have showed the superiority of atezolizumab over docetaxel in pretreated patients with any histology. Median overall survival, the primary end point of the study, was 13.8 months with atezolizumab vs 9.6 months with docetaxel (p = 0.0003), and this difference was greater in patients with high expression of PDL-1 (20.5 vs 8.9 months, p < 0.0001) (Barlesi et al., 2016).

In conclusion, different drugs are now or will be soon available for the second-line treatment of patients with advanced non-squamous NSCLC, without clear and validated biomarkers. Moreover, recent studies conducted in Italy showed an increase in the number of NSCLC patients candidates for second-line (from 35% observed in 2011 to 70% in 2015) or third-line therapy (56% according to the LUME Lung 1 study and 42% according to the CheckMate 057 trial) (Gridelli et al, 2011, de Marinis et al, 2014, and Barni et al, 2015). At the present time the Italian National Health System reimburses nivolumab for pretreated squamous cell lung cancer while it is pending the decision regarding non-squamous counterpart. The docetaxel + nintedanib doublet is available as compassionate use while docetaxel + ramucirumab indication is waiting for regulatory agency submission. Therefore, the definition of a therapeutic pathway for patients with advanced non-squamous NSCLC is crucial, to exploit all the available options in the different lines of treatment, in order to guarantee the best clinical results.

3. Rationale and aims of the project

A project aimed to define an optimal therapeutic pathway for patients with non-squamous NSCLC, was designed and implemented in three successive steps. In the first step, a Board of Italian Oncologists experienced in the management of NSCLC cancer, supported by an Expert in molecular pathology, discussed and defined the structure of the project, proposing a list of predefined key topics on the second-line treatment of patients with non-squamous NSCLC to be discussed in three subsequent Italian regional meetings, as reported in Table 3. In the second step, 3 regional meetings, each one coordinated by two members of the Board and involving local oncologists representative of 40 different Institutions (General Hospitals, Cancer Centers, Academic Hospitals) experienced in NSCLC, were performed (Appendix A). During each meeting, a short review of literature data was presented, and then all participants discussed interactively the topics proposed, on the basis of literature data and their own personal experience. In particular, based on choice criteria for the second-line therapy previously identified, the more significant criteria for set up a therapeutic pathway for addressing the choice to anti-angiogenic plus chemotherapy combination or immunotherapy were selected. Panellists expressed their opinion on each criterion, defining their own preference for an anti-angiogenic plus chemotherapy treatment or immunotherapy or both. The results were graphically summarized and discussed in a plenary session. In the third step, the results of the 3 regional meetings were combined, to build a proposal of a decision-making tree for second-line treatment of non-squamous NSCLC.

Table 3

Key topics discussed by the Italian Lung Cancer Working Group.


A. Why should we talk today about of a treatment pathway for non-squamous NSCLC patients?
B. Can docetaxel be considered the standard second-line treatment today?
C. Which are the choice criteria for the second-line therapy?
D. What is the best treatment pathway for patients with advanced non-squamous NSCLC on the basis of clinical evidence?
E. What would it change in the second line in the light of a definite bio-marker?

4. Results of the project

4.1. Why should we talk today about of a treatment pathway for non-squamous NSCLC patients?

Currently, a higher number of patients affected by advanced NSCLC undergoes second-line treatment than in the past, thanks to a better overall management of NSCLC. Moreover, new effective second-line treatments for patients with wild-type advanced NSCLC are available, with 20–25% of patients achieving long survival. The Panellists agreed that the possibility of using several effective drugs with different mechanisms of action in a sequential mode, according to the characteristics of the patient and the disease, supports the need of a therapeutic pathway for each patient. Such therapeutic pathway should be planned before starting the first line therapy, on the basis of clinical characteristics of patients, in absence of defined predictive biomarkers that could influence the decision.

