Platinum rechallenge in patients with advanced NSCLC: A pooled analysis

Lung Cancer 81 (2013) 337–342

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Review

Platinum rechallenge in patients with advanced NSCLC: A pooled analysis Fausto Petrelli ∗ , Andrea Coinu, Mary Cabiddu, Mara Ghilardi, Mara Ardine, Sandro Barni Azienda Ospedaliera di Treviglio, Oncology Department, Medical Oncology Unit, Piazzale Ospedale 1, 24047 Treviglio, BG, Italy

a r t i c l e

i n f o

Article history: Received 6 February 2013 Received in revised form 18 June 2013 Accepted 29 June 2013 Keywords: NSCLC Metastatic Second line Platinum-based doublets Rechallenge

a b s t r a c t Introduction: The sole agents pemetrexed (PEM), docetaxel and anti-EGFR agents are approved secondline therapies for non-small cell lung cancer (NSCLC) after failure with cisplatin-based doublets. The potential usefulness of platinum-based doublets as rechallenge for second-line chemotherapy has not yet been established. Methods: Studies that enrolled NSCLC platinum pre-treated patients were identified using electronic databases (MEDLINE and EMBASE). Pemetrexed and taxanes (TAXs)-based platinum combinations were considered. A systematic review was conducted using Comprehensive Meta-Analysis (version 2.2.064) software to calculate the event rate of response and 95% confidence interval. Median weighted progression-free survival (PFS) and overall survival (OS) time for PEM and TAXs-based doublets were compared by two-sided Student’s t test. We tested for significant heterogeneity by Cochran’s chi-square test and I2 index. Results: Eleven studies published between 1999 and 2012 were included in this analysis with a total of 607 patients enrolled; 468 were treated with PEM-doublets and 139 with TAXs-doublets. The overall response rate was 27.5% with a higher response rate of 37.8% (range, 29.7–46.7%) for TAXs-based treatment vs. 22% (range, 13.4–34.1%) for PEM-based combinations; (p < 0.0001). Median PFS and OS were 3.9 and 8.7 months with weighted PFS of 3.9 vs. 5.3 months (p < 0.0001) and similar OS for PEM vs. TAXs-based doublets. Conclusions: With the limitations of small and not randomised trials included, this pooled analysis shows that NSCLC patients who relapsed after a first-line platinum-based chemotherapy obtain a tumour response of 27% from a platinum rechallenge containing PEM or TAXs. Response rate and median PFS appear better with TAXs-than with PEM-doublets. © 2013 Elsevier Ireland Ltd. All rights reserved.

Cisplatin-based chemotherapy is the standard first-line treatment for advanced, EGFR wild-type, non-small cell lung cancer (NSCLC). After the first-line failure, conventional second-line chemotherapy treatment with docetaxel (DOC) or pemetrexed (PEM) gains a low response rate (RR), a relatively short progression free survival (PFS) and overall survival (OS) [1–3]. The primary aims of the second-line treatment are the control of disease symptoms, improvements in the quality of life and a prolongation of survival. In general, second-line poly-chemotherapy increased RR and PFS compared to single agents, but at the expense of increased toxicity, according to a meta-analysis of Di Maio et al. [4]. In this meta-analysis, 6 studies were analysed, but only one compared a platinum-based doublet to a single agent (PEM vs. carboplatin/PEM) in patients with stage IV NSCLC that relapsed >3 months after platinum-based first-line treatment.

