European Journal of Cancer (2014) 50, 1571– 1580
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
A randomised phase II study of pemetrexed versus pemetrexed + erlotinib as second-line treatment for locally advanced or metastatic non-squamous non-small cell lung cancer Christian Dittrich a,⇑, Zsolt Papai-Szekely b, Nuria Vinolas c, Christer Sederholm d, Joerg T. Hartmann e, Dirk Behringer f, Gbenga Kazeem g, Durisala Desaiah h, Monika I. Leschinger i, Joachim von Pawel j a
LBI-ACR VIEnna and ACR-ITR VIEnna, Kaiser Franz Josef-Spital, Vienna, Austria St. George Hospital of Feje´r County, Szekesfehervar, Hungary c Hospital Clinic I Provincial, Barcelona, Spain d University Hospital, Linko¨ping, Sweden e Department of Internal Medicine II-Hematology and Medical Oncology, Kiel, Germany and Catholic Hospital Consortium Ostwestfalen, Bielefeld, Germany f Clinic of Hematology and Oncology, Bochum, Germany g Eli Lilly UK, Erl Wood Manor, Windlesham, Surrey, United Kingdom h Eli Lilly Corporate Center, Indianapolis, USA i Lilly Deutschland GmbH, Bad Homburg, Germany j Asklepios Hospital Mu¨nchen-Gauting, Gauting, Germany b
Received 10 December 2013; received in revised form 5 March 2014; accepted 9 March 2014 Available online 2 April 2014
KEYWORDS Non-small cell lung cancer Non-squamous Second-line therapy Pemetrexed Erlotinib
Abstract Introduction: Pemetrexed and erlotinib have been approved as second-line monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC). This multicentre, randomised, open-label, parallel phase II study assessed efficacy and safety of pemetrexed versus pemetrexed + erlotinib in patients with advanced non-squamous NSCLC. Methods: NSCLC stage III–IV patients who failed one prior platinum-based chemotherapy regimen, 1 measurable lesion by Response Evaluation Criteria in Solid Tumors, and Eastern Cooperative Oncology Group performance status 2 were eligible. Patients received pemetrexed 500 mg/m2 with vitamin B12 and folic acid q3w alone or combined with erlotinib 150 mg
⇑ Corresponding author: Address: Ludwig Boltzmann Institute for Applied Cancer Research (LBI-ACR VIEnna) – LBC Translational Oncology, 3rd Medical Department-Centre for Oncology and Haematology, Kaiser Franz Josef-Spital, Kundratstrasse 3, 1100 Vienna, Austria. Tel.: +43 1 60 191 2301; fax: +43 1 60 191 2329. E-mail address: [email protected] (C. Dittrich).
http://dx.doi.org/10.1016/j.ejca.2014.03.007 0959-8049/Ó 2014 Elsevier Ltd. All rights reserved.
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daily. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), time-to-treatment failure (TTTF), response and toxicity. Results: Of 165 randomised non-squamous patients, 159 were treated (pemetrexed: 83; pemetrexed + erlotinib: 76). The median PFS (months; 95% CI) was 2.89 (1.94, 3.38) for pemetrexed versus 3.19 (2.86, 4.70) for pemetrexed + erlotinib (hazard ratio [HR] 0.63; 95% CI: (0.44, 0.90); P = 0.0047). The median OS (months; 95% CI) was 7.75 (5.29, 10.41) for pemetrexed versus 11.83 (8.18, 16.66) for pemetrexed + erlotinib (HR: 0.68; 95% CI: 0.46, 0.98; P = 0.019). The median TTTF (months: 95% CI) was 2.4 (1.74, 2.99) for pemetrexed versus 3.0 (2.23, 4.07) for pemetrexed + erlotinib (HR 0.64; 95% CI: 0.46, 0.89; P = 0.0034). One patient died in pemetrexed + erlotinib arm due to febrile neutropenia. Grades 3/4 drug-related toxicities (in 5% of patients) in pemetrexed/pemetrexed + erlotinib were febrile neutropenia (2.4%/10.5%), diarrhoea (1.2%/5.3%), rash (1.2%/9.2%); anaemia (6%/11.8%), leukopenia (9.6%/23.7%), neutropenia (9.6%/25.0%), and thrombocytopenia (4.8%/14.5%). Conclusions: Pemetrexed + erlotinib treatment significantly improved PFS, OS and TTTF in 2nd line non-squamous NSCLC and was associated with an increase in grade 3/4 toxicities compared with pemetrexed alone. Ó 2014 Elsevier Ltd. All rights reserved.
