==== Front ESMO OpenESMO OpenesmoopenesmoopenESMO Open2059-7029BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR esmoopen-2018-00039410.1136/esmoopen-2018-000394Original Research1506Phase II study assessing the benefit of cisplatin re-introduction (stop-and-go strategy) in patients with advanced non-squamous non-small cell lung cancer: the IFCT-1102 BUCiL study (a Better Use of Cisplatin in Lung cancer) Bennouna Jaafar 1Barlesi Fabrice 2Do Pascal 3Dumont Patrick 4Cadranel Jacques 5Debieuvre Didier 6Hilgers Werner 7Molinier Olivier 8Quoix Elisabeth 9Raimbourg Judith 10Langlais Alexandra 11Morin Franck 11Souquet Pierre-Jean 12 1 Thoracic Oncology, Department of Pneumology, Centre Hospitalier Universitaire de Nantes, Nantes, France 2 Multidisciplinary Oncology and Therapeutic Innovations Department, Aix Marseille University, Assistance Public Hôpitaux de Marseille, Marseille, France 3 Centre François Baclesse, Caen, France 4 Centre Hospitalier, Chauny, France 5 Assistance Publique Hôpitaux de Paris, Hôpital Tenon, service de Pneumologie and GRC 04 Theranoscan P&M Curie Université Paris 6, Paris, France 6 Service de Pneumologie, GHRMSA—Hôpital Emile Muller, Mulhouse, France 7 Oncologie—Médecine interne, Institut Sainte Catherine, Avignon, France 8 Thoracic Oncology, Centre Hospitalier Général, Le Mans, France 9 Service de Pneumologie, Nouvel Hôpital Civil, Strasbourg, France 10 Medical Oncology, Institut de cancérologie de l’Ouest—Centre René Gauducheau, St Herblain, France 11 Intergroupe Francophone de Cancérologie Thoracique, Paris, France 12 Centre Hospitalier Universitaire Lyon Sud, Pierre Bénite, France Correspondence to Professor Jaafar Bennouna; jaafar.bennouna@univ-nantes.fr2018 23 7 2018 3 5 e00039407 5 2018 14 6 2018 15 6 2018 © European Society for Medical Oncology 2018. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.2018This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.Introduction This single-arm phase II trial aimed to evaluate a stop-and-go strategy with cisplatin-based chemotherapy and bevacizumab in advanced non-squamous non-small cell lung cancer (NSCLC). Methods Patients were initially treated with three cycles of pemetrexed, cisplatin plus bevacizumab (sequence 1) followed by bevacizumab maintenance and after progression, re-introduction of three cycles of pemetrexed, cisplatin plus bevacizumab (sequence 2) and pemetrexed plus bevacizumab maintenance. The primary endpoint was the proportion of patients with advanced non-squamous NSCLC receiving the complete sequence 2 without platinum dose reduction (hypothesis ≥75%). Results 120 patients with performance status ≤1 were included. Of 113 patients evaluable for efficacy, 65 (57.5%) entered in sequence 2 and 56 (86%) received the three planned cycles including 37 (56.9%, 95% CI 45.1 to 73.6) without platinum dose reduction. The median progression-free survival 1 (PFS1; inclusion to progression 1) was 5.6 months (95% CI 5.0 to 6.3) and median PFS2 (progression 1 to progression 2) was 6.8 months (95% CI 5.8 to 8.8). The median disease control duration (PFS1+PFS2; n=65) was 12.4 months (95% CI 11.2 to 14.9). The median overall survival was 17.7 months (95% CI 13.1 to 21.6) and 20.5 months (95% CI 16.9 to 26.9) for patients reaching the sequence 2 (n=65). Conclusion Although the stringent primary endpoint was not met, this stop-and-go strategy with platinum-based chemotherapy plus bevacizumab continuation beyond progression compares favourably with standard schedule, deserving to be further studied in advanced non-squamous NSCLC. nsclcmetastaticcisplatinpemetrexedbevacizumabLigue Nationale contre le Cancerhttp://dx.doi.org/10.13039/501100006364Institut National Du Cancerhttp://dx.doi.org/10.13039/100004337Rochespecial-featureunlocked ==== Body Key questions What is already known about this subject? No clinical data are available about the re-introduction of pemetrexed+cisplatin following the first progression after three cycles of the same regimen in advanced non-small cell lung cancer (NSCLC). What does this study add? This phase II study underlines the feasibility of the stop-and-go strategy with bevacizumab continuation beyond progression. How might this impact on clinical