∗ Corresponding author. Tel.: +39 0363424420; fax: +39 0363424380. E-mail address: [email protected] (F. Petrelli). 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.06.022

In small cell lung cancer, re-challenge with the same platinum regimen used for initial treatment confers a potential benefit in patients with late relapse and can be considered in patients with a prolonged time to progression from the prior chemotherapy regimen (at least 6 months) [5]. Also, the management of relapsed ovarian cancer is regularly planned according to the interval that has elapsed between the end of platinum-based treatment and the diagnosis of relapse, which is known as the platinum-free interval [6]. In the NSCLC setting, no phase III trials have been conducted in a second-line setting to prove the value of platinum-doublets, including the newer agents, taxanes (TAXs) and PEM. Recently, two meta-analyses [7,8] evaluated DOC- and PEM-based doublets as second-line treatments and showed a RR and PFS advantage compared to single agents. In these meta-analyses, only 2 trials included platinum-agents, and only one of these studies enrolled patients who were previously treated with platinum-agents. Recently, Ardizzoni et al. [9] reported a pooled analysis of two randomised phase II trials comparing PEM/carboplatin with PEM alone in stage IV NSCLC pre-treated with platinum agents. Overall, RR and PFS

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1. Materials and methods

was formally assessed by Cochran’s chi-square test and the I2 index where a p value <0.1 by chi-square test and I2 value <0.25 indicate a low degree of heterogeneity. Mixed-effect meta-regression was conducted using the unrestricted maximum-likelihood method to assess predictors such as response to the first-line platinum-based chemotherapy. Response rate, PFS and OS were calculated for pure second-line vs. mixed-lines (second and beyond) trials and for PEM vs. TAXs-doublets. Finally, sensitivity analyses for pooled RR were conducted to eliminate potential confounding of the results by a particular study or a group of studies by repeating the analysis after excluding each study in turn (leave-one-out model); by excluding studies of carboplatin combinations; after excluding retrospective or prospective studies and after excluding smaller studies that enrolled less than 50 patients. Median pooled PFS and OS were summarised using descriptive statistics. Statistical differences in the weighted median RR, PFS and OS for PEM and TAX doublets were assessed by two-sided t-tests. Publication bias for RR analysis were assessed by Begg’s funnel plot and Egger’s test. Analyses were performed using the Comprehensive MetaAnalysis (version 2.2.064, July 2011) and NCSS (version 07.1.21, June 2011) programs.

1.1. Study eligibility

2. Results

Prospective clinical trials that enrolled patients with advanced NSCLC for the evaluation of second-line, platinum-based doublets, containing PEM or TAX agents, were included in this analysis. In addition, qualifying studies must have enrolled a minimum of 10 patients and reported on the clinical outcome of interest: OS or PFS and RR. Studies published in a language other than English or that included less than 90% of patients pre-treated with platinum-based first-line doublets were excluded.

The search identified 1196 studies, with 27 studies published between 1998 and 2012 deemed potentially eligible for this analysis. Based on the predefined eligibility criteria, we selected 11 studies from 10 publications that met the qualitative and quantitative requirements of the systematic analysis [9,11–19]. One article actually included the pooled analysis of two trials. A consort diagram of the stepwise identification of eligible studies is detailed in Fig. 1. Overall, two were randomised phase II trials, three were phase II single arm trials, four were prospective series, and two were retrospective analyses. A total of 607 patients were enrolled in the selected trials. The rate of response was available for 591 patients pre-treated with at least one line of chemotherapy including platinum agents; 364 (61.5%) were treated in the second-line setting only and 227 (38.5%) in the third-line or beyond. Progression-free survival and OS were available in 10 and 9 trials, respectively. Details of patient demographics and study designs are included in Table 1.

increased significantly from 9% to 15% and from 3 to 3.9 months in the combination arm, although OS was similar. In a phase III trial lead by Pallis et al. carboplatin/DOC showed a better PFS compared to DOC alone, with similar RR and OS, but it was conducted in patients pre-treated with paclitaxel only [10]. The availability of different effective drugs makes a cisplatin or carboplatin-based salvage therapy unusual. In a second-line setting, a significant benefit in randomised trials has never been demonstrated, and a potential cumulative toxicity with cisplatin re-challenge (e.g. neurotoxicity) is of concern. Retreatment with platinum-agents could be proposed hypothetically for patients with platinum-sensitive NSCLC, with a long time to progression (TTP) from the last platinum treatment of at least some months, in patients with a good performance status, and those that may be symptomatic. In this setting, however, no phase III trials have been published. This systematic analysis is the first review aiming to assess the clinical efficacy of platinum-doublet re-challenge, by using data pooled from clinical studies that enrolled patients with relapsed NSCLC after the first-line (platinum-based) failure.

