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Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial

Lung Cancer. 2016;102:65-73.

Highlights

  • Nintedanib plus docetaxel improved PFS for pretreated NSCLC compared with docetaxel in LUME-Lung 1.
  • LUME-Lung 2 investigated nintedanib plus pemetrexed in pretreated non-squamous NSCLC.
  • The trial was stopped early although did meet the primary endpoint (PFS).
  • There were no safety concerns with the addition of nintedanib to pemetrexed.

Abstract

Objectives

LUME-Lung 2 investigated the efficacy/safety of nintedanib plus pemetrexed in patients with pretreated non-squamous non-small cell lung cancer (NSCLC).

Materials and methods

Patients with stage IIIB/IV or recurrent non-squamous NSCLC who had received one prior chemotherapy regimen were randomized (1:1 stratified by histology [adenocarcinoma/non-adenocarcinoma], prior bevacizumab, Eastern Cooperative Oncology Group performance status and presence of brain metastases) to receive intravenous pemetrexed 500 mg/m2 on Day 1 plus nintedanib 200 mg orally twice daily or matching placebo on Days 2–21, every 3 weeks until progression/unacceptable toxicity. Progression-free survival (PFS) by independent central review was the primary endpoint. Overall survival (OS) was the key secondary endpoint.

Results

Based on the pre-planned futility analysis of investigator-assessed PFS, conducted by an independent data monitoring committee, recruitment was halted on 18 June 2011 after 713 (n = 353 nintedanib/pemetrexed; n = 360 placebo/pemetrexed)/1300 planned patients had enrolled. There were no safety concerns. Subsequent analysis demonstrated a significant improvement in PFS favoring nintedanib/pemetrexed over placebo/pemetrexed (median 4.4 months vs 3.6 months; hazard ratio [HR] = 0.83, 95% confidence interval [CI] 0.70–0.99, p = 0.0435). There was no significant difference in OS (median 12.0 months vs 12.7 months; HR = 1.01, 95% CI 0.85–1.21, p = 0.8940) after 514 deaths. Nintedanib/pemetrexed resulted in a higher incidence of grade ≥3 elevated alanine aminotransferase (23.3% vs 7.3%), elevated aspartate aminotransferase (12.1% vs 1.7%) and diarrhea (3.5% vs 1.1%) compared with placebo/pemetrexed, but no difference in hypertension, bleeding or thrombosis.

Conclusion

Although recruitment stopped prematurely, combining nintedanib with pemetrexed significantly prolonged PFS in patients with advanced non-squamous NSCLC after first-line chemotherapy, with a manageable safety profile.

Abbreviations: NSCLC - non small cell lung cancer, VEGF(R) - vascular endothelial growth factor (receptor), PDGF(R) - platelet-derived growth factor (receptor), FGR(R) - fibroblast growth factor (receptor), PFS - progression-free survival, HR - hazard ratio, CI - confidence interval, OS - overall survival, RECIST - response evaluation criteria in solid tumors, ECOG PS - Eastern Cooperative Oncology Group performance status, CT - computed tomography, MRI - magnetic resonance imaging, AE - adverse event, CTCAE - common toxicity criteria for adverse events, QoL - quality of life, DMC - data monitoring committee, ITT - intention-to-treat, IQR - interquartile range, EGFR - epidermal growth factor receptor, ALK - anaplastic lymphoma kinase.

Keywords: Angiogenesis inhibitor, Phase III, Nintedanib, Non-small cell lung cancer, Second-line.

1. Introduction

For patients with advanced non-small cell lung cancer (NSCLC), without known targetable mutations, platinum-based combination therapy is the recommended first-line therapy [1] and [2]. However, nearly all patients experience disease progression and eligible patients will require second-line treatment, mainly with pemetrexed, docetaxel or erlotinib monotherapy [1] and [2].

Signaling pathways regulated by vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF), and their associated receptors (VEGFR, PDGFR and FGFR, respectively), play an important role in tumor angiogenesis [3]. Inhibition of these angiogenic targets has shown substantial antitumor activity in preclinical models of human cancer, including NSCLC [4]. Nintedanib is an oral, potent triple angiokinase inhibitor with proven preclinical antiangiogenic and antitumor activity, targeting all subtypes of VEGFR, PDGFR and FGFR [4].