1. INTRODUCTION Of the NSCLC patients experiencing disease progression after first-line standard therapy, about 40–50% will receive second-line therapy [1]. However, only limited therapeutic options are available for second-line treatment [2]. The choice of any second-line treatment should represent a rational selection of a drug or drug combination depending on their activity against tumours pretreated with distinct first-line therapies [3]. Currently, three cytotoxic or cytostatic agents are approved for second-line treatment of NSCLC: docetaxel, pemetrexed, and erlotinib [4–6]. Single-agent treatments represent still the standard procedure in this therapeutic setting [7]. The combination of pemetrexed and erlotinib has demonstrated synergistic or additive activity in preclinical studies [8]. The synergistic interactions between the two drugs are mediated by several mechanisms and are independent from the genetic characteristics of the underlying cancer cells [9]. Erlotinib did not appear to increase the toxicities of the cytotoxic anticancer agent pemetrexed when administered in combination in an early phase clinical study [10]. In that study, the safety profile of pemetrexed plus erlotinib was comparable with the safety profiles established for pemetrexed and erlotinib separately [11,12]. Because the two drugs have different routes of elimination (erlotinib is primarily metabolised by the liver enzymes CYP3A4 and CYP1A2 and excreted in the faeces, whereas pemetrexed is primarily eliminated via the kidney), a lack of pharmacokinetic interactions is presumed when both drugs are combined. The current study was designed to primarily evaluate progression-free survival (PFS) in patients treated with a combination of pemetrexed plus erlotinib and those treated with single-agent pemetrexed as second-line
therapy for the treatment of locally advanced or metastatic non-squamous NSCLC. 2. Materials and methods 2.1. Study design This multicentre, randomised, phase II, open-label, parallel trial was designed to evaluate PFS of pemetrexed and pemetrexed plus erlotinib in an overall advanced NSCLC patient population. The study enrolled its first patient in April 2007. Following a label change for Alimta (pemetrexed) in EU and the USA [13,5] restricting the patient population to non-squamous NSCLC only, the protocol was amended (approved on 1st August 2008) to narrow the patient population to non-squamous NSCLC to bring the study in line with the approved indication for appropriate pemetrexed use in NSCLC. In this paper, we focus on the analyses of the enrolled non-squamous patients. The data obtained from the overall study population have been posted on ClinicalTrials.gov (Registration ID: NCT00447057 http://www.clinicaltrials.gov/ct2/ show/NCT00447057?term=NCT00447057&rank=1). 2.2. Patients Study participants included patients 18 years of age with a histologic or cytologic diagnosis of locally advanced or metastatic NSCLC (Stage IIIA, IIIB, or IV at entry) [14] not amenable to curative therapy, who had failed 1 prior platinum-based chemotherapy regimen for advanced or metastatic non-squamous NSCLC and were considered eligible for further chemotherapy following progression of their disease. Prior adjuvant or neoadjuvant platinum-based chemotherapy had to be completed at least 2 weeks before study
C. Dittrich et al. / European Journal of Cancer 50 (2014) 1571–1580
enrolment and the patient had to have recovered from the acute toxic effects of the treatment. Patient had to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2, 1 measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) [15], adequate (bone marrow, renal and hepatic) organ function and life expectancy 8 weeks. Both smokers and non-smokers were eligible; however, patients were strongly advised not to smoke during the course of the study. Prior radiation therapy to 15 pack-years who had smoked within the last 25 years; non-smokers = those who did not smoke at all or has a history of 15 pack-years or those who had quit smoking >25 years before. Smoking stratification data were missing for four patients in each arm.
Kaplan-Meier Estimate (± Standard Error)
100.0
PEM PEM + ERLO
90.0 PEM
80.0 N Patients
70.0
Events 60.0
Censored
50.0
Median Time 95% CI
40.0
PEM + ERLO
83
76
70 (84.3%)
60 (78.9%)
13 (15.7%)
16 (21.1%)
2.89 months
3.19 months
[1.94-3.38]
[2.86-4.70]
Log-rank p-value one-sided: 0.0047 30.0
HR [95% CI]
0.63 [0.44-0.90]
20.0 10.0 0.0 0
3
6
9
12
15
18
21
24
27
30
33
36
0 2
0 1
0 1
0 0
0 0
PFS time (± Months) Number at Risk PEM 83 PEM + ERLO 76
30 38
14 20
6 15
2 11
0 5
0 2
0 2
Fig. 2. Kaplan–Meier distribution of PFS in treated patients with non-squamous NSCLC (primary end-point analysis). Abbreviations: PFS = progression-free survival; NSCLC = non-small cell lung cancer; PEM = pemetrexed; ERLO = erlotinib; CI = confidence interval.
C. Dittrich et al. / European Journal of Cancer 50 (2014) 1571–1580
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Kaplan-Meier Estimate (± Standard Error)
100.0 PEM PEM + ERLO
90.0 PEM 80.0 70.0
Events Censored
60.0 50.0
PEM + ERLO
83
76
66 (79.5%)
48 (63.2%)
N Patients
17 (20.5%)
28 (36.8%)
Median Time
7.75 months
11.83 months
95% CI
[5.29-10.41]
[8.18-16.66]
40.0
Log-rank p-value one-sided: 0.0190
30.0
HR [95% CI]
0.68 [0.46-0.98]
20.0 10.0 0.0 0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
3 6
2 3
2 2
1 0
1 0
0 0
0 0
Survival Time (± Months) Number at Risk PEM PEM + ERLO
83 76
64 62
47 50
34 38
26 34
16 21
12 14
9 12
4 8
3 6
Fig. 3. Kaplan–Meier distribution of overall survival in treated patients with non-squamous NSCLC (secondary end-point analysis). Abbreviations: NSCLC = non-small cell lung cancer; PEM = pemetrexed; ERLO = erlotinib; CI = confidence interval.