1.2. Literature search strategy We identified eligible clinical trials using the main computerised databases of published biomedical literature (MEDLINE, EMBASE). We used the search terms “non-small cell lung cancer OR NSCLC” AND “cisplatin or carboplatin” AND “second-line or pre-treated or previously treated” along with the following limit terms: humans, clinical trial, English, and cancer, all adult: 19+ years for the MEDLINE search. The retrieved studies were reviewed independently by two of the authors (AC and FP). Final determination of study eligibility was made by the concurrence of both investigators by a consensus. 1.3. Data extraction and synthesis Pertinent extracted data included patient demographics, number and median age of enrolled patients, specific therapy, rates of platinum-agent exposure during first-line therapy, RR to firstline therapy and clinical outcome of RR, and survival (PFS and/or OS). The RR data (our primary endpoint) was pooled to produce a weighted overall RR. We also calculated the weighted median OS and PFS for all trials. Outcome data were also pooled for the two patient subgroups (PEM vs. TAX-based doublets) to generate a weighted median overall RR, median PFS and OS. Main toxicities were evaluated accordingly.

2.1. Tumour response (Fig. 2) Fig. 2. The overall RR of NSCLC patients to the second-line treatment with platinum-combinations was 27.5%, with 22% in (in all histologies) for patients treated with PEM-based doublets (range: 13.4%–34.1%) and 37.8% (range: 29.7%–46.7%) for TAX-based doublets (p < 0.0001). Progression-free and overall survival (Fig. 3) The weighted overall median PFS and survival time following second-line therapy were 3.9 (range 2.3–6.43) and 8.7 (range 8–17.4) months with weighted median PFS/OS of 3.9/8.7 months for PEM- and 5.3/8.5 months for TAXs-doublets (p < 0.0001 for PFS). 2.2. Toxicities

1.4. Statistical analysis Using a random-effect model, the rate of response to platinumdoublets (all studies and PEM vs. TAX-based studies) treatment was calculated as event rate along with a 95% confidence interval. Significant heterogeneity among the studies employed for this analysis

The haematological and non-haematological toxicities of the combinations (grade 3–4) were analysed separately for PEM and TAX doublets, where information were available. For the first trials, neutropenia, anaemia and thrombocytopenia ranged from 7.5 to 18.8%, 0 to 12.5% and 0 to 18.8%, respectively. Among

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Records idenfied through PubMed and EMBASE searching (including conferences abstracts) (n = 1,196) Records excluded (n =1169) review, meta-analysis, 687 leers, commentaries or duplicates, 129 publicaons not English language 353 studies not including planum-doublets Records screened (n =27)

Full-text arcles assessed for eligibility (n = 27)

Studies included in qualitave synthesis (n =10)

Publicaons excluded (n=17) 10 used agents different from pemetrexed or taxanes included paents not 7 planum-pretreated

Studies included in quantave synthesis (meta-analysis) (n =10) Fig. 1. Selection of publications included in the pooled-analysis.

non-haematological toxicities the most frequent was fatigue, with nausea, vomiting and diarrhoea being rare (<3%). In TAX-based studies, as expected, neutropenia, anaemia and thrombocytopenia were more frequent and ranged from 33 to 76%, 8 to 24% and 2 to 15%, respectively. Asthenia, neuropathy and alopecia were the main non-haematological toxicities. 2.3. Sensitivity testing The heterogeneity was high (I2 77.9%), so a random effect model was used for RR calculation. The leave-one-out procedure did not change the final result. Response rates were 25.4% and 29.6% for real second-line trials and mixed lines (second and beyond lines of treatment) studies. The chance of response was dependent on the line of treatment in the meta-regression, with a trend for greater RR in studies which also included heavily pre-treated patients (third-line or beyond; p = 0.0003). Response rate was also not