The combination of nintedanib plus docetaxel in previously treated patients with advanced or recurrent NSCLC was assessed in the phase III LUME-Lung 1 trial (NCT00805194; 1199.13) [5]. In LUME-Lung 1, patients who met similar eligibility criteria as in the current study (except that patients with squamous cell carcinoma were enrolled in LUME-Lung 1) were randomized to receive nintedanib plus docetaxel or placebo plus docetaxel. Nintedanib plus docetaxel significantly improved centrally reviewed progression-free survival (PFS; median 3.4 months vs 2.7 months; hazard ratio [HR] = 0.79, 95% confidence interval [CI]: 0.68–0.92, p = 0.0019) in all patients and significantly prolonged overall survival (OS) in the prespecified population of patients with adenocarcinoma tumor histology (median 12.6 months vs 10.3 months; HR = 0.83, 95% CI: 0.70–0.99, p = 0.0359) compared with docetaxel alone. Nintedanib combined with docetaxel is approved in the European Union and other countries for the treatment of patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumor histology after first-line chemotherapy, and has also been approved as monotherapy for the treatment of patients with idiopathic pulmonary fibrosis.

Combination therapy with nintedanib and pemetrexed has been shown to enhance antitumor activity compared with either agent alone in in vivo experiments in xenograph models, and has also shown a marked impact on the proliferation and survival of tumor and endothelial cells in vitro[6]. Nintedanib in combination with pemetrexed has previously been shown to have a manageable tolerability in platinum-pretreated patients with advanced NSCLC in a phase I study, with a median PFS of 5.4 months [7]. Although pemetrexed is frequently used in the first-line setting as part of platinum doublet therapy in patients with non-squamous NSCLC [8], it is not used universally and pemetrexed continues to be used in the second-line setting in some patients. Based on the expected lack of drug–drug interactions, a global, randomized, placebo-controlled, phase III trial (LUME-Lung 2, NCT00806819; 1199.14) was conducted in parallel to LUME-Lung 1 to assess whether using nintedanib plus pemetrexed (nintedanib–pemetrexed) for previously treated patients with advanced or recurrent, non-squamous NSCLC led to greater efficacy than using pemetrexed alone.

2. Materials and methods

2.1. Patients

We carried out this study in 202 centers in 32 countries (North and South America, Europe, Asia and Australia/Oceania). Patients were 18 years or older with histologically or cytologically confirmed stage IIIB/IV or recurrent, non-squamous NSCLC, and either had relapsed or had failed one prior line of chemotherapy (excluding neoadjuvant and/or adjuvant chemotherapy for recurrent disease). All patients had at least one measurable target tumor lesion, according to modified Response Evaluation Criteria In Solid Tumors version 1.0 (RECIST v1.0) [9], that had not been irradiated within the past 3 months; an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; and a life expectancy of at least 3 months. Exclusion criteria included patients with active brain metastases (defined as stable for <4 weeks, no adequate previous treatment with radiotherapy, symptomatic or requiring treatment with anticonvulsants). Patients with radiographic evidence of cavitary or necrotic tumors, centrally located tumors with radiographic evidence (computed tomography [CT] or magnetic resonance imaging [MRI]) of local invasion of major blood vessels, or a recent history ( <3 months) of clinically significant hemoptysis or a major thrombotic or clinically relevant major bleeding event in the past 6 months, were also excluded from the study, as were those who had received prior therapy with VEGF/VEGFR inhibitors (other than bevacizumab) or pemetrexed. Detailed eligibility criteria are described in Appendix Table S1.

The trial was approved by local independent ethics committees, including an independent review board, and complied with the Declaration of Helsinki and Good Clinical Practice principles. All patients provided written informed consent and were free to withdraw from the study at any time.

2.2. Procedures

Patients were randomized in a 1:1 ratio to receive nintedanib–pemetrexed or placebo–pemetrexed (see Appendix for details). Patients were stratified by ECOG PS (0 vs 1), previous bevacizumab treatment (yes vs no), histology (adenocarcinoma vs non-adenocarcinoma) and presence of stable brain metastases (yes vs no). Pemetrexed 500 mg/m2 was administered intravenously on Day 1, combined with either oral nintedanib 200 mg twice daily or matching placebo, given on Days 2–21, every 3 weeks. Two capsules of nintedanib 100 mg or placebo were to be taken in the morning and again in the evening, after food. Patients received treatment until unacceptable toxicity or disease progression, or until they met another of the predefined withdrawal criteria (see Appendix for details of adverse event (AE) management).