4.2. Can docetaxel be considered the standard second-line treatment today?

According to the Panellists, docetaxel in monotherapy has been considered up to now the standard second-line treatment, in particular after first-line platinum doublets with pemetrexed. However, due to the superiority of docetaxel plus nintedanib or docetaxel plus ramucirumab versus docetaxel alone showed by trials LUME-Lung-1 and REVEL, three-weekly docetaxel regimen should not be longer considered the gold standard in second line setting.

4.3. Which are the choice criteria for the second-line therapy?

Panellists agreed that the most important clinical criteria that influence therapeutic choice for the second-line therapy for patients with advanced non squamous NSCLC are: (1) “fit for chemotherapy”, defined as patients without significant cardiovascular, hepatic or renal comorbidities, major residual toxicities from first-line therapy or poor bone-marrow function; (2) autoimmune pathologies and active chronic viral liver diseases; (3) treatment with high-dose steroids; (4) haemorrhagic diathesis and sites of disease; (5) smoking status; (6) early progression after first-line therapy; (7) therapeutic pathway beyond second line; (8) T790 M negative tumours in patients harbouring EGFR activating mutations resistant to first line TKIs and platinum based doublets; (9) high tumour burden.

4.4. D. What is the best treatment pathway for patients with advanced non-squamous NSCLC on the basis of clinical evidence?

The Panellists discussed each criteria, expressing their preferences for a second-line therapy based on docetaxel plus angiogenesis inhibitors, or immunotherapy or both. The results of the survey are reported in Fig. 1.

  • 1. Patient FIT for chemotherapy: in this setting, all Panellists (100%) considered adequate the use angiogenesis inhibitors plus docetaxel, in absence of significant comorbidities, major residual toxicities of first-line therapy, poor bone-marrow function or hepatic/renal failure. However, the use of immunotherapy was not a priori ruled out in selected cases by 53% of Panellists. For defining the “fit for chemotherapy” status, Panellists agreed that the assessment of performance status (PS) is mandatory. PS 0–1 was a major inclusion criterion in LUME-Lung 1, REVEL, CheckMate 057 and KEYNOTE 010 studies.
  • 2. Autoimmune pathologies and active viral liver diseases: these criteria were unanimously considered for excluding immunotherapeutic agents such as nivolumab, and all the other checkpoint inhibitors (100% of Panellists).
  • 3. High-dose steroids: treatment with high dose steroids (prednisone >10 mg/day), before the beginning of second-line treatment, was unanimously considered a contraindication to the use of the immunotherapy (97% of Panellists).
  • 4. Haemorrhagic diathesis: angiogenesis inhibitors were considered not indicated in patients concomitantly treated with anticoagulant drugs, or with lesions infiltrating the vessels or with episodes of haemoptysis (88% of Panellists): in these case all Panellists (100%) considered adequate immunotherapy.
  • 5. Smoking: the Panellists preference (96%) was for the combination of chemotherapy and angiogenesis inhibitors in case of non-smoking patients, since the literature data (subgroup analysis of the CheckMate 057 study) show that in this population the advantage of immunotherapy is smaller, probably because of the lower immunogenicity of this type of tumours. On the contrary, in the LUME-Lung-1 there was not interaction between smoking status and effect of the combination of docetaxel and nintedanib. In smoker population, a choice between docetaxel + nintedanib vs nivolumab was considered not possible on the basis of smoking criterion only.
  • 6. Early progression: the best definition of rapid or early progression was discussed. Two main criteria should be considered: clinical and temporal. The results of the LUME-Lung 1 and REVEL trials, which show that the combination is more active on an aggressive tumour (both high disease burden and in rapid progression) induced most of the Panellists to prefer the docetaxel plus angiogenesis inhibitors (94%).
  • 7. Thinking about a therapeutic pathway beyond second line: in the perspective of planning a long therapeutic strategy for NSCLC patients and in consideration on the possibility of using immunotherapy also in the third line, most of Panellists prefer to use docetaxel plus angiogenesis inhibitors in the second line and immunotherapy in the third line, mainly due to safety considerations (86%).
  • 8. EGFR TKIs pretreated mutated positive and T790 M negative tumours: in the limited but nevertheless existing population of patients with a non T790 M EGFR resistance mutation after first-line treatment with TKI and with platinum based doublets, for which there are no specific biological drugs, docetaxel plus angiogenesis inhibitors may be preferred (75%). This regimen is preferable to immunotherapy with nivolumab on the basis of the negative subgroup data of the CheckMate 057 study.
  • 9. High disease burden: in case of high disease burden (there is not a unanimous definition), most of Panellists (75%) would choice chemotherapy associated with nintedanib, as this is able to reduce the disease symptoms more rapidly than immunotherapy.
Fig. 1