dependent as a function of RR on the first-line treatment (p = 0.24). According to histology analysis, RR in PEM trials does not seem largely different in squamous (that represent 10–53% of patients) compared to not-squamous subtypes (as reported by Metro e Kim). However a systemstic investigation was not possible for other trials. An analysis according to TTP with 1st line therapy was not performed to due to lack of information. Nevertheless, in the trials where the majority of patients had a TTP from 1st line treatment of >6 months, the RR was always >40%. Considering only phase II or III studies and trials with more than 50 patients enrolled, the final result for RR was similar even if slightly inferior to the overall RR (23.7% and 21.6%). If we consider only the cisplatinum combinations the pooled RR was 26.9%. The median weighted PFS and OS were 3.9 and 8.7 for secondline trials and 5.8 and 10 months for trials that included patients treated both as second-line and beyond.

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Study name

Statistics for each study

Event rate and 95% CI

Weight (Random) Relative Relative Std Std Std weight weight Residual Residual Residual

Event Lower Upper rate limit limit Z-Value p-Value ardizzoni 2012 metro 2011 arrieta 2011 zhang 2010 kim 2010 zhang 2009 yoh 2007 seto 2004 numico 2005 stathopoulos 1999

0,150 0,425 0,304 0,132 0,188 0,190 0,367 0,320 0,406 0,400 0,275

0,110 0,322 0,152 0,064 0,087 0,098 0,216 0,169 0,252 0,255 0,196

0,201 0,535 0,515 0,252 0,360 0,336 0,549 0,522 0,581 0,565 0,371

-9,555 -1,337 -1,827 -4,641 -3,234 -3,687 -1,439 -1,758 -1,057 -1,192 -4,305

0,000 0,181 0,068 0,000 0,001 0,000 0,150 0,079 0,290 0,233 0,000

12,43 11,90 8,73 9,39 8,75 9,57 9,78 9,07 10,05 10,33 -0,50

-0,25

0,00

0,25

-1,28 1,09 0,19 -1,31 -0,68 -0,69 0,62 0,30 0,87 0,85

0,50

Fig. 2. Pooled analysis for response rate.

2.4. Publication bias The traditional Begg’s funnel plot did not show obvious asymmetry in RR analysis (p = 0.28; Fig. 4). Accordingly, the Egger’s test was not significant for bias (p = 0.58). 3. Discussion This pooled analysis is the first to evaluate the value of platinum-based chemotherapy doublets in pre-treated patients with advanced NSCLC, who had been previously exposed to platinum-agents. The results confirm that, in this population of patients, RR is 27.5%, and the median PFS and OS are 3.9 and 8.7 months. The results for RR are independent of response to the first-line platinum doublets and are greater in subsequent lines of therapy. Overall, these results are similar for survival to standard second-line therapy (either DOC or PEM), but demonstrate that a platinum-combination is associated with a higher tumour response (about 3-fold higher than that obtained with single agents according to Hanna phase III study [3]). This analysis confirms that an

increasing RR of the second-line treatment does not lead to a better survival compared to single agent DOC or PEM. Two meta-analyses evaluated whether DOC or PEM doublets are better than either single agent [7,8]. These showed that combinations increased both RR and PFS but not OS. Similar results were found from the metaanalysis of Di Maio et al. [4]. In the two Asiatic meta-analyses, only the trial by Smit et al. [20] included patients pre-treated with platinum-agents, so no formal comparison, even indirect, could be performed. In the small cell lung cancer setting, a potential benefit with platinum retreatment can be obtained if at least 3–6 months have elapsed from the last platinum treatment. In this analysis, time to progression with the first-line chemotherapy was not known for almost all of the trials; however, meta-regression demonstrated that RR is not proportional to RR of the first-line treatment. The results in the highly pre-treated populations are appealing. Our pooled analysis included 5 trials that enrolled patients who were pre-treated with at least two previous lines of chemotherapy. Meta-regression showed that RR is significantly greater in these studies, almost suggesting that when more time has elapsed from

Fig. 3. PFS (grey) and OS (black) of all trials (in horizontal X axis median months of PFS and OS duration, in vertical Y axis the name of first author).