practice? The stop-and-go strategy in advanced NSCLC should be re-evaluated in the era of immunotherapy+chemotherapy combination. Introduction Within the last years, the identification of genetic alterations in non-squamous (nsq) non-small cell lung cancer (NSCLC) has positioned this tumour pathology as a model for therapeutic innovation in oncology, and the search of actionable genomic alteration is now entered in routine practice.1 2 Taken together, epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase rearrangements are present in about 16% of cases while about half of nsqNSCLC did not exhibit any molecular alteration.1 That being said, platinum-based chemotherapy, combined or not with bevacizumab, remains a standard therapy in the management of advanced NSCLC.3–6 More recently, the anti-PD-1 antibody, pembrolizumab, has modified first-line strategy by becoming the standard for advanced NSCLC with PD-L1 expression on ≥50% of tumour cells.7 In second line, efficacy findings with pemetrexed monotherapy were disappointing in patients with advanced nsqNSCLC with a median overall survival (OS) of 9.3 months and a median progression-free survival (PFS) of 3.1 months.8 One study reported that the median PFS on such patients receiving pemetrexed–carboplatin combination after disease progression following a cisplatin-based regimen had a median PFS of 4.2 months compared with 2.8 months with pemetrexed alone (p=0.005). Nevertheless, no impact on OS was observed.9 Based on these results, the BUCiL (a Better Use of Cisplatin in Lung cancer) trial was designed to evaluate a stop-and-go strategy in advanced nsqNSCLC, introducing a therapeutic break with bevacizumab maintenance after a first three-cycle-sequence platinum-based chemotherapy with pemetrexed, followed with a similar chemotherapy sequence at disease progression. Thus, such strategy will make theoretically possible to delay the introduction of the second-line chemotherapy, with satisfactory safety. Materials and methods Patients and regulatory issues Adult patients with previously untreated documented advanced nsqNSCLC were eligible to the BUCiL study if they presented with at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST V.1.1). Patients had to be in good health condition (Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≤1) with adequate haematological, liver and renal functions. Patients should not present with EGFR mutation, symptomatic brain metastases, neither history of malignant tumours for less than 5 years except for in situ cervical tumours and basal cell carcinoma, nor common contraindication of bevacizumab in NSCLC. This study (EUDRACT 2012-002647-18) was approved by a local Ethic Committee and complied with French legislation, Good Clinical Practices and the principles outlined in the latest version of the Declaration of Helsinki. Study design This single-arm, multicentre, phase II clinical trial was conducted in patients with advanced nsqNSCLC who received a stop-and-go strategy (figure 1). At inclusion, patients started SEQUENCE 1 treatment with 3-week cycles of cisplatin (75 mg/m²)–pemetrexed (500 mg/m²) chemotherapy combined with bevacizumab (7.5 mg/kg). Afterwards, non-progressing patients received bevacizumab alone (7.5 mg/kg every 3 weeks) as maintenance therapy until progression or unacceptable toxicity. At disease progression, patients resumed similar platinum-based regimen (SEQUENCE 2) followed by pemetrexed–bevacizumab maintenance. Cisplatin could be switched to carboplatin according to investigator decision in case of unacceptable cisplatin toxicity. Figure 1 Study design. Assessments At inclusion, patient’s characteristics, CT-scan assessments, relevant medical history, concomitant treatments, disease history, EGFR status and laboratory tests to confirm selection criteria were collected. At each follow-up visit, clinical data, disease evolution, regimens of bevacizumab and chemotherapy, and other concomitant treatments were reported. At each cycle, clinical examination and all the laboratory tests were performed, including haematological, liver and renal function tests. Adverse events (AEs) were reported including AEs of special interest for bevacizumab (hypertension, pulmonary embolism, proteinuria, haemorrhages). AE severity was assessed using WHO Handbook for Reporting Results of Cancer Treatment 4-grade classification.10 CT-scan assessments were performed at the end of the induction chemotherapy (three cycles) and every two cycles during maintenance treatments using RECIST V.1.1. Statistical methods Using a single-step Fleming method, a sample size of 59 assessable patients was required to make possible to estimate with an alpha risk of 5% (one-sided) and a power of 95% the proportion of those receiving three cycles of chemotherapy without dose reduction of platinum-based chemotherapy during SEQUENCE 2 (null hypothesis H0: p≤p0=55%; alternative hypothesis H1: p≥p1=75%). Assuming that 10% of patients may not be assessable and 55% of patients were expected to enter SEQUENCE 2, a total of 118 patients had to be enrolled in the study. Patient and disease characteristics were analysed for all the included patients. The primary efficacy criterion was the percentage of eligible patients who received the three-cycle SEQUENCE 2 chemotherapy without platinum dose reduction or switch to carboplatin after the first disease progression. OS was defined as the time between patient’s inclusion and the death from any cause. PFS1 was defined as the time from inclusion to the first disease progression (as assessed by the investigator, using RECIST V.1.1) or death from any cause, whatever came first. The time taken into account for PFS2 was between first and second disease progressions or death. Disease control duration (DDC) was the sum of PFS1 and PFS2. Median OS, PFS and DDC were estimated using the Kaplan-Meier method with associated 95% CI. Safety data were analysed all over the study period in included patients, with a focus on study treatment-related AEs and AEs of special interest related to bevacizumab. Statistical analyses were performed using SAS software V.9.3 (SAS Institute, Cary, North Carolina, USA), and two-sided tests with type I error α=0.05 were applied for all analyses. Results Patients’ disposal and characteristics From December 2012 to August 2014, 14 hospital centres from the French Cooperative Thoracic Intergroup included 120 patients. Among these patients, 113 were evaluable for efficacy at SEQUENCE 1 and 65 of them for SEQUENCE 2 (figure 2). Otherwise, the safety analysis was initially performed for 118 patients because two patients were never treated in the protocol (one contraindication to bevacizumab and one rapid progression disease). For the SEQUENCE 2, 68 patients were considered for safety. Figure 2 Study flowchart. EGFR, epidermal growth factor receptor. C, cycle. Most of the patients were men (64%), less than 70 years old (88%) at inclusion, current smokers (83%), with adenocarcinoma without bronchioloalveolar component (94%) and metastasis (99%) (table 1). ECOG-PS was scored ‘1’ for half of them. Table 1 Patient and disease characteristics at baseline—analysis population (n=120) Total (n=120) Male, n (%) 77 (64.2) Age, years  Median (min; max) 60.6 (36.0–77.3)  ≤70 years, n (%) 105 (87.5) Smoking status, n (%)  Never and former/current 21 (17.5)/99 (82.5)  No of pack-years*, median (min; max) 40.0 (5.0–160.0) ECOG performance status*, n (%)  0 60 (50)  1 60 (50) Disease stage at inclusion n (%)  M0 1 (0.8)  M1a 39 (32.5)  M1b 80 (66.7) Pathological type, n (%)  Adenocarcinoma without bronchioloalveolar component 113 (94.2)  Adenocarcinoma with bronchioloalveolar component 2 (1.7)  Large cell carcinoma 5 (4.2) *Missing data: number of pack-years (3). ECOG, Eastern Cooperative Oncology Group; M, metastatic stage. Efficacy results Out of the 65 patients entered in the SEQUENCE 2, 37 patients (56.9%; 95% CI 45.1 to 73.6) received all the three cycles of chemotherapy without dose reduction of cisplatin or switch for carboplatin (primary criterion, figure 3). Otherwise, for 16 patients, cisplatin has been switched for carboplatin during SEQUENCE 2, and 56 patients (86%) completed this sequence disregarding platinum-salt dose reduction or not. Overall, 47 patients received pemetrexed plus bevacizumab in maintenance therapy after sequence 2. Figure 3 Proportion of patients receiving three