A retrospective analysis of outcomes across histological subgroups in a three-arm phase III trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin for advanced non-small cell lung cancer

Lung Cancer 70 (2010) 340–346

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A retrospective analysis of outcomes across histological subgroups in a three-arm phase III trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin for advanced non-small cell lung cancer夽,夽夽 Joseph Treat a,∗ , Martin J. Edelman b , Chandra P. Belani c , Mark A. Socinski d , Matthew J. Monberg a , Ruqin Chen a , Coleman K. Obasaju a , for the Alpha Oncology Research Network a

Lilly USA, LLC, Indianapolis, IN 46285, USA University of Maryland Greenbaum Cancer Center, Baltimore, MD, USA c Penn State Hershey Cancer Institute, Hershey, PA, USA d Multidisciplinary Thoracic Oncology Group, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA b

a r t i c l e

i n f o

Article history: Received 29 September 2009 Received in revised form 12 February 2010 Accepted 22 February 2010 Keywords: Histology NSCLC Phase III Paclitaxel Gemcitabine Carboplatin Non-platinum doublets Squamous

a b s t r a c t Purpose: Three phase III trials have shown pemetrexed to be associated with improved clinical outcomes among patients with adenocarcinoma and large cell histology compared with patients with squamous histology in advanced non-small cell lung cancer (NSCLC). The current retrospective analysis examined whether differences were present by histology in a three-arm trial of gemcitabine–carboplatin (GCb) or gemcitabine–paclitaxel (GP) versus a standard regimen of paclitaxel–carboplatin (PCb). Materials and methods: 1135 chemonaïve patients with stage IIIB or IV NSCLC were randomly allocated to receive: gemcitabine 1000 mg/m2 days 1 and 8 plus carboplatin area under the curve (AUC) 5.5 day 1 (GCb); or gemcitabine 1000 mg/m2 days 1 and 8 plus paclitaxel 200 mg/m2 day 1 (GP); or paclitaxel 225 mg/m2 plus carboplatin AUC 6.0 day 1 (PCb). Cycles were repeated every 21 days up to 6 cycles or disease progression. Clinical results were retrospectively analyzed in by patient histology. Results: 202 patients (17.8%) had squamous, 555 (48.9%) had adenocarcinoma, 45 (4.0%) had large cell, and 333 (29.3%) had another histologic type. The overall response rate for squamous patients was greater than non-squamous (35.1% versus 27.8%, P = 0.04). Median survival (9.5 months for squamous and 8.3 months for non-squamous) and median time to progression (5.0 months for squamous and 4.4 months for non-squamous) did not significantly vary by histologic group. For squamous histology, median survival was 6.6 months for GCb, 10.2 months for GP, and 10.3 months for PCb. For non-squamous disease, median survival was 8.2 months for GCb, 8.4 months for GP, and 8.3 months for PCb. A formal test for a histologyby-treatment interaction effect between GCb and PCb was significant (P = 0.04). Conclusion: In this trial of commonly used agents for advanced NSCLC, overall survival and time to progression were similar when comparing patients across histologies. The effect of treatment, however, varied across histologies. © 2010 Published by Elsevier Ireland Ltd.

1. Background In advanced non-small cell lung cancer (NSCLC), standard doublet chemotherapy produces modest improvements in survival and quality of life compared with supportive care alone [1–6].

夽 Study ID Numbers—Alpha Oncology: A1-99002L; NCI, PDQ: CDR0000270434; ClinicalTrials.gov: NCT00054392. 夽夽 Preliminary results were presented at the 2008 Chicago Multidisciplinary Symposium in Thoracic Oncology. ∗ Corresponding author at: Lilly USA, LLC, Drop Code 6831, Indianapolis, IN 46285, USA. Tel.: +1 317 433 6078; fax: +1 317 277 3533. E-mail address: [email protected] (J. Treat). 0169-5002/$ – see front matter © 2010 Published by Elsevier Ireland Ltd. doi:10.1016/j.lungcan.2010.02.011

Several large randomized trials comparing commonly prescribed platinum doublets have failed to support any specific regimen as the evidenced-based practice standard for advanced NSCLC [7–10]. In addition, non-platinum doublets have produced outcomes comparable to platinum doublets [5,6]. In recent years, however, there has been a growing recognition that the benefits of therapy may be maximized through the selection of patients with specific tumor characteristics. No histologic subtype of NSCLC has been consistently associated with improved or worsened prognosis in advanced disease [11–13]. Historically, NSCLC histology has not played a prominent role in the selection of first-line cytotoxic regimens. Recently, however, a prespecified analysis of a first-line, phase III NSCLC study showed that treatment with pemetrexed/cisplatin was more effective among