CIs of the respective PFS curves overlap until 6 months, but not from 9 months onwards any further. The logrank test which assesses long-time difference between the curves of the two treatment regimens yielded the significant P-value of 0.0047, and the 95% CI of the HR did not contain 1, therewith underlining the sustainability of the therapeutic effect reached. In addition, there was a statistically significant improvement in the secondary study end-point OS (HR 0.68; 95% CI: 0.46, 0.98; log-rank P = 0.019), with a 4-month longer median survival in the pemetrexed + erlotinib arm (11.83 months) compared with the pemetrexed (7.75 months) arm. Whereas pemetrexed + erlotinib kept its significant superiority over pemetrexed alone after adjusting for smoking status, ECOG status, and gender (HR 0.68; 95% CI: 0.46, 0.98; P = 0.019), the difference of OS diminished to trend size (HR 0.69; 95% CI: 0.47, 1.02; P = 0.062) after applying a Cox regression model in this phase II trial. The pemetrexed arm yielded a RR of 10.8%, a DCR of 51.8%, a median PFS time of 2.89 months, and a median OS of 7.75 months. The respective results of the pivotal registration trial for pemetrexed in secondline therapy for NSCLC done in an overall advanced NSCLC patient population were a RR of 9.1%, a DCR of 54.9%, a PFS of 2.9 months, and an OS of 8.3 months [12]. The comparator in the latter trial, docetaxel 75 mg/m2 every 3 weeks, against which pemetrexed was proven to be not inferior, had a RR of 8.8%, a DCR of 55.2%, a PFS of 2.9 months, and an OS of 7.9 months. These findings are similar to the efficacy results for the two different dosages of docetaxel tested (100 mg/m2 and 75 mg/m2 every 3 weeks) versus best
supportive care [17]. The survival results for the pemetrexed arm of the present study are also in the range of the data reported in the INTEREST study, a prospective randomised trial that compared docetaxel with gefitinib in previously treated NSCLC patients [18], with median overall survival durations of 8.0 versus 7.6 months, respectively. A study of the EGFR tyrosine kinase inhibitor (TKI) erlotinib as switch maintenance therapy versus placebo yielded both, significantly longer PFS (P < 0.0001) and OS (P = 0.0088) for erlotinib [19]. Although the prolongation of PFS, the primary objective of both studies, (with 2 weeks in the present study versus 1.2 weeks in the phase III study by Cappuzzo et al. [19]) was merely the same, the gain in median survival in the combination arm of this study was 4 months while in the Cappuzzo et al. trial it was one month. Whereas at the first glance, it cannot be denied that this study disposes to a certain extent on a continuation maintenance character, considering especially that one patient of the combined drug arm who stopped pemetrexed after six cycles and continued only erlotinib for the remainder of the 36 cycles. But, the protocol did not foresee the stopping of the chemotherapy at a predefined number of cycles, but merely to modify the dosage of pemetrexed and/or erlotinib independently from each other according to the character or degree of specific toxicities and according to a prefixed scheme and to stop otherwise only in case of progression or patient request. Thus, only six of the patients on the pemetrexed and erlotinib arm who started the combined therapy discontinued pemetrexed and continued with only erlotinib. Two patients discontinued pemetrexed after six cycles of the combined
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Table 2 Efficacy end-points for randomised and treated patients with non-squamous NSCLC. Efficacy measure
Pemetrexed N = 83
Pemetrexed + Erlotinib N = 76
Hazard ratio (95% CI)
P-value
PFS Median, months (95% CI) Range, months Patients censored, n (%)
2.89 (1.94, 3.38) 0.0, 13.9 13 (15.7)
3.19 (2.86, 4.70) 0.0, 32.2 16 (21.1)
0.63 (0.44, 0.90)
0.0047
0.64 (0.4, 0.9)
0.019
0.68 (0.46, 0.98)
0.019
0.69 (0.47, 1.02)
0.062
0.64 (0.46, 0.89)
0.003
Covariate-adjusted HRa PEM + ERLO versus PEM (reference) PFS rate% (95% CI) at 3 months 6 months 12 months
42.4 (31.2, 53.3) 22.7 (13.6, 33.1) 3.5 (0.7, 10.6)
57.2 (44.6, 68.0) 31.5 (20.8, 42.8) 18.8 (10.4, 29.1)
OS Median, months (95% CI) Range, months Patients censored, n (%)
7.75 (5.29, 10.41) 0.6, 42.6 17 (20.5)
11.83 (8.18, 16.66) 0.4, 38.4 28 (36.8)
Probability (95% CI) that OS time was at least . . . OS rate% (95% CI) at 1 year 34.1 (23.8, 44.6) 49.4 (37.3, 60.4) 2 year 13.7 (6.6, 23.4) 26.8 (15.7, 39.3) Covariate-adjusted HRa PEM + ERLO versus PEM (reference) TTTF Median, months (95% CI) Range, months Patients censored, n (%)
2.40 (1.74, 2.99) 0.6, 11.3 0 (0.0)
3.00 (2.23, 4.07) 0.3, 32.2 3 (3.9)
Best overall response, n (%) Complete response Partial response Stable disease Overall RR, n (%) DCR, n (%)
0 (0.0) 9 (10.8) 34 (41.0) 9 (10.8) 43 (51.8)
1 (1.3) 12 (15.8) 29 (38.2) 13 (17.1) 42 (55.3)
0.180 0.390
Abbreviations: NSCLC = non-small cell lung cancer; PFS = progression-free survival; CI = confidence interval; HR = hazard ratio; PEM = pemetrexed; ERLO = erlotinib; OS = overall survival; TTTF = time-to-treatment failure; DCR = disease control rate (best response of complete, partial, or stable disease). a From Cox proportional hazard model adjusted for smoking status, Eastern Cooperative Oncology Group performance status (0–1 versus 2), and gender.