cycles of chemotherapy without dose reduction of cisplatin or switch to carboplatin during the second sequence of chemotherapy (primary criterion). C, cycle; EGFR, epidermal growth factor receptor. At the time of analysis, five patients (4%) were still treated in SEQUENCE 1 bevacizumab maintenance at the end of the study. After a median follow-up of 31.6 months (95% CI 29.7 to not reached), the median PFS1 (defined as the time from inclusion to the first disease progression or death) was 5.6 months (95% CI 5.0 to 6.3) in the 113 eligible patients. The median PFS2 (defined as the time from first to second disease progression or death) was 6.8 months (95% CI 5.8 to 8.8) for the 65 eligible patients entered in SEQUENCE 2. The median DDC (PFS1+PFS2) was 12.4 months (95% CI 11.2 to 14.9). After SEQUENCE 2, 75.4% of the patients (49/65) reached a disease control with 10 of these 65 patients having reached RECIST objective response (15.4%; 95% CI 6.6 to 24.2). From inclusion, the median OS was 17.7 months (95% CI 13.1 to 21.6) in the 113 patients evaluable for efficacy (figure 4). For the 65 patients eligible for SEQUENCE 2, it was 20.5 months (95% CI 16.9 to 26.9) and 14.1 months (95% CI 11.6 to 20.0) from the introduction of the SEQUENCE 2 (at first disease progression). Figure 4 Overall survival (OS) from patient inclusion—eligible population (n=113). Safety results Over the study period, at least one chemotherapy-related or bevacizumab-related AE was reported in 100% of the patients of the safety population (n=118) and at least one grade ≥3 AE related to study treatments was reported in 50 patients (42.4%). At least one study treatment-related AE was reported in 66 patients (97.1%) of SEQUENCE 2 safety population (n=68), and at least one grade ≥3 related AE was reported in 41 patients (60.3%) (table 2). Two patients (2.9%) had at least one fatal study treatment-related AE (one haemoptysis and one sepsis). Thus, 33.8% of the 68 patients experienced at least one grade ≥3 study treatment-related haematological AE (mainly neutropenia, 26.5% of the patients) and 11.8% at least one grade ≥3 AE of special interest related to bevacizumab (mainly hypertension, 7.4% of the patients). Table 2 Treatment-emergent adverse events related to bevacizumab or chemotherapy—safety population of patients entered in the SEQUENCE 2 chemotherapy (n=68) AEs n (%) Grade 3–4 AEs n (%) Grade 5 AEs n (%) AEs of special interest for bevacizumab 44 (64.7) 8 (10.3) 1 (1.5)  Epistaxis 22 (32.4) 0 0  Hypertension 16 (23.5) 5 (7.4) 0  Haemoptysis 4 (5.9) 0 1 (1.5)  Pulmonary embolism 1 (1.5) 1 (1.5) 0  Proteinuria 12 (17.6) 1 (1.5) 0  Other haemorrhage* 5 (7.4) 1 (1.5) 0 Haematological AEs 49 (72.1) 23 (33.8) 0  Anaemia 46 (67.6) 11 (16.2) 0  Neutropenia 31 (45.6) 18 (26.5) 0  Thrombocytopenia 21 (30.9) 10 (14.7) 0  Febrile neutropenia 4 (5.9) 4 (5.9) 0 Other AEs 61 (89.7) 13 (19.1) 1 (1.5)  Asthenia† 54 (79.4) 10 (14.7) 0  Nausea 38 (55.9) 2 (2.9) 0  Vomiting 14 (20.6) 2 (2.9) 0  Diarrhoea 13 (19.1) 0 0  Constipation 12 (17.6) 0 0  Stomatitis‡ 20 (29.4) 4 (5.9) 0  Renal failure 6 (8.8) 0 0  Anorexia 22 (32.4) 4 (5.9) 0  Conjunctivitis§ 17 (25.0) 0 0  Sepsis 1 (1.5) 0 1 (1.5)  Peripheral neuropathy¶ 8 (11.8) 0 0  Alopecia 4 (5.9) 0 0  Hypoacusis** 4 (5.9) 0 0 *Rectal haemorrhage, gingival bleeding and haemorrhoids. †Asthenia, general physical health deterioration and fatigue. ‡Stomatitis, dry mouth, aphthous stomatitis and oral candidiasis. §Lacrimation increased and conjunctivitis. ¶Paraesthesia and peripheral neuropathy. **Tinnitus and hypoacusis. AE, adverse event. Discussion The identification of actionable genomic alterations has entered in routine practice to select the appropriate patients for target therapy.1 Similarly, immune checkpoint inhibitors, promoting the restoration of host immunity against tumours, are making possible a durable response for patients in several cancers.7 11–15 Thus, more predictive biomarkers for immunotherapy response will be integrated in the guide therapeutic decision-making, as many patients respond to such treatment.16 However, for patients not eligible for tailored treatment, platinum-based chemotherapy, combined or not with bevacizumab, remains a major