Target lesions were evaluated by central independent review according to modified RECIST [9] at baseline (within 4 weeks of the start of study treatment) and every 6 weeks after the first administration of pemetrexed thereafter. One additional scan was also performed after progression if the patient had received no further anticancer treatment. All imaging (MRI or CT) data were evaluated by central independent review and investigator assessment.

AEs classified according to Common Toxicity Criteria for Adverse Events (CTCAE) v3.0, and laboratory safety parameters, were monitored throughout the trial and also beyond if AEs had not resolved at the end of treatment.

2.3. Outcomes

The primary endpoint was PFS (according to modified RECIST), as assessed by independent central review. PFS was defined as the time from randomization to progression or death, whichever occurred earlier. The key secondary endpoint was OS, defined as the time from randomization to death. Other secondary outcomes included investigator-assessed PFS, best tumor response (modified RECIST), disease control (objective responses plus stable disease) and safety/tolerability of nintedanib.

Lung cancer symptoms and health-related quality of life (QoL) were assessed every 21 days using the European Organisation for Research and Treatment of Cancer Quality of Life-C30 [10] and [11] and Lung Cancer-13 [12] questionnaires. Analyses of cough, dyspnea and pain were pre-planned.

2.4. Statistical analysis

Based on a stratified log-rank test with a two-sided α-level of 0.05, 713 PFS events were needed for the primary analysis to detect a HR of 0.78 (27.5% increase in median PFS) with 90% power. For the final analysis of OS, 1151 deaths would have 80% power to detect a HR of 0.85 (18% improvement in median OS) at a two-sided α-level of 0.05 using a stratified log-rank test and a two-look Lan–DeMets group sequential design with an O’Brien–Fleming-type boundary. Assuming a 10% loss to follow-up, 1300 patients were to be randomized. A pre-planned futility analysis was to be performed by the independent data monitoring committee (DMC) after 50% of the events for the primary PFS analysis had been observed (∼356 events); further details are reported separately [13].

All efficacy analyses were performed in the intention-to-treat (ITT) population. Time-to-event distribution data (PFS and OS) were analyzed using Kaplan–Meier methodology. Differences between the two regimens were explored using a log-rank test stratified by the randomization stratification factors at the two-sided α = 0.05 level. The HRs and corresponding 95% CIs were estimated using a stratified Cox proportional hazards model at the two-sided α = 0.05 level. The stratified log-rank test p-value was obtained from the score test. A logistic regression model, adjusted for ECOG PS, was used to test for a difference between regimens regarding objective tumor response and disease control.

Pre-planned sensitivity analyses were undertaken to assess the robustness of the statistical model assumptions and study conduct (i.e. image collection) of the primary analysis of PFS (further details are given in the appendices).

All analyses were conducted using Statistical Analysis Software version 9.2.

3. Results

Patients were enrolled between 23 December 2008 and 4 July 2011. Of the 1116 patients screened, 713 were randomized to treatment (353 to nintedanib–pemetrexed, 360 to placebo–pemetrexed) and comprised the ITT population (Fig. 1). The main reason for exclusion after screening was the presence of newly detected brain metastases. Demographics, baseline disease characteristics and previous response to first-line treatment were well balanced between the groups (Table 1). Most patients (670/713, 94.0%) had a tumor of adenocarcinoma histology; five patients with squamous cell histology were randomized in error (nintedanib n = 3; placebo n = 2) but were included in the efficacy and safety analyses.

Fig. 1

Fig. 1

Randomization and follow-up of patients enrolled in the study.

aOn 18 June 2011, 700 patients had been randomized to treatment; an additional 13 patients entered the trial after this date. 183 patients who were on treatment at this time were unblinded, placebo was discontinued and patients receiving pemetrexed alone, nintedanib alone or nintedanib–pemetrexed had the option to continue their treatment after discussion with the investigator. 28 patients permanently stopped their current treatment (placebo–pemetrexed, n = 18; nintedanib–pemetrexed, n = 10). Of the 85 patients who were receiving nintedanib at this time, 49 continued treatment (either as combination or monotherapy); one patient started nintedanib–pemetrexed treatment after 18 June 2011. New written informed consent was obtained from all patients who opted to remain in the study. All patients enrolled in the study continued to be followed up for safety and efficacy after 18 June 2011, according to the trial protocol.

bOn 15 February 2013, seven patients in the nintedanib–pemetrexed group and two in the placebo–pemetrexed group were still receiving treatment – either combination therapy (three patients in the nintedanib–pemetrexed group) or pemetrexed monotherapy (the remaining patients).