therapy, two patients after 10 and one patient after 11 cycles, respectively. The combination of a cytotoxic drug with a TKI in this study was significantly more efficacious than that of the cytotoxic agent alone. The medians and percentiles of cycles in both arms show similar treatment patterns in general, but with the exception of a small number of patients (6/7.9%) receiving a high number of cycles (17 cycles) of combination therapy. Overall, higher cumulative toxicity of the combination therapy can also be excluded with a range of 1–36 cycles of the combination versus a range of 1–16 cycles of the single-agent therapy, both showing a median of four cycles (Table 3). In this context, we cannot exclude that the longer median PFS and the even longer median OS of 4 months in patients treated with pemetrexed + erlotinib may be explained by the fact that it is mainly patients with the EGFR mutations who benefit from therapy with a TKI. Nevertheless, the fact, that almost half of the
patients (40 out of 83) of the pemetrexed only arm received erlotinib single agent or combination therapy at consecutive treatment lines, makes this as explanation unlikely (Table 3). With regard to a potential effect of a consecutive uneven treatment distribution as explanation, we can only speculate since we do not dispose on these data. But, the fact that there exists no established third-line treatment which significantly increases overall survival, makes that possibility not very probable. When the study was conceived and started, there was no unanimous recommendation to perform mandatory biomarker assessments or to use any of them as a stratification criterion [20]. Hence, neither determination of EGFR mutation nor collection of EGFR mutation data has been performed, respectively. Shepherd and colleagues (who did only optional tissue banking in their pivotal trial) concluded at that time that the EGFR gene mutations were not predictive of a survival benefit from erlotinib [11]. Tsao emphasised that according to a multivariate analysis of the data of the BR.21 study [21], OS
C. Dittrich et al. / European Journal of Cancer 50 (2014) 1571–1580 Table 3 Summary of cycles administered by treatment arm in patients with non-squamous non-small cell lung cancer. Parameter
Pemetrexed N = 83
Pemetrexed + Erlotinib N = 76
Patients who received 1 cycle, n (%) Mean no. of cycles (SD) Median no. of cycles (range) Total number of cycles received
83 (100)
76 (100)
4.3 (3.3) 4.0 (1, 16) 358
6.3 (6.4) 4.0 (1, 36) 489
Table 4 Possibly drug-related maximum grade 3 and 4 CTCAE toxicities in >5% of patients with non-squamous NSCLC. Event
Pemetrexed N = 83, n (%)
Pemetrexed + Erlotinib N = 76, n (%)
Grade 3
Grade 4
Grade 3
Grade 4
Laboratory Anaemia Leukopenia Neutropenia Thrombocytopenia
4 5 4 2
1 3 4 2
7 (9.2) 15 (19.7) 6 (7.9) 6 (7.9)
2 3 5 5
Non-laboratory Rash/desquamation Diarrhoea Febrile neutropeniaa
1 (1.2) 1 (1.2) 2 (2.4)
6 (7.9) 4 (5.3) 5 (6.6)
1 (1.3) – 3 (3.9)a
(4.8) (6.0) (4.8) (2.4)
(1.2) (3.6) (4.8) (2.4)
0 (0.0) – 0 (0.0)
(2.6) (3.9) (6.6) (6.6)
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events, version 3.0. a Includes 1 grade 5 toxicity, fatal.