issue in advanced NSCLC as established in several experimental and real-life studies.3 5 17–20 To improve outcome in such patients, new schedules may be explored. Recently, in metastatic colorectal cancer, a stop-and-go strategy with oxaliplatin-based chemotherapy showed limited toxicity without any pejorative impact on efficacy.21–23 On the basis of these positive findings, the aim of our study was to demonstrate the relevance of a stop-and-go strategy in patients with non-squamous advanced NSCLC with ECOG-PS ≤1, by assessing the feasibility of platinum-salt re-introduction after disease progression following bevacizumab maintenance, with a shortened first chemotherapy period (three cycles instead of four to six as usually recommended).24–26 The primary endpoint was not met: 56.9% (95% CI 45.1% to 73.6%) of the 65 patients entered in the second sequence received the three full cycles of chemotherapy without platinum-salt dose reduction, instead of 75% as expected. However, 56 patients (86%) completed all the three cycles with or without platinum-salt dose reduction. This primary endpoint could be thus considered as too stringent, and this study highlighted that a ‘stop-and-go’ strategy compares favourably with standard schedule. The median OS from inclusion was 17.7 months, which is longer than in the PointBreak Study (patients with stage IIIB or IV non-squamous NSCLC, ECOG-PS ≤1, up to four cycles of induction therapy: 12.6 months in the pemetrexed–carboplatin–bevacizumab arm).27 It was also longer than in previous studies with other standard chemotherapies combined with bevacizumab (median OS in the SAiL study: 14.6 months).17 In our study, the median OS of patients who reached SEQUENCE 2, re-challenged with pemetrexed–cisplatin–bevacizumab followed by pemetrexed–bevacizumab maintenance, was 20.5 months, which is similar to the 19.8 months observed in the AVAPERL study (patients with advanced nsqNSCLC, ECOG-PS ≤2, four cycles with pemetrexed–cisplatin–bevacizumab followed by pemetrexed–bevacizumab maintenance).28 Otherwise, the median OS calculated from the start of the SEQUENCE 2 chemotherapy (14.1 months) could be compared with the second-line studies showing a median OS of about 8 months with pemetrexed monotherapy.29 Moreover, when considering the median OS of patients with advanced nsqNSCLC treated with second-line immunotherapy, it was 12.2 months in patients treated with nivolumab (and 9.4 months for the docetaxel comparator arm), but it did not exceed 10 months in both arms when PD-L1 expression <10%.10 However, the impact of immune checkpoint inhibitor is delayed and 1-year or 2-year PFS rate parameters better reflect their efficacy. Otherwise, the median PFS from the re-introduction of chemotherapy was 6.8 months, which corresponded to a disease control in 75.4% of these patients. This proportion is higher than in the PointBreak study (65.9%). Finally, the median DDC (ie, PFS1 plus PFS2) was 12.4 months, allowing to delay the second-line therapy. Regarding safety data of the population who entered in SEQUENCE 2 combination therapy, the proportion of patients with at least one grade ≥3 related adverse event is consistent with previous findings on bevacizumab combination therapy, without any unexpected trend.30 31 Our stop-and-go strategy (with two sequences of three-cycle platinum–pemetrexed chemotherapy combined with bevacizumab) could be compared with the PointBreak study based on four successive cycles containing the same components.26 Regarding grade ≥3 related haematological adverse events, similar results were observed apart from thrombocytopeniae less frequently reported in our SEQUENCE 2 population (14.7% vs 23.3%). For grade ≥3 related clinical adverse events, no fatigue was reported in our SEQUENCE 2 patients (vs in 11% of patients in the PointBreak study), but hypertension onset was more often reported (7.4% vs 3.4% of patients). Finally, our stop-and-go strategy tends to show satisfactory safety findings in patients with advanced nsqNSCLC. In conclusion, even though the emergence of immune checkpoint inhibitors led to postulate that therapeutic strategy in NSCLC will be fully modified in the near future as it was the case with