 

Table 1

Demographics and baseline disease characteristics.

 

Characteristic Nintedanib–pemetrexed
(n = 353)
Placebo–pemetrexed
(n = 360)
Median age (years [range]) 60 (21–84) 59 (26–86)
Age ≥65 years, n (%) 109 (30.9) 110 (30.6)
Sex, n (%)
 Men 195 (55.2) 208 (57.8)
 Women 158 (44.8) 152 (42.2)
Race, n (%)
 White 225 (63.7) 230 (63.9)
 Asian 103 (29.2) 106 (29.4)
 Black or African American 11 (3.1) 8 (2.2)
 American Indian or Alaskan native 11 (3.1) 15 (4.2)
 Hawaiian or Pacific islander 3 (0.8) 1 (0.3)
ECOG PS, n (%)
 0 135 (38.2) 139 (38.6)
 1 218 (61.8) 221 (61.4)
Smoking history, n (%)
 Current smoker 51 (14.4) 44 (12.2)
 Ex-smoker 193 (54.7) 194 (53.9)
 Never smoker 109 (30.9) 122 (33.9)
EGFR mutation-positive, n (%)
 Yes 17 (4.8) 11 (3.1)
 Unknown 267 (75.6) 276 (76.7)
Clinical stage at diagnosis (UICC/AJCC),an (%)
 Stage <IIIB 57 (16.1) 69 (19.2)
 Stage IIIB 77 (21.8) 52 (14.4)
 Stage IV 219 (62.0) 239 (66.4)
Local recurrence without metastases at screening, n (%) 44 (12.5) 30 (8.3)
Metastases at screening, n (%) 307 (87.0) 328 (91.1)
Brain metastases at baseline, n (%) 36 (10.2) 36 (10.0)
Histology, n (%)
 Adenocarcinoma 335 (94.9) 335 (93.1)
 Large-cell carcinoma 7 (2.0) 12 (3.3)
 Squamous cell carcinomab 3 (0.8) 2 (0.6)
 Combination 1 (0.3) 2 (0.6)
 Other 7 (2.0) 9 (2.5)
Months since first diagnosis (median [range]) 9.6 (1.9–86.4) 9.1 (1.3–94.3)
Previous treatments, n (%)
 Previous surgery 80 (22.7) 99 (27.5)
 Previous radiotherapy 102 (28.9) 115 (31.9)
 Previous first-line therapyc 350 (99.2) 355 (98.6)
  Platinum-based therapy 341 (97.4) 347 (97.7)
  Non-platinum-based therapy 9 (2.6) 8 (2.3)
  First-line bevacizumab 27 (7.7) 27 (7.8)
Best response to first-line therapy, n (%)
 Complete response 7 (2.0) 9 (2.5)
 Partial response 88 (25.1) 94 (26.5)
 Stable disease 156 (44.6) 146 (41.1)
 Progressive disease 76 (21.7) 78 (22.0)
 Unknown 16 (4.6) 20 (5.6)
 Unavailable 7 (2.0) 8 (2.3)

a The 6th edition was used to stage 309 of 713 patients (43.3) and the 7th edition was used to stage 404/713 patients (56.7).

b Randomized in error.

c Three patients in the nintedanib plus pemetrexed group and five patients in the placebo–pemetrexed group did not receive first-line therapy.ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; UICC/AJCC, Union Internationale Contre le Cancer/American Joint Committee on Cancers (6th or 7th edition).

The results of a pre-planned futility analysis conducted by the independent DMC on a database snapshot, as of 14 March 2011, using the investigator-assessed PFS, suggested that the study was unlikely to reach the predefined efficacy criteria for the primary endpoint according to the protocol, and led to their recommendation that study enrollment be stopped. No safety concerns were raised and study recruitment was held on 18 June 2011 and stopped on 29 July 2011. Patients (n = 183) who were still on study treatment on 18 June 2011 could continue in the trial. Placebo was discontinued and patients receiving pemetrexed alone, nintedanib alone or nintedanib–pemetrexed had the option to continue their treatment after discussion with the investigator. Twenty-eight patients permanently stopped their current treatment (placebo–pemetrexed, n = 18; nintedanib–pemetrexed, n = 10). Of the 85 patients who were receiving nintedanib at this time, 49 continued treatment (either as combination or monotherapy); one patient started nintedanib–pemetrexed treatment after 18 June 2011. New written informed consent was obtained from all patients who opted to remain in the study. All patients enrolled in the study continued to be followed up for safety and efficacy after 18 June 2011, according to the trial protocol.