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patients with adenocarcinoma and large cell carcinoma compared with gemcitabine/cisplatin (median survival of 11.8 months versus 10.4 months, P = 0.005) [14]. This finding has been supported by other results from phase III trials of pemetrexed, which have shown a consistent and significant histology-by-treatment effect. These include a retrospective analysis of a trial comparing monotherapy with pemetrexed or docetaxel in the second-line setting [15] and a prospective analysis of a trial comparing maintenance therapy with single-agent pemetrexed to best supportive care following 4 cycles of chemotherapy [16]. These trials and additional analyses of phase II studies [17,18] indicate that treatment with pemetrexed is associated with enhanced efficacy outcomes among patients with non-squamous compared with squamous histology. Gemcitabine and paclitaxel are active, commonly used agents in platinum-based regimens for advanced NSCLC. Eastern Cooperative Oncology Group (ECOG) 5592 demonstrated the utility of paclitaxel in a platinum-based regimen [19] and gemcitabine has been evaluated in regimens including paclitaxel [20–23] and carboplatin [24–26]. The primary objective of the current phase III study was to compare the outcomes associated with a reference regimen of paclitaxel and carboplatin (PCb) to an alternative platinum regimen of gemcitabine and carboplatin (GCb) and a non-platinum regimen of gemcitabine and paclitaxel (GP) in patients with advanced or metastatic NSCLC. The overall clinical results of this trial have been previously reported [27]. While patient histologic subtypes are routinely collected and reported in clinical trials, outcomes by histology are rarely reported [11]. Therefore, it is unknown whether agents other than pemetrexed exhibit a treatment-by-histology effect. The current retrospective analysis examined whether any differences by histology were observed in the three-arm trial of GCb or GP versus the standard regimen of PCb. 2. Patients and methods 2.1. Study design Study design elements of this trial have been previously reported in detail [27]. Eligible patients with advanced or recurrent chemonaïve NSCLC were randomly allocated to receive one of three platinum or non-platinum regimens as follows—GCb: gemcitabine 1000 mg/m2 infused over 30 min on days 1 and 8 plus carboplatin AUC 5.5 over 15–30 min on day 1; GP: gemcitabine 1000 mg/m2 infused over 30 min on days 1 and 8 plus paclitaxel 200 mg/m2 infused over 3 h on day 1; or PCb: paclitaxel 225 mg/m2 infused over 3 h on day 1 plus carboplatin AUC 6.0 over 15–30 min on day 1. Treatment cycles for all three treatment arms were repeated every 21 days for 6 cycles, or until unacceptable toxicity or disease progression. Carboplatin dosing was based on the formula described by Calvert et al. [28]. Guidelines for dose adjustments were provided for chemotherapy-related hematologic, gastrointestinal, cardiovascular, or hepatic toxicity. 2.2. Patient selection Patients with a histologically confirmed diagnosis of stage IIIB (with pleural or pericardial effusion), stage IV, or recurrent NSCLC were enrolled in this study [29]. Mixed tumors were categorized by the predominant cell type unless small-cell anaplastic elements were present, in which case the patient was ineligible. For the purposes of analysis, all patients with bronchioloalveolar disease histology were grouped with adenocarcinoma. All patients were required to be ≥18 years of age and have measurable or evaluable disease (according to ECOG solid tumor criteria); an ECOG performance status of 0 or 1; and adequate bone marrow reserve