the raising of targeted therapy, platinum-based chemotherapy will likely remain one major therapy. To patients with advanced nsqNSCLC who do not positively answer to predictive biomarkers for tailored therapy, the BUCiL study proposes a new therapeutic option with a stop-and-go strategy, which deserved to be further studied. In addition, with the emergence of immunotherapy, new therapeutic strategies are being evaluated. One schedule that can be proposed could combine two cycles of cisplatin-based chemotherapy with an immune checkpoint inhibitor (ICI). The ICI will be maintained until progression of disease. In this situation, the issue of cisplatin or carboplatin re-introduction will be raised. Short clinical practice points section A stop-and-go strategy with cisplatin or carboplatin re-introduction could be a valid option in patients with advanced NSCLC and not eligible for immunotherapy or targeted therapy. The authors thank all the patients for their participation in the study as well as all the investigators. For this study, support was provided by Roche (bevacizumab supply for the second sequence of treatment and unrestricted grant), IFCT (monitoring and logistic services), IFCT (data management and statistical analyses) and AUXESIA (manuscript preparation). Funding: This work was supported by Roche, the French National Cancer Institute (INCa) and French League Against Cancer. Competing interests: JB: advisory board for Roche, Bristol-Myers Squibb, Boehringer-Ingelheim and Astra-Zeneca. FB: personal fees for Astra-Zeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Clovis Oncology, Eli Lilly Oncology, F Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre and Pfizer. JC: participation to boards of experts for Lilly, Roche, Astra-Zeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Pfizer and Novartis. OM: advisory board for Roche. EQ: advisory board for Novartis, Abbvie and Roche; travel meeting grant and honoraria for Boehringer-Ingelheim; travel meeting grant for Pfizer, Amgen and Lilly. JR: personal fees for Pierre Fabre, Bayer and Novartis. P-JS: grants and non-financial support for Roche and Lilly. Patient consent: Not required. Ethics approval: Comité de Protection des Personnes. Provenance and peer review: Not commissioned; internally peer reviewed. ==== Refs References 1. Richer AL , Friel JM , Carson VM , et al Genomic profiling toward precision medicine in non-small cell lung cancer: getting beyond EGFR . Pharmgenomics Pers Med 2015 ;8 :63 –79 . 10.2147/PGPM.S52845 25897257 2. Barlesi F , Mazieres J , Merlio JP , et al Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT) . Lancet 2016 ;387 :1415 –26 . 10.1016/S0140-6736(16)00004-0 26777916 3. Reck M , von Pawel J , Zatloukal P , et al Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL) . Ann Oncol 2010 ;21 :1804 –9 . 10.1093/annonc/mdq020 20150572 4. Reck M , Popat S , Reinmuth N , et al Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up . Ann Oncol 2014 ;25 :iii27 –39 . 10.1093/annonc/mdu199 25115305 5. Sandler A , Gray R , Perry MC , et al Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer . N Engl J Med 2006 ;355 :2542 –50 . Erratum in: N Engl J Med 2007;356:318 10.1056/NEJMoa061884 17167137 6. Niho S , Kunitoh H , Nokihara H , et al Randomized phase II study of first-line carboplatin–paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer . Lung Cancer 2012 ;76 :362 –7 . 10.1016/j.lungcan.2011.12.005 22244743 7. Reck M , Rodríguez-Abreu D , Robinson AG , et al Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer . N Engl J Med 2016 ;375 :1823 –33 . 10.1056/NEJMoa1606774 27718847 8. Scagliotti G , Hanna N , Fossella F , et al The differential efficacy of pemetrexed according to NSCLC histology: a review of two phase III studies . Oncologist 2009 ;14 :253 –63 . 10.1634/theoncologist.2008-0232 19221167 9. Smit EF , Burgers SA , Biesma B , et al Randomized phase II and pharmacogenetic study of pemetrexed compared with pemetrexed plus carboplatin in pretreated patients with advanced non-small-cell lung cancer . J Clin Oncol 2009 ;27 :2038 –45 . 10.1200/JCO.2008.19.1650 19307503 10. World Health Organisation . WHO Handbook for reporting results of cancer treatment . London : ISBN , 1979 ;92 :3 . 