25 36 CDDP/DOC CDDP/3wPAC II Prospective study 62/76 60/80.5 2004 1999 Seto Stathopoulos

341

Funnel Plot of Standard Error by Logit event rate 0,0

0,1

Standard Error

PS, performance status; ADK, adenocarcinoma; SCC, squamous cell carcinoma; CBDCA, carboplatin; PEM, pemetrexed; CDDP, cisplatin; GEM, gemcitabine; PAC, paclitaxel; DOC, docetaxel; pts, patients; TTP, time to progression; RR, response rate; PFS, progression free-survival; OS, overall survival; 3w, 3 weekly; w, weekly; 1st, first; 2nd, second; NA, not available.

8.5 NA 3.2 NA 32 40 48 22.2 NA NA

5.3 6.1 36.7 42.3 42.8 47 0.8–12.9 in responders 13.7 76.6% 67

70/23 33/35 (n = 48 1st–2nd line) 56/36 NA 30 48 2007 2005 Yoh Numico

II Prospective series

2009 Zhang

60/100 67/NA

NA/NA

2010 2011 Kim Arrieta

Retrospective

62.5/87.5 59/65.2

2011 2010 Metro Zhang

II Prospective series

100 100

NA 6.43 19 24 42

78/10

100%

NA

9.9 8

9.4 12.5 2.3 5.9 34.4/53.1 86.9/NA

90.60% 100%

21.9% > 6 12.6

53.2 43.5

18.8 30.4

80 53

CBDCA/PEM CDDP/PEM (32); CBDCA/PEM (21) CBDCA/PEM CBDCA/GEM (n = 6) or CBDCA/PEM (n = 17) Platinumbased/PEM CBDCA/3wPAC CBDCA/wPAC

32 23

17.4 10 5.8 6 42.5 13.2 47.5 NA 78.8% > 6 NA 57.50% 64.20%

8.7 3.9 15 35.3/61 33.6% > 6 100%

71.4/14.3 GOIRC; 41/24 NVALT7 72.5/16.3 58.5/26.4 238 CBDCA/PEM

II (pooled analysis of 2 trials) Retrospective Prospective series 2012 Ardizzoni

64/95.8 (GOIRC); 59/92 (NVALT7) 59/97.5 52/75.4

Schedule Type of study Median age (years)/PS 0–1 (%) Year Author

Table 1 Characteristics of the included studies.

Pts

ADK/SCC %

2nd line (%)

TTP 1st line (mo)

RR 1st line

RR

PFS

OS

F. Petrelli et al. / Lung Cancer 81 (2013) 337–342

0,2

0,3

0,4

0,5 -3

-2

-1

0

1

2

3

Logit event rate

Fig. 4. Funnel plot for event rate in RR analysis.