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(neutrophils >1500/mm3 , platelets >100,000/mm3 ), adequate hepatic function (aspartate transaminase [AST] ≤5 times institutional upper limit of normal [ULN] and serum bilirubin ≤1.5 mg/dL), and adequate renal function (creatinine clearance ≥40 mL/min or serum creatinine ≤1.5 mg/dL). Patients with stage IV disease and brain metastases (BM) were eligible provided the BM were, in the opinion of the site investigator, clinically stable after treatment with surgery and/or radiation therapy. During the study, brain CT or MRI scans were only required prior to each chemotherapy cycle if indicated by the presence of clinical symptoms. Patients with no CT scan of the head and with no clinical evidence of brain metastases were classified as brain metastases absent. No monitoring was required of patients without clinical symptoms. No previous irradiation to the only area of measurable or evaluable disease was allowed, unless that site had subsequent progression of disease documented by physical exam, radiograph, or pathology. Patients receiving prior chemotherapy for this diagnosis were excluded from participation. Pregnant or breastfeeding women were not eligible, and all women of childbearing potential and sexually active men were required to use an approved method of birth control. Patients with a known or suspected hypersensitivity to agents that utilize polyoxyethylated castor oil were excluded from participation. This study was reviewed and approved by an ethical review board at each participating institution, and it was conducted in accordance with the precepts established by the Declaration of Helsinki and Good clinical Practices. Patients who were eligible for participation provided written informed consent consistent with all applicable governing regulations prior to undergoing any study procedure or receiving any study drug. 2.3. Statistical analysis The planned sample size for this study was 1134 patients. The large number of patients accrued in this study allowed for statistical analyses of outcomes by specific patient subgroups. The current analysis focused on assessing outcomes by tumor histology, which used investigator-reported histologic classifications. Overall survival (OS), response rates (RRs), time to progression (TTP), and safety results were stratified by presence or absence of BM. Survival and TTP were assessed using the intention-to-treat (ITT) population and calculated from the date of randomization to the date of death or documented progression. The Kaplan–Meier product-limit method was used to construct survival and TTP curves and calculate unadjusted medians [30]. Time to progression was defined as the time from randomization to the first date of disease progression. For patients who did not have documented disease progression and did not receive any other anti-tumor therapy, TTP was censored at the date of death or date of last visit. TTP was also censored for patients who received other anti-tumor therapy prior to disease progression. Response Evaluation Criteria in Solid Tumors (RECIST) was used for response evaluation [31]. Response rates were calculated by determining the proportion of patients with complete responses (CRs) and partial responses (PRs), and clinical benefit rates were calculated by determining the proportion of patients with CRs, PRs, and stable disease (SD). Safety was assessed by calculating the percentage of patients experiencing Grade 3 or 4 adverse events using NCI Common Terminology Criteria (CTC) version 2.0 [32]. All tests were two-sided [33]. To compare outcomes by histology and test for a potential treatment-by-histology interaction, Cox proportional hazard models [34] and a logistic regression model were created. The reported multivariate models were cofactor adjusted for weight loss, sex, performance status, ethnicity, and disease stage and included main effects terms for treatment and histology. The treatmentby-histology interaction was tested separately by adjusting for

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Table 1 Patient characteristics by histology group. Characteristic Age (years) Median Range Age ≥70 years, n (%)

Squamous (N = 202)

Adenocarcinoma (N = 555)

Large cell (N = 45)

Other (N = 333)

All non-squamous (N = 933)

65.8 40–91 64 (31.7)

64.0 32–85 168 (30.3)

63.5 45–85 12 (26.7)

63.4 32–88 94 (28.2)

63.9 32–88 274 (29.4)

Gender, n (%) Female Male

76 (37.6) 126 (62.4)

224 (40.4) 331 (59.6)

15 (33.3) 30 (66.7)

132 (39.6) 201 (60.4)

371 (39.8) 562 (60.2)

Performance Status, n (%) 0 1 2 Brain metastases, n (%)

77 (38.1) 125 (61.9) 0 (0.0) 14 (6.9)

219 (39.5) 334 (60.2) 1 (0.2) 103 (18.6)

15 (33.3) 30 (66.7) 0 (0.0) 6 (13.3)

116 (34.8) 210 (63.1) 3 (0.9) 71 (21.3)

350 (37.5) 574 (61.5) 4 (0.4) 180 (19.3)

Weight loss, n (%) <5% ≥5%

123 (60.9) 79 (39.1)

344 (62.0) 211 (38.0)

28 (62.2) 17 (37.8)

215 (64.6) 118 (35.4)

587 (62.9) 346 (37.1)

Race or ethnic group, n (%) White Black Other

170 (84.2) 27 (13.4) 5 (2.5)

487 (87.7) 60 (10.8) 8 (1.4)

38 (84.4) 6 (13.3) 1 (2.2)

277 (83.2) 45 (13.5) 10 (3.0)

802 (86.0) 111 (11.9) 19 (2.0)

Disease stage, n (%) IIIB with effusion IV or recurrent disease

11 (5.4) 191 (94.6)

71 (12.8) 484 (87.2)

3 (6.7) 42 (93.3)

31 (9.3) 262 (78.7)

105 (11.3) 828 (88.7)

67 (33.2) 74 (36.6) 61 (30.2)

192 (34.6) 167 (30.1) 196 (35.3)

15 (33.3) 18 (40.0) 12 (26.7)

105 (31.5) 118 (35.4) 110 (33.0)

312 (33.4) 303 (32.5) 318 (34.1)

Assignment to treatment Gemcitabine–carboplatin Gemcitabine–paclitaxel Paclitaxel–carboplatin

Abbreviations: N = number of patients; n = number in group.

those factors. In the current analysis, histologic subtype was considered “prognostic” if it was associated with a clinical outcome independent of a given therapy. Histologic subtype was considered “predictive” when it was associated with the effectiveness of a particular treatment (i.e., when there is a significant treatment-by-histology interaction). The presence of a significant treatment-by-histology interaction indicates that the treatment effect