Fig. 1

Preferences of Panellists. Red: preference for angiogenesis inhibitor + docetaxel. Blue: preference for immunotherapy. The sum could not be 100%. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)


4.5. What would it change in the second line in the light of a definite bio-marker?

The therapeutic scenario could be significantly different with the availability of a biomarker that could orient the choice of second-line therapy. To date, the technical definition of the PD-L1 analysis (antibody clone to be used, dedicated detection system) is still not defined. Moreover, all the pivotal clinical studies evaluated PD-L1 expression by immunohistochemistry on histological specimens (small tissue biopsies), but the majority of samples available in clinical practice for second-line treatment are cytological specimens. To date, no harmonisation studies have been carried out on cytological specimens in order to provide assessment criteria reproducible and applicable in the clinical practice. Moreover, pembrolizumab has been developed with a companion test (a test necessary for the safe and efficacious use of the drug), while this is not the case for nivolumab and atezolizumab, developed with a complementary test (a test providing additional information regarding the use of the drug for patient management).

5. Discussion

The positive results with clinically significant survival improvement observed with new drugs in the second-line treatment of advanced non-squamous NSCLC will profoundly change the therapeutic approach of this kind of patients. Docetaxel as single agent will be not considered longer as the standard treatment and two different strategies will be soon available: immunotherapy and the combination of angiogenesis inhibitors with docetaxel. In the absence of definite biomarkers for immunotherapy or anti-angiogenesis treatment, only clinical criteria could be used in the next future to choice the right treatment.

This project of a large Italian Lung Cancer Working Group aimed to critically discuss all the available evidences for the second-line treatment of patients with advanced non-squamous NSCLC and to implement a therapeutic pathway that could help Oncologists in the choice of the best therapy, building a decision-making tree (Fig. 2).

Fig. 2

Fig. 2

Decision-making tree for second-line treatment of non-squamous NSCLC.


According to the Panellists, the first criteria to be considered for the choice of second-line treatment was the possibility of using chemotherapy (patient fit for chemotherapy). In case of patients unfit for chemotherapy or with conditions contraindicating the use of angiogenesis inhibitors, such as haemorragic diathesis or vascular infiltration, the preference of Panellists was for immunotherapy. On the contrary, in case of patients with conditions contraindicating the use of immunotherapy, such as autoimmune pathologies, active chronic viral liver diseases and high dose steroids needs, the Panellists considered a treatment with docetaxel and angiogenesis inhibitors as preferred. For patients fit for chemotherapy, without particular contraindications to the treatment with angiogenesis inhibitors plus docetaxel or with nivolumab, the preference of the Panellists favoured the choice of a second line treatment with docetaxel and angiogenesis inhibitors in case of non-smoker status, early progression, therapeutic pathway expected beyond second line, EGFR mutation positive with T790 M negative resistant to TKIs and platinum based chemotherapy, high disease burden.

The decision-making tree was not the result of a formal consensus meeting of a selected group of Lung Cancer experts, because the strict, precise methodological rules necessary for that purpose were not followed, but it was rather the expression and the result of a large independent working group of Italian experts in lung cancer, representing about 40 Institution of whole Italy. Another possible weakness of this project is that Panellists consider all the treatment options equally granted by local regulatory agencies. However reimbursement mechanisms and Health System affordability make differences of availability of this drugs across countries and sometimes nationwide. It is the case of nivolumab indication in pretreated non-squamous NSCLC, that was rejected by National Institute for Health and Care Excellence (NICE).