was not influenced by the status of the EGFR expression, the number of EGFR copies, or the presence of EGFR mutations. Even in the remission maintenance study of erlotinib, the prolongation of PFS was evident regardless of the EGFR expression, although the EGFR mutation positive patients yielded the greatest benefit from erlotinib therapy [19]. Very recently, results of a 3-arm phase II study similar to ours comparing pemetrexed + erlotinib with pemetrexed or erlotinib in the second-line of non-squamous NSCLC patients have been presented by Lee et al.in 2013 [22]. The combination of pemetrexed + erlotinib was significantly better than pemetrexed alone (HR = 0.58; (95% CI: 0.39, 0.85; P = 0.005). Median PFS of pemetrexed + erlotinib was 7.4 months (95% CI: 4.4, 12.9), that of pemetrexed alone was 4.4 months (95% CI: 3.0, 6.0). In contrast to our study results, no significant difference was reported for OS (HR = 0.75 (95% CI: 0.49, 1.13; P = 0.168). Based on the EGFR status analysable in
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
A randomised phase II study of pemetrexed versus pemetrexed + erlotinib as second-line treatment for locally advanced or metastatic non-squamous non-small cell lung cancer Christian Dittrich a,⇑, Zsolt Papai-Szekely b, Nuria Vinolas c, Christer Sederholm d, Joerg T. Hartmann e, Dirk Behringer f, Gbenga Kazeem g, Durisala Desaiah h, Monika I. Leschinger i, Joachim von Pawel j a
LBI-ACR VIEnna and ACR-ITR VIEnna, Kaiser Franz Josef-Spital, Vienna, Austria St. George Hospital of Feje´r County, Szekesfehervar, Hungary c Hospital Clinic I Provincial, Barcelona, Spain d University Hospital, Linko¨ping, Sweden e Department of Internal Medicine II-Hematology and Medical Oncology, Kiel, Germany and Catholic Hospital Consortium Ostwestfalen, Bielefeld, Germany f Clinic of Hematology and Oncology, Bochum, Germany g Eli Lilly UK, Erl Wood Manor, Windlesham, Surrey, United Kingdom h Eli Lilly Corporate Center, Indianapolis, USA i Lilly Deutschland GmbH, Bad Homburg, Germany j Asklepios Hospital Mu¨nchen-Gauting, Gauting, Germany b
Received 10 December 2013; received in revised form 5 March 2014; accepted 9 March 2014 Available online 2 April 2014
KEYWORDS Non-small cell lung cancer Non-squamous Second-line therapy Pemetrexed Erlotinib
Abstract Introduction: Pemetrexed and erlotinib have been approved as second-line monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC). This multicentre, randomised, open-label, parallel phase II study assessed efficacy and safety of pemetrexed versus pemetrexed + erlotinib in patients with advanced non-squamous NSCLC. Methods: NSCLC stage III–IV patients who failed one prior platinum-based chemotherapy regimen, 1 measurable lesion by Response Evaluation Criteria in Solid Tumors, and Eastern Cooperative Oncology Group performance status 2 were eligible. Patients received pemetrexed 500 mg/m2 with vitamin B12 and folic acid q3w alone or combined with erlotinib 150 mg
⇑ Corresponding author: Address: Ludwig Boltzmann Institute for Applied Cancer Research (LBI-ACR VIEnna) – LBC Translational Oncology, 3rd Medical Department-Centre for Oncology and Haematology, Kaiser Franz Josef-Spital, Kundratstrasse 3, 1100 Vienna, Austria. Tel.: +43 1 60 191 2301; fax: +43 1 60 191 2329. E-mail address: [email protected] (C. Dittrich).
http://dx.doi.org/10.1016/j.ejca.2014.03.007 0959-8049/Ó 2014 Elsevier Ltd. All rights reserved.
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daily. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), time-to-treatment failure (TTTF), response and toxicity. Results: Of 165 randomised non-squamous patients, 159 were treated (pemetrexed: 83; pemetrexed + erlotinib: 76). The median PFS (months; 95% CI) was 2.89 (1.94, 3.38) for pemetrexed versus 3.19 (2.86, 4.70) for pemetrexed + erlotinib (hazard ratio [HR] 0.63; 95% CI: (0.44, 0.90); P = 0.0047). The median OS (months; 95% CI) was 7.75 (5.29, 10.41) for pemetrexed versus 11.83 (8.18, 16.66) for pemetrexed + erlotinib (HR: 0.68; 95% CI: 0.46, 0.98; P = 0.019). The median TTTF (months: 95% CI) was 2.4 (1.74, 2.99) for pemetrexed versus 3.0 (2.23, 4.07) for pemetrexed + erlotinib (HR 0.64; 95% CI: 0.46, 0.89; P = 0.0034). One patient died in pemetrexed + erlotinib arm due to febrile neutropenia. Grades 3/4 drug-related toxicities (in 5% of patients) in pemetrexed/pemetrexed + erlotinib were febrile neutropenia (2.4%/10.5%), diarrhoea (1.2%/5.3%), rash (1.2%/9.2%); anaemia (6%/11.8%), leukopenia (9.6%/23.7%), neutropenia (9.6%/25.0%), and thrombocytopenia (4.8%/14.5%). Conclusions: Pemetrexed + erlotinib treatment significantly improved PFS, OS and TTTF in 2nd line non-squamous NSCLC and was associated with an increase in grade 3/4 toxicities compared with pemetrexed alone. Ó 2014 Elsevier Ltd. All rights reserved.