The primary endpoint, PFS by central independent review, was analyzed in all enrolled patients after 498 centrally assessed PFS events (database lock: 9 July 2012). A follow-up analysis of PFS and OS was also performed after 504 and 514 events, respectively (database lock: 15 February 2013, at the time of the planned LUME-Lung 1 final OS analysis).

Median (range) duration of exposure to nintedanib or placebo was 3.7 (0.03–30.8) months in the nintedanib–pemetrexed group and 2.8 (0.03–22.1) months in the placebo–pemetrexed group. Median follow-up was 19.4 months (interquartile range [IQR] = 13.6–26.9) at the time of the primary PFS analysis and 26.8 months (IQR = 21.2–34.1) at the time of the follow-up analysis. In total, 31.6% (109/345) of patients in the nintedanib–pemetrexed group and 9.2% (32/349) in the placebo–pemetrexed group required at least one dose reduction of nintedanib or placebo.

In the primary analysis (9 July 2012), nintedanib–pemetrexed significantly prolonged centrally assessed PFS compared with placebo–pemetrexed (HR = 0.83, 95% CI: 0.70–0.99, p = 0.0435) (Fig. 2A, Table 2). These findings were confirmed in the follow-up analysis of PFS (15 February 2013; Table 2). The results of sensitivity analyses for PFS were similar (data not shown). The effect of nintedanib on centrally assessed PFS was consistent in most of the prespecified subgroup analyses (Fig. 2B; follow-up analysis: 15 February 2013). Of note, non-Asian patients showed a HR of 0.75 (95% CI: 0.60–0.94) and a median PFS of 4.2 months on nintedanib–pemetrexed versus 3.0 months on placebo–pemetrexed, whereas Asian patients had a HR of 0.94 (95% CI: 0.68–1.29).

Fig. 2

Fig. 2

PFS by central independent review and OS. (A) Kaplan–Meier curve for PFS at the time of primary analysis after 498 events (database lock: 9 July 2012), (B) effect of treatment on PFS in subgroups by baseline characteristics at the time of the follow-up analysis after 504 events (database lock: 15 February 2013) and (C) Kaplan–Meier curve for OS after 514 deaths (database lock: 15 February 2013).

1 CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

 

Table 2

Efficacy results: PFS, OS and tumor response according to modified Response Evaluation Criteria in Solid Tumors v1.0 (central independent review).

 

Total study population Patients with adenocarcinoma
Nintedanib–pemetrexed Placebo–pemetrexed Nintedanib–pemetrexed Placebo–pemetrexed
Primary PFS analysis (database lock: 9 July 2012) (n = 353) (n = 360) (n = 335) (n = 335)
Median PFS, months (95% CI) 4.4 (4.0–5.5) 3.6 (2.8–4.2) 4.5 (4.1–5.6) 3.9 (2.8–4.3)
HR = 0.83 (95% CI: 0.70–0.99), p = 0.0435 HR = 0.84 (95% CI: 0.70–1.01), p = 0.0569
Follow-up analysis (database lock: 15 February 2013) (n = 353) (n = 360) (n = 335) (n = 335)
Median PFS, months (95% CI) 4.4 (4.0–5.5) 3.4 (2.8–4.2) 4.5 (4.1–5.6) 3.9 (2.8–4.3)
HR = 0.84 (95% CI: 0.70–1.00), p = 0.0506 HR = 0.84 (95% CI: 0.70–1.01), p = 0.0660
Median OS, months (95% CI) 12.0 (10.3–13.9) 12.7 (10.4–14.8) 12.3 (10.5–14.2) 13.1 (11.0–15.4)
HR = 1.01 (95% CI: 0.85–1.21), p = 0.8940 HR = 1.00 (95% CI: 0.84–1.20), p = 0.9616
Tumor response
 Objective response 32 (9.1) 30 (8.3) 32 (9.6) 30 (9.0)
  Complete response 0 0 0 0
  Partial response 32 (9.1) 30 (8.3) 32 (9.6) 30 (9.0)
 Stable disease 183 (51.8) 162 (45.0) 175 (52.2) 153 (45.7)
 Disease controla 215 (60.9) 192 (53.3) 207 (61.8) 183 (54.6)
 Progressive diseaseb 84 (23.8) 115 (31.9) 78 (23.3) 106 (31.6)
 Otherc 54 (15.3) 53 (14.7) 50 (14.9) 46 (13.7)

a OR (by logistic regression adjusted for baseline ECOG PS) for disease control was 1.37 (95% CI: 1.02–1.85, p = 0.0387) in the total study population and 1.36 (95% CI: 1.00–1.86, p = 0.0521) in patients with adenocarcinoma.

b Includes patients with stable disease within 6 weeks, followed by disease progression.

c Includes patients with stable disease within 6 weeks and without any non-evaluable responses thereafter.CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; OR, objective response; OS, overall survival; PFS, progression-free survival.