Finally, the Panellists identified as a priority for future clinical research, the identification of predictive biomarkers for immunotherapy, that could orient more precisely the choice of a second-line therapy for patients with advanced non-squamous NSCLC. The panellists are also aware that the newer clinical trials employing immune check-point modulators in first line setting maybe change the therapeutic strategy and accordingly part of the conclusion of this consensus.

In conclusion, this large Italian Lung Cancer Working Group has identified and discussed the more significant clinical criteria that should be considered in the definition of a shared therapeutic decision between the combination of angiogenesis inhibitors plus chemotherapy or immunotherapy, implementing a therapeutic pathway and building a proposal of a decision-making tree that could help Oncologists in the choice of the best second-line treatment for patients with non-squamous NSCLC.

Conflicts of interest

No relevant conflicts to disclose.


The Thoracic Medical Oncology of the National Cancer Institute of Naples is partially supported by Associazione Italiana per la Ricerca sul Cancro (AIRC). The project has been partially supported by Boehringer Ingelheim.

Appendix A. List of panellists attending the 3 meetings.

2 November, Milan 12 November, Rome 23 November, Naples
M.I. Abate, Monza M.I. Abate, Monza E. Baldino, Lucca
G.L. Banna, Catania F. Ambrosio, Naples C. Bareggi, Milan
F. Barbieri, Modena A. Bettini, Bergamo A. Bearz, Aviano
A. Bulotta, Milan F.L. Cecere, Rome G. Cerea, Milan
R. Buosi, Novara A. Delmonte, Meldola E. D’Argento, Rome
A.M. Carta, Cagliari R. Giusti, Rome U. Malapelle, Naples
C. Casartelli, Como U. Malapelle, Naples A. Manzo, Naples
G. Ceresoli, Bergamo F. Mazzoni, Florence M.R. Migliorino, Rome
R. Chiari, Perugia M.R. Migliorino, Rome A. Morabito, Naples
D. Cortinovis, Monza A. Morabito, Naples F. Oniga, Mestre
A. Follador, Udine G. Pasello, Padua D. Rocco, Naples
V. Gergorc, Milan F. Piantedosi, Naples G. Romano, Lecce
A. Luciani, Milan E. Roca, Brescia L. Rossi, Vicenza
U. Malapelle, Naples A. Russo, Palermo V. Scotti, Florence
A. Manzo, Naples C. Teragni, Pavia
H.J. SotoParra, Catania F. Verderame, Palermo
M. Tiseo, Parma
A. Tuzi, Varese
E. Vasile, Pisa
E. Vattemi, Bolzano
F.Zanelli,Reggio Emilia