11. Borghaei H , Paz-Ares L , Horn L , et al Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer . N Engl J Med 2015 ;373 :1627 –39 . 10.1056/NEJMoa1507643 26412456 12. Langer CJ , Gadgeel SM , Borghaei H , et al Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study . Lancet Oncol 2016 ;17 :1497 –508 . 10.1016/S1470-2045(16)30498-3 27745820 13. Topalian SL , Hodi FS , Brahmer JR , et al Safety, activity, and immune correlates of anti-PD-1 antibody in cancer . N Engl J Med 2012 ;366 :2443 –54 . 10.1056/NEJMoa1200690 22658127 14. Garon EB , Rizvi NA , Hui R , et al Pembrolizumab for the treatment of non-small-cell lung cancer . N Engl J Med 2015 ;372 :2018 –28 . 10.1056/NEJMoa1501824 25891174 15. Brahmer J , Reckamp KL , Baas P , et al Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer . N Engl J Med 2015 ;373 :123 –35 . 10.1056/NEJMoa1504627 26028407 16. Spencer KR , Wang J , Silk AW , et al Biomarkers for immunotherapy: current developments and challenges . Am Soc Clin Oncol Educ Book 2016 ;35 :e493 –503 . 10.14694/EDBK_160766 27249758 17. Lynch TJ , Spigel DR , Brahmer J , et al Safety and effectiveness of bevacizumab-containing treatment for non-small-cell lung cancer: final results of the ARIES observational cohort study . J Thorac Oncol 2014 ;9 :1332 –9 . 10.1097/JTO.0000000000000257 25122429 18. Dansin E , Cinieri S , Garrido P , et al MO19390 (SAiL): bleeding events in a phase IV study of first-line bevacizumab with chemotherapy in patients with advanced non-squamous NSCLC . Lung Cancer 2012 ;76 :373 –9 . 10.1016/j.lungcan.2011.11.020 22236866 19. Crinò L , Dansin E , Garrido P , et al Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study . Lancet Oncol 2010 ;11 :733 –40 . 10.1016/S1470-2045(10)70151-0 20650686 20. Chouaid C , Falchero L , Schott R , et al [Bevacizumab in combination with first-line treatment for metastatic non-small cell lung cancer in clinical practice. Results of the EOLE study] . Rev Mal Respir 2017 ;34 :30089 –4 . 10.1016/j.rmr.2016.05.003 21. Tournigand C , Cervantes A , Figer A , et al OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer—a GERCOR study . J Clin Oncol 2006 ;24 :394 –400 . 10.1200/JCO.2005.03.0106 16421419 22. Chibaudel B , Maindrault-Goebel F , Lledo G , et al Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study . J Clin Oncol 2009 ;27 :5727 –33 . 10.1200/JCO.2009.23.4344 19786657 23. Hochster HS , Grothey A , Hart L , et al Improved time to treatment failure with an intermittent oxaliplatin strategy: results of CONcePT . Ann Oncol 2014 ;25 :1172 –8 . 10.1093/annonc/mdu107 24608198 24. National Comprehensive Cancer Network . NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer . 2012 http://www.nccn.org/professionals/physician_gls/f_guidelines.asp 25. D’Addario G , Früh M , Reck M , et al Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up . Ann Oncol 2010 ;21 :v116 –19 . 10.1093/annonc/mdq189 20555059 26. Azzoli CG , Temin S , Aliff T , et al 2011 Focused update of 2009 American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non-small-cell lung cancer . J Clin Oncol 2011 ;29 :3825 –31 . 10.1200/JCO.2010.34.2774 21900105 27. Patel JD , Socinski MA , Garon EB , et al PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer . J Clin Oncol 2013 ;31 :4349 –57 . 10.1200/JCO.2012.47.9626 24145346 28. Barlesi F , Scherpereel A , Gorbunova V , et al Maintenance bevacizumab–pemetrexed after first-line cisplatin–pemetrexed–bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial . Ann Oncol 2014 ;25 :1044 –52 . 10.1093/annonc/mdu098 24585722 29. Hanna N , Shepherd FA , Fossella FV , et al Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy . J Clin Oncol 2004 ;22 :1589 –97 . 10.1200/JCO.2004.08.163 15117980 30. Reck M , von Pawel J , Zatloukal P , et al Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil . J Clin Oncol 2009 ;27 :1227 –34 . 10.1200/JCO.2007.14.5466 19188680 31. Sandler A , Yi J , Dahlberg S , et al Treatment outcomes by tumor histology in Eastern Cooperative Group Study E4599 of bevacizumab with paclitaxel/carboplatin for advanced non-small cell lung cancer . J Thorac Oncol 2010 ;5 :1416 –23 . 10.1097/JTO.0b013e3181da36f4 20686429