1. INTRODUCTION Of the NSCLC patients experiencing disease progression after first-line standard therapy, about 40–50% will receive second-line therapy [1]. However, only limited therapeutic options are available for second-line treatment [2]. The choice of any second-line treatment should represent a rational selection of a drug or drug combination depending on their activity against tumours pretreated with distinct first-line therapies [3]. Currently, three cytotoxic or cytostatic agents are approved for second-line treatment of NSCLC: docetaxel, pemetrexed, and erlotinib [4–6]. Single-agent treatments represent still the standard procedure in this therapeutic setting [7]. The combination of pemetrexed and erlotinib has demonstrated synergistic or additive activity in preclinical studies [8]. The synergistic interactions between the two drugs are mediated by several mechanisms and are independent from the genetic characteristics of the underlying cancer cells [9]. Erlotinib did not appear to increase the toxicities of the cytotoxic anticancer agent pemetrexed when administered in combination in an early phase clinical study [10]. In that study, the safety profile of pemetrexed plus erlotinib was comparable with the safety profiles established for pemetrexed and erlotinib separately [11,12]. Because the two drugs have different routes of elimination (erlotinib is primarily metabolised by the liver enzymes CYP3A4 and CYP1A2 and excreted in the faeces, whereas pemetrexed is primarily eliminated via the kidney), a lack of pharmacokinetic interactions is presumed when both drugs are combined. The current study was designed to primarily evaluate progression-free survival (PFS) in patients treated with a combination of pemetrexed plus erlotinib and those treated with single-agent pemetrexed as second-line
therapy for the treatment of locally advanced or metastatic non-squamous NSCLC. 2. Materials and methods 2.1. Study design This multicentre, randomised, phase II, open-label, parallel trial was designed to evaluate PFS of pemetrexed and pemetrexed plus erlotinib in an overall advanced NSCLC patient population. The study enrolled its first patient in April 2007. Following a label change for Alimta (pemetrexed) in EU and the USA [13,5] restricting the patient population to non-squamous NSCLC only, the protocol was amended (approved on 1st August 2008) to narrow the patient population to non-squamous NSCLC to bring the study in line with the approved indication for appropriate pemetrexed use in NSCLC. In this paper, we focus on the analyses of the enrolled non-squamous patients. The data obtained from the overall study population have been posted on ClinicalTrials.gov (Registration ID: NCT00447057 http://www.clinicaltrials.gov/ct2/ show/NCT00447057?term=NCT00447057&rank=1). 2.2. Patients Study participants included patients 18 years of age with a histologic or cytologic diagnosis of locally advanced or metastatic NSCLC (Stage IIIA, IIIB, or IV at entry) [14] not amenable to curative therapy, who had failed 1 prior platinum-based chemotherapy regimen for advanced or metastatic non-squamous NSCLC and were considered eligible for further chemotherapy following progression of their disease. Prior adjuvant or neoadjuvant platinum-based chemotherapy had to be completed at least 2 weeks before study
C. Dittrich et al. / European Journal of Cancer 50 (2014) 1571–1580
enrolment and the patient had to have recovered from the acute toxic effects of the treatment. Patient had to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2, 1 measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) [15], adequate (bone marrow, renal and hepatic) organ function and life expectancy 8 weeks. Both smokers and non-smokers were eligible; however, patients were strongly advised not to smoke during the course of the study. Prior radiation therapy to 15 pack-years who had smoked within the last 25 years; non-smokers = those who did not smoke at all or has a history of 15 pack-years or those who had quit smoking >25 years before. Smoking stratification data were missing for four patients in each arm.
Kaplan-Meier Estimate (± Standard Error)
100.0
PEM PEM + ERLO
90.0 PEM
80.0 N Patients
70.0
Events 60.0
Censored
50.0
Median Time 95% CI
40.0
PEM + ERLO
83
76
70 (84.3%)
60 (78.9%)
13 (15.7%)
16 (21.1%)
2.89 months
3.19 months
[1.94-3.38]
[2.86-4.70]
Log-rank p-value one-sided: 0.0047 30.0
HR [95% CI]
0.63 [0.44-0.90]
20.0 10.0 0.0 0
3
6
9
12
15
18
21
24
27
30
33
36
0 2
0 1
0 1
0 0
0 0
PFS time (± Months) Number at Risk PEM 83 PEM + ERLO 76
30 38
14 20
6 15
2 11
0 5
0 2
0 2
Fig. 2. Kaplan–Meier distribution of PFS in treated patients with non-squamous NSCLC (primary end-point analysis). Abbreviations: PFS = progression-free survival; NSCLC = non-small cell lung cancer; PEM = pemetrexed; ERLO = erlotinib; CI = confidence interval.
C. Dittrich et al. / European Journal of Cancer 50 (2014) 1571–1580
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Kaplan-Meier Estimate (± Standard Error)
100.0 PEM PEM + ERLO
90.0 PEM 80.0 70.0
Events Censored
60.0 50.0
PEM + ERLO
83
76
66 (79.5%)
48 (63.2%)
N Patients
17 (20.5%)
28 (36.8%)
Median Time
7.75 months
11.83 months
95% CI
[5.29-10.41]
[8.18-16.66]
40.0
Log-rank p-value one-sided: 0.0190
30.0
HR [95% CI]
0.68 [0.46-0.98]
20.0 10.0 0.0 0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
3 6
2 3
2 2
1 0
1 0
0 0
0 0
Survival Time (± Months) Number at Risk PEM PEM + ERLO
83 76
64 62
47 50
34 38
26 34
16 21
12 14
9 12
4 8
3 6
Fig. 3. Kaplan–Meier distribution of overall survival in treated patients with non-squamous NSCLC (secondary end-point analysis). Abbreviations: NSCLC = non-small cell lung cancer; PEM = pemetrexed; ERLO = erlotinib; CI = confidence interval.