the last platinum treatment, the chance of response to platinum retreatment is better (alternatively, two chemotherapy lines may have selected a patient population destined to a better RR). Similar data were observed in ovarian cancer. In fact, patients treated with second-line trabectedin and pegylated liposomal doxorubicin, showed a better outcome when retreated with cisplatin thereafter [21]. Results for PEM and TAXs doublets are slightly different with seemingly better RR and PFS for TAXs ones. This can be explained with the inclusion of squamous histology NSCLC patients in the PEM trials. It is known that the outcome is inferior in squamous cell carcinoma treated with PEM compared to adenocarcinoma [22]. Response rates in particular, with the limitation of a small number of patients, does not look different in squamous or not histology. However, the addition of a platinum agent could have been compensated the relative inefficacy of PEM in squamous histology. Even the toxicities profiles seem different, with more haematological events with TAX-combinations. The message that derives from this pooled-analysis is that combination with platinum-agents could employ a role in the second-line setting or beyond, in particular in terms of RR, but overall, the outcome seems similar to conventional second-line agents. The authors feel that a platinum retreatment can be proposed to particularly symptomatic patients with excellent performance status, in particular those who are younger and fitter, and patients with adenocarcinoma histology. However, this apparently better rate of response has to be balanced with the greater toxicity profile of combinations as demonstrated also by the meta-analysis performed by Di Maio et al. [4]. Targeted agents have been tested as second-line treatments. In particular, the anti-VEGFR drug vandetanib has been added to both PEM and DOC in randomised trials. In 2 phase III trials, the median PFS was about 4 months and the median OS was about 10 months with the addition of vandetanib to single agent PEM and DOC [23,24]. A meta-analysis of 4 randomised trials calculated an advantage in RR and PFS but not in OS with the addition of vandetanib to the second-line agents [25]. Similarly, the standard agent erlotinib, which is approved as a second- or third-line treatment after cisplatin failure, produced to a median PFS and OS of 2.2 and 6.7 months, respectively, in a phase III trial [26]. Our analysis portends some obvious limitations. The main weakness is that it includes mainly retrospective or small prospective trials with low quality features. So possible bias has been included; also, the possible inclusion of a fairly well selected group of patients may have affected the overall results. The lack of a control arm without the use of platinum-agents cannot prove the

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superiority of the platinum-doublets compared to single agents. Finally, the inclusion of squamous cell NSCLC in PEM trials could have resulted in a more inferior outcome than expected according to the current knowledge of histology selection for the choice of the second-line chemotherapy. Nevertheless to our knowledge, this analysis using pooled data across 11 different prospective and retrospective studies of second-line chemotherapy with platinumbased doublets in patients previously treated with platinum agents is the first in this setting. An intriguing RR was calculated, and this result could also even be underestimated for the inclusion of squamous cell histology NSCLCs in PEM publications. Moreover the results were similar for retrospective and prospective studies, and for trials that enrolled >50 patients. With these limitations in mind, a definite conclusion about the usefulness and benefit of platinum-based polychemotherapy in the second line setting cannot be stated. A robust confirmation through a solid phase III trial is needed before any recommendation can be performed. Emphasising the results of this analysis requires anyhow some caution, because the patient population enrolled in clinical trials likely represents a selected subset with good performance status who may have preserved organ function, meaning that they are not representative of the general patient population. In conclusion, we could affirm that platinum-doublets are an effective treatment option, even in patients previously exposed to platinum-agents as first-line chemotherapy. The combination with PEM or TAXs leads to an RR close to 30% even if the PFS and OS are similar to traditional second-line monotherapies. Conflict of interest statement None declared. References [1] Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O’Rourke M, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinumbased chemotherapy. J Clin Oncol 2000;18:2095. [2] Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinumcontaining chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000;18:2354. [3] Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, 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. [4] Di Maio M, Chiodini P, Georgoulias V, Hatzidaki D, Takeda K, Wachters FM, et al. Meta-analysis of single-agent chemotherapy compared with combination chemotherapy as second-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 2009;27:1836. [5] Garassino MC, Torri V, Michetti G, Lo Dico M, La Verde N, Aglione S, et al. Outcomes of small-cell lung cancer patients treated with secondline chemotherapy: a multi-institutional retrospective analysis. Lung Cancer 2011;72:378. [6] Cantù MG, Buda A, Parma G, Rossi R, Floriani I, Bonazzi C, et al. Randomized controlled trial of single-agent paclitaxel versus cyclophosphamide, doxorubicin, and cisplatin in patients with recurrent ovarian cancer who responded to first-line platinum-based regimens. J Clin Oncol 2002;20:1232. [7] Qi WX, Tang LN, He AN, Shen Z, Yao Y. Effectiveness and safety of pemetrexedbased doublet versus pemetrexed alone as second-line treatment for advanced non-small-cell lung cancer: a systematic review and meta-analysis. J Cancer Res Clin Oncol 2012;138(May (5)):745–51.

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