Objective response rate by central independent review was similar between the two treatment groups, whereas disease control rate favored nintedanib–pemetrexed over placebo–pemetrexed (Table 2).

Median PFS by investigator assessment was 5.3 months (95% CI: 4.2–5.6) in the nintedanib–pemetrexed group compared with 4.3 months (95% CI: 4.0–5.2) in the placebo–pemetrexed group (HR = 0.86, 95% CI: 0.73–1.02, p = 0.0865; 15 February 2013).

For OS, no difference was noted between the groups at the time of the primary PFS analysis (data not shown) or at the time of the follow-up analysis (15 February 2013; HR = 1.01, 95% CI: 0.85–1.21, p = 0.8940; Table 2, Fig. 2C). Efficacy outcomes in the prespecified subgroup of patients with adenocarcinoma histology revealed a similar treatment effect of nintedanib–pemetrexed compared with placebo–pemetrexed as that observed in the total population (Table 2).

The incidence of patients with drug-related AEs (all CTCAE grades and grade ≥3) and CTCAE grade ≥3 AEs was numerically higher in the nintedanib–pemetrexed group compared with the placebo–pemetrexed group (Table 3). However, nintedanib–pemetrexed was not associated with an increase in serious AEs (30.0% vs 32.8%) or in AEs leading to permanent discontinuation (16.1% vs 17.9%) compared with placebo–pemetrexed (Table S2). Most AEs were mild or moderate in severity, and manageable with symptomatic treatment and/or dose reduction. Hepatic enzyme increases were reversible in most patients. The incidence of patients with AEs of special interest commonly associated with antiangiogenic agents was similar in both groups (Table S3). Likewise, the safety profile in patients with adenocarcinoma was similar to that for the total study population (Table S4).

Table 3

Overview of AEs (≥10% incidence in either group), classified by CTCAE v3.0.

 

Nintedanib–pemetrexed
(n = 347)
Placebo–pemetrexed
(n = 357)
All grades Grade ≥3 All grades Grade ≥3
Patients with any adverse eventa 331 (95.4%) 237 (68.3%) 336 (94.1%) 194 (54.3%)
Increased ALT 149 (42.9%) 81 (23.3%) 87 (24.4%) 26 (7.3%)
Increased AST 129 (37.2%) 42 (12.1%) 68 (19.0%) 6 (1.7%)
Nausea 128 (36.9%) 10 (2.9%) 119 (33.3%) 5 (1.4%)
Diarrhea 121 (34.9%) 12 (3.5%) 55 (15.4%) 4 (1.1%)
Fatigue 117 (33.7%) 21 (6.1%) 130 (36.4%) 24 (6.7%)
Decreased appetite 98 (28.2%) 4 (1.2%) 90 (25.2%) 7 (2.0%)
Vomiting 86 (24.8%) 6 (1.7%) 72 (20.2%) 10 (2.8%)
Decreased neutrophils 75 (21.6%) 43 (12.4%) 48 (13.4%) 26 (7.3%)
Decreased WBC count 57 (16.4%) 15 (4.3%) 38 (10.6%) 19 (5.3%)
Cough 55 (15.9%) 1 (0.3%) 60 (16.8%) 8 (2.2%)
Dyspnea 54 (15.6%) 15 (4.3%) 79 (22.1%) 15 (4.2%)
Constipation 50 (14.4%) 1 (0.3%) 65 (18.2%) 2 (0.6%)
Headache 44 (12.7%) 1 (0.3%) 48 (13.4%) 1 (0.3%)
Abdominal pain 43 (12.4%) 2 (0.6%) 29 (8.1%) 3 (0.8%)
Decreased hemoglobin 41 (11.8%) 11 (3.2%) 44 (12.3%) 5 (1.4%)
Pyrexia 38 (11.0%) 1 (0.3%) 46 (12.9%) 2 (0.6%)
Back pain 37 (10.7%) 1 (0.3%) 40 (11.2%) 7 (2.0%)
Dizziness 31 (8.9%) 1 (0.3%) 39 (10.9%) 1 (0.3%)
Insomnia 29 (8.4%) 1 (0.3%) 37 (10.4%) 1 (0.3%)

a Reported as AEs of all grades occurring in at least 10% of patients in either treatment group.AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Toxicity Criteria for Adverse Events; WBC, white blood cell.