CIs of the respective PFS curves overlap until 6 months, but not from 9 months onwards any further. The logrank test which assesses long-time difference between the curves of the two treatment regimens yielded the significant P-value of 0.0047, and the 95% CI of the HR did not contain 1, therewith underlining the sustainability of the therapeutic effect reached. In addition, there was a statistically significant improvement in the secondary study end-point OS (HR 0.68; 95% CI: 0.46, 0.98; log-rank P = 0.019), with a 4-month longer median survival in the pemetrexed + erlotinib arm (11.83 months) compared with the pemetrexed (7.75 months) arm. Whereas pemetrexed + erlotinib kept its significant superiority over pemetrexed alone after adjusting for smoking status, ECOG status, and gender (HR 0.68; 95% CI: 0.46, 0.98; P = 0.019), the difference of OS diminished to trend size (HR 0.69; 95% CI: 0.47, 1.02; P = 0.062) after applying a Cox regression model in this phase II trial. The pemetrexed arm yielded a RR of 10.8%, a DCR of 51.8%, a median PFS time of 2.89 months, and a median OS of 7.75 months. The respective results of the pivotal registration trial for pemetrexed in secondline therapy for NSCLC done in an overall advanced NSCLC patient population were a RR of 9.1%, a DCR of 54.9%, a PFS of 2.9 months, and an OS of 8.3 months [12]. The comparator in the latter trial, docetaxel 75 mg/m2 every 3 weeks, against which pemetrexed was proven to be not inferior, had a RR of 8.8%, a DCR of 55.2%, a PFS of 2.9 months, and an OS of 7.9 months. These findings are similar to the efficacy results for the two different dosages of docetaxel tested (100 mg/m2 and 75 mg/m2 every 3 weeks) versus best
supportive care [17]. The survival results for the pemetrexed arm of the present study are also in the range of the data reported in the INTEREST study, a prospective randomised trial that compared docetaxel with gefitinib in previously treated NSCLC patients [18], with median overall survival durations of 8.0 versus 7.6 months, respectively. A study of the EGFR tyrosine kinase inhibitor (TKI) erlotinib as switch maintenance therapy versus placebo yielded both, significantly longer PFS (P < 0.0001) and OS (P = 0.0088) for erlotinib [19]. Although the prolongation of PFS, the primary objective of both studies, (with 2 weeks in the present study versus 1.2 weeks in the phase III study by Cappuzzo et al. [19]) was merely the same, the gain in median survival in the combination arm of this study was 4 months while in the Cappuzzo et al. trial it was one month. Whereas at the first glance, it cannot be denied that this study disposes to a certain extent on a continuation maintenance character, considering especially that one patient of the combined drug arm who stopped pemetrexed after six cycles and continued only erlotinib for the remainder of the 36 cycles. But, the protocol did not foresee the stopping of the chemotherapy at a predefined number of cycles, but merely to modify the dosage of pemetrexed and/or erlotinib independently from each other according to the character or degree of specific toxicities and according to a prefixed scheme and to stop otherwise only in case of progression or patient request. Thus, only six of the patients on the pemetrexed and erlotinib arm who started the combined therapy discontinued pemetrexed and continued with only erlotinib. Two patients discontinued pemetrexed after six cycles of the combined
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C. Dittrich et al. / European Journal of Cancer 50 (2014) 1571–1580
Table 2 Efficacy end-points for randomised and treated patients with non-squamous NSCLC. Efficacy measure
Pemetrexed N = 83
Pemetrexed + Erlotinib N = 76
Hazard ratio (95% CI)
P-value
PFS Median, months (95% CI) Range, months Patients censored, n (%)
2.89 (1.94, 3.38) 0.0, 13.9 13 (15.7)
3.19 (2.86, 4.70) 0.0, 32.2 16 (21.1)
0.63 (0.44, 0.90)
0.0047
0.64 (0.4, 0.9)
0.019
0.68 (0.46, 0.98)
0.019
0.69 (0.47, 1.02)
0.062
0.64 (0.46, 0.89)
0.003
Covariate-adjusted HRa PEM + ERLO versus PEM (reference) PFS rate% (95% CI) at 3 months 6 months 12 months
42.4 (31.2, 53.3) 22.7 (13.6, 33.1) 3.5 (0.7, 10.6)
57.2 (44.6, 68.0) 31.5 (20.8, 42.8) 18.8 (10.4, 29.1)
OS Median, months (95% CI) Range, months Patients censored, n (%)
7.75 (5.29, 10.41) 0.6, 42.6 17 (20.5)
11.83 (8.18, 16.66) 0.4, 38.4 28 (36.8)
Probability (95% CI) that OS time was at least . . . OS rate% (95% CI) at 1 year 34.1 (23.8, 44.6) 49.4 (37.3, 60.4) 2 year 13.7 (6.6, 23.4) 26.8 (15.7, 39.3) Covariate-adjusted HRa PEM + ERLO versus PEM (reference) TTTF Median, months (95% CI) Range, months Patients censored, n (%)
2.40 (1.74, 2.99) 0.6, 11.3 0 (0.0)
3.00 (2.23, 4.07) 0.3, 32.2 3 (3.9)
Best overall response, n (%) Complete response Partial response Stable disease Overall RR, n (%) DCR, n (%)
0 (0.0) 9 (10.8) 34 (41.0) 9 (10.8) 43 (51.8)
1 (1.3) 12 (15.8) 29 (38.2) 13 (17.1) 42 (55.3)
0.180 0.390
Abbreviations: NSCLC = non-small cell lung cancer; PFS = progression-free survival; CI = confidence interval; HR = hazard ratio; PEM = pemetrexed; ERLO = erlotinib; OS = overall survival; TTTF = time-to-treatment failure; DCR = disease control rate (best response of complete, partial, or stable disease). a From Cox proportional hazard model adjusted for smoking status, Eastern Cooperative Oncology Group performance status (0–1 versus 2), and gender.