  • Barlesi et al., 2016 Barlesi, F, Park, F, Ciardiello, F et al., Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC. ESMO 2016, Abstract LBA44_PR.
  • Barni et al., 2015 S. Barni, E. Maiello, M. Di Maio, et al. Adherence to AIOM (Italian Association of Medical Oncology) lung cancer guidelines in Italian clinical practice: Results from the RIGHT-3 (research for the identification of the most effective and highly accepted clinical guidelines for cancer treatment) study. Lung Cancer. 2015;90(2):234-242
  • Borghaei et al., 2015 H. Borghaei, L. Paz-Ares, L. Horn, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med.. 2015;373(17):1627-1639
  • de Marinis et al., 2014 F. de Marinis, A. Ardizzoni, G. Fontanini, et al. Management of Italian patients with advanced non-small-cell lung cancer after second-line treatment: results of the longitudinal phase of the LIFE observational study. Clin. Lung Cancer. 2014;15(5):338-345
  • Di Maio et al., 2007 M. Di Maio, F. Perrone, P. Chiodini, et al. Individual patient data meta-analysis of docetaxel administered once every 3 weeks compared with once every week second-line treatment of advanced non-small-cell lung cancer. J. Clin. Oncol.. 2007;25(11):1377-1382 Crossref
  • European Medicines Agency, 2016 European Medicines Agency, Opdivo (nivolumab): EU summary of product characteristics. 2016. (Accessed 8 August 2016).
  • Fehrenbacher et al., 2016 L. Fehrenbacher, A. Spira, M. Ballinger, et al. 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(10030):1837-1846
  • Fossella et al., 2000 F.V. Fossella, R. DeVore, R.N. Kerr, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J. Clin. Oncol.. 2000;18(12):2354-2362
  • Garon et al., 2014 E.B. Garon, T.E. Ciuleanu, O. Arrieta, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673 Crossref
  • Gridelli et al., 2011 C. Gridelli, A. Ardizzoni, S. Barni, et al. Medical treatment choices for patients affected by advanced NSCLC in routine clinical practice: results from the Italian observational SUN (Survey on the lUng cancer maNagement) study. Lung Cancer. 2011;74(3):462-468 Crossref
  • Hanna et al., 2004 N. Hanna, F.A. Shepherd, F.V. Fossella, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-smallcell lung cancer previously treated with chemotherapy. J. Clin. Oncol.. 2004;22(9):1589-1597 Crossref
  • Herbst et al., 2016 R.S. Herbst, P. Baas, D.W. Kim, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540-1550
  • Novello et al., 2015 S. Novello, R. Kaiser, A. Mellemgaard, et al. Analysis of patient-reported outcomes from the LUME-Lung 1 trial: a randomised, double-blind, placebo-controlled, Phase III study of second-line nintedanib in patients with advanced non-small cell lung cancer. Eur. J. Cancer. 2015;51(3):317-326 Crossref
  • Reck et al., 2014a M. Reck, S. Popat, N. Reinmuth, D. De Ruysscher, K.M. Kerr, S. Peters, on behalf of the ESMO Guidelines Working Group. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol.. 2014;25(Suppl. 3):27-39
  • Reck et al., 2014b M. Reck, D. Heigener, N. Reinmuth. Nintedanib for the treatment of patients with advanced non-small-cell lung cancer. Expert Rev. Clin. Pharmacol.. 2014;7(5):579-590 Crossref
  • Reck et al., 2014c M. Reck, R. Kaiser, A. Mellemgaard, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol.. 2014;15(2):143-155 Crossref
  • Reck et al., 2016 M. Reck, D. Rodríguez-Abreu, A. Robinson, et al. Pembrolizumab or chemotherapy in PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med.. 2016; 10.1056/NEJMoa1606774
  • Shepherd et al., 2000 F.A. Shepherd, J. Dancey, R. ramlau, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J. Clin. Oncol.. 2000;18(10):2095-2103
  • Shepherd et al., 2005 F.A. Shepherd, J.R. Pereira, T. Ciuleanu, et al. Erlotinib in previously treated non-small-cell lung cancer. N. Engl. J. Med.. 2005;353(2):123-132 Crossref


a SC Oncologia Medica asst, Monza H S Gerardo, Italy

b Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy

c UOSD Pneumologia Oncologica, Azienda Ospedaliera San Camillo-Forlanini, Roma, Italy

d SC Thoracic Medical Oncology Istituto Nazionale Tumori, “Fondazione G. Pascale”—IRCCS, Napoli, Italy

e Dipartimento di Sanità Pubblica, Università degli Studi di Napoli Federico II, Italy

Corresponding author at: Thoracic Medical Oncology, National Cancer Institute Via Mariano Semola, 80131 Naples, Italy.

1 Appendix A for a complete list of Italian Lung Cancer Working Group.

© 2016 Elsevier Ireland Ltd. All rights reserved.

No responsibility is assumed by Elsevier, its licensors or associates for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.  Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.  

This e-print is distributed with the support of Boehringer Ingelheim.

Edited for:
Elsevier España, S.L.U.
(A member of Elsevier)
Av. Josep Tarradellas, 20-30
08029 Barcelona
Tel.: 932 000 711
Fax: 932 091 136