There were 34 (9.8%) deaths due to AEs in the nintedanib–pemetrexed group and 44 (12.3%) in the placebo–pemetrexed group. AEs leading to death (≥1% incidence; nintedanib–pemetrexed vs placebo–pemetrexed) included respiratory failure (1.4% vs 1.7%), dyspnea (1.2% vs 1.4%) and pneumonia (0.6% vs 1.7%).

There was no detrimental effect of treatment with nintedanib–pemetrexed on the patients’ QoL (follow-up analysis: 15 February 2013), as measured by the prespecified, disease-related symptoms of time to deterioration of cough (HR = 0.83, 95% CI: 0.66–1.05), dyspnea (HR = 0.93, 95% CI: 0.77–1.12) and pain (HR = 1.01, 95% CI: 0.84–1.23). Global health status/QoL was not affected by the addition of nintedanib to pemetrexed (HR = 1.00, 95% CI: 0.82–1.21). Median time to clinical deterioration was similar in both arms (HR = 0.93, 95% CI: 0.74–1.16).

4. Discussion

Despite premature closure of the trial, treatment with nintedanib–pemetrexed significantly prolonged centrally assessed PFS in patients with advanced, recurrent non-squamous NSCLC who had progressed following first-line chemotherapy. The trial was stopped based on a pre-planned futility analysis of investigator-assessed PFS data, suggesting that these data represented an inadequate estimate of the true futility of the trial. Patients in the nintedanib–pemetrexed group had a significantly higher rate of disease control than those in the placebo–pemetrexed group. A similar treatment effect was also observed in patients with adenocarcinoma histology.

Although improvements in PFS were observed between treatment groups, no differences in OS between nintedanib–pemetrexed and placebo–pemetrexed were noted. Although phase III trials with other antiangiogenic therapies combined with chemotherapy (pemetrexed or docetaxel) or erlotinib in the second-line NSCLC setting had also failed to show significant OS benefits, despite some PFS improvements [14], [15], [16], [17], and [18], results from the LUME-Lung 1 trial [5] showed that adding nintedanib to docetaxel significantly improved both PFS and OS in patients with adenocarcinoma histology. A further study in second-line NSCLC patients showed similar findings; ramucirumab, a monoclonal antibody targeting the VEGFR-2 receptor, in combination with docetaxel, significantly improved PFS and OS (REVEL) [19]. Since this trial was conducted, a number of additional immunotherapy treatment options have become available after first-line therapy, including nivolumab in patients with advanced squamous [20] and non-squamous [21] NSCLC, without a requirement for programmed death-ligand 1 (PD-L1) expression testing, and pembrolizumab for patients with metastatic NSCLC after first-line therapy in patients whose tumors express PD-L1 [22].

It is possible that no OS differences were observed in the LUME-Lung 2 trial due to the premature hold and unblinding. At the time that the trial was stopped, treatment assignment of the patients who were still on treatment was unblinded. Treatment decisions made henceforth were potentially influenced by knowledge of treatment assignment and by the presumed futility of the study, violating the fundamental premise of double-blind trial design, and potentially biasing analysis of OS conducted after this time point. Of note, a retrospective review of the futility analysis was conducted to explore potential reasons for the discrepancy between the PFS outcome at the time of the futility assessment and at the time of the final analysis. This analysis showed that the threshold for futility was crossed only at the time point of the futility analysis, suggesting that the futility calculation on which the DMC based its decision to stop the study was an inadequate estimate of the final results; had the DMC analysis been performed at another time point, or had centrally reviewed PFS data been used, the futility outcome may have been different and the trial may have been continued [13]. Moreover, analysis of OS in patients with an OS event before the trial was stopped, and thus not influenced by external knowledge of treatment assignment, showed a lower HR compared with later analyses (HR = 0.92, 95% CI: 0.73–1.18). This may suggest that an OS treatment effect could have been discernible had the study been allowed to continue to completion. Improvements in OS observed in LUME-Lung 1 but not LUME-Lung 2 may also suggest that docetaxel is a more suitable combination partner for use with antiangiogenic agents than pemetrexed. It should be noted that testing for epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements was not standard practice at the time that this study was conducted; the ALK status of patients was unknown and information on EGFR status was limited. However, due to the low frequency of Asian patients in the study, the overall relative frequency of EGFR mutation-positive patients is estimated to have been low and unlikely to have impacted on the study findings. Improvements in disease control were observed with the addition of nintedanib to pemetrexed; however, statistically significant differences in the objective response rate between nintedanib plus pemetrexed and nintedanib plus placebo would not necessarily be expected based on the mechanism of action of nintedanib and were not observed.