therapy, two patients after 10 and one patient after 11 cycles, respectively. The combination of a cytotoxic drug with a TKI in this study was significantly more efficacious than that of the cytotoxic agent alone. The medians and percentiles of cycles in both arms show similar treatment patterns in general, but with the exception of a small number of patients (6/7.9%) receiving a high number of cycles (17 cycles) of combination therapy. Overall, higher cumulative toxicity of the combination therapy can also be excluded with a range of 1–36 cycles of the combination versus a range of 1–16 cycles of the single-agent therapy, both showing a median of four cycles (Table 3). In this context, we cannot exclude that the longer median PFS and the even longer median OS of 4 months in patients treated with pemetrexed + erlotinib may be explained by the fact that it is mainly patients with the EGFR mutations who benefit from therapy with a TKI. Nevertheless, the fact, that almost half of the
patients (40 out of 83) of the pemetrexed only arm received erlotinib single agent or combination therapy at consecutive treatment lines, makes this as explanation unlikely (Table 3). With regard to a potential effect of a consecutive uneven treatment distribution as explanation, we can only speculate since we do not dispose on these data. But, the fact that there exists no established third-line treatment which significantly increases overall survival, makes that possibility not very probable. When the study was conceived and started, there was no unanimous recommendation to perform mandatory biomarker assessments or to use any of them as a stratification criterion [20]. Hence, neither determination of EGFR mutation nor collection of EGFR mutation data has been performed, respectively. Shepherd and colleagues (who did only optional tissue banking in their pivotal trial) concluded at that time that the EGFR gene mutations were not predictive of a survival benefit from erlotinib [11]. Tsao emphasised that according to a multivariate analysis of the data of the BR.21 study [21], OS
C. Dittrich et al. / European Journal of Cancer 50 (2014) 1571–1580 Table 3 Summary of cycles administered by treatment arm in patients with non-squamous non-small cell lung cancer. Parameter
Pemetrexed N = 83
Pemetrexed + Erlotinib N = 76
Patients who received 1 cycle, n (%) Mean no. of cycles (SD) Median no. of cycles (range) Total number of cycles received
83 (100)
76 (100)
4.3 (3.3) 4.0 (1, 16) 358
6.3 (6.4) 4.0 (1, 36) 489
Table 4 Possibly drug-related maximum grade 3 and 4 CTCAE toxicities in >5% of patients with non-squamous NSCLC. Event
Pemetrexed N = 83, n (%)
Pemetrexed + Erlotinib N = 76, n (%)
Grade 3
Grade 4
Grade 3
Grade 4
Laboratory Anaemia Leukopenia Neutropenia Thrombocytopenia
4 5 4 2
1 3 4 2
7 (9.2) 15 (19.7) 6 (7.9) 6 (7.9)
2 3 5 5
Non-laboratory Rash/desquamation Diarrhoea Febrile neutropeniaa
1 (1.2) 1 (1.2) 2 (2.4)
6 (7.9) 4 (5.3) 5 (6.6)
1 (1.3) – 3 (3.9)a
(4.8) (6.0) (4.8) (2.4)
(1.2) (3.6) (4.8) (2.4)
0 (0.0) – 0 (0.0)
(2.6) (3.9) (6.6) (6.6)
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events, version 3.0. a Includes 1 grade 5 toxicity, fatal.
was not influenced by the status of the EGFR expression, the number of EGFR copies, or the presence of EGFR mutations. Even in the remission maintenance study of erlotinib, the prolongation of PFS was evident regardless of the EGFR expression, although the EGFR mutation positive patients yielded the greatest benefit from erlotinib therapy [19]. Very recently, results of a 3-arm phase II study similar to ours comparing pemetrexed + erlotinib with pemetrexed or erlotinib in the second-line of non-squamous NSCLC patients have been presented by Lee et al.in 2013 [22]. The combination of pemetrexed + erlotinib was significantly better than pemetrexed alone (HR = 0.58; (95% CI: 0.39, 0.85; P = 0.005). Median PFS of pemetrexed + erlotinib was 7.4 months (95% CI: 4.4, 12.9), that of pemetrexed alone was 4.4 months (95% CI: 3.0, 6.0). In contrast to our study results, no significant difference was reported for OS (HR = 0.75 (95% CI: 0.49, 1.13; P = 0.168). Based on the EGFR status analysable in