Regarding safety, adding nintedanib to pemetrexed increased the incidence of patients with hepatic enzyme elevation and diarrhea, but not the incidence of patients with side effects typically associated with antiangiogenic therapy, e.g. hemorrhage, hypertension and venous thromboembolism [23]. This manageable side-effect profile, largely comprising reversible increases in liver enzymes and mild–moderate gastrointestinal events, compares favorably with those of other antiangiogenic therapies [23] and is consistent with that reported for nintedanib in other clinical studies [5], [7], [24], [25], and [26].

One limitation of this study is that the majority of patients had adenocarcinoma histology making it difficult to draw conclusions as to the effect of nintedanib in other histologic subtypes. It should also be noted that some patients with squamous cell carcinoma were enrolled in the study in error, although the small number of patients for which this was the case is unlikely to have impacted the study findings.

5. Conclusion

The results of the LUME-Lung 2 study support some of the findings of the LUME-Lung 1 study [5]. In both trials, the combination of nintedanib with docetaxel or pemetrexed improved PFS and related endpoints such as disease control, although the premature discontinuation of the LUME-Lung 2 study meant that improvements in OS were not observed, unlike in the adenocarcinoma population in LUME-Lung 1.

Conflict of interest

RK, IV, JB, BG-M, PS and CS are employees of Boehringer Ingelheim. RK and BG-M have patents pending for Boehringer Ingelheim. JvP has received fees for consultancy from Novartis, Roche, Daiichi, Pfizer, AbbVie, Vertex and Clovis. VK has received fees from Boehringer Ingelheim for his role as a principal investigator on this study, lecture fees from Roche, consultancy fees from Pfizer, lecture fees from GlaxoSmithKline, a travel grant from Merck, and is a principal investigator for projects for PRA International, CIRG and CECOG. J-HK has received a grant from Boehringer Ingelheim and ORA has received funding from Boehringer Ingelheim for data collection in this study. RNS, NHH, JA, M-JA and BT declare that they have no conflicts of interest.

Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Duncan Campbell, PhD, of GeoMed (Macclesfield, UK), and Aurora O’Brate, PhD, and Suzanne Patel, PhD, of inVentiv Medical Communications (Maidenhead, UK), during the preparation of this manuscript.

Funding

This study was supported by Boehringer Ingelheim. The academic investigators and representatives of the sponsor, Boehringer Ingelheim, co-designed the trial. With funding from the sponsor, the clinical research organization Parexel was responsible for managing the study, monitoring the patients and collecting the data. The sponsor’s statistical team (of which BG-M and PS are members) performed the statistical analyses. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Acknowledgments

The authors would like to thank the study investigators, study center staff, and all trial participants and their families. The authors thank Charles Schloss, Stephanie Ounpuu and Isabelle Voccia (Boehringer Ingelheim) who performed study oversight.

Appendix A. Supplementary data

The following are Supplementary data to this article:

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Footnotes

a Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indiana University, Indianapolis, IN, USA

b Boehringer Ingelheim Pharmaceuticals GmbH & Co. KG, Biberach, Germany

c Institute of Clinical Pharmacology, Georg-August-University Göttingen, Germany

d Department of Oncology, Auckland City Hospital, Auckland, New Zealand

e Instituto Nacional del Cáncer, Santiago, Chile

f Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

g Internal Medicine, National Kidney and Transplant Institute, Quezon City, Philippines

h Boehringer Ingelheim (Canada) Ltd, Burlington, ON, Canada

i Pneumology Clinic, Asklepios Fachkliniken, Gauting, Germany

j Clinical Hospital Center Bezanijska Kosa, Belgrade, Serbia

k Jewish General Hospital, Montréal, Québec, Canada

l Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA

m Yonsei Cancer Center, Yonsei University Health System, Seoul, South Korea

Correspondence to: Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, 535 Barnhill Drive, RT 473, Indianapolis, IN 46202, USA.

1 Drs Hanna and Kaiser contributed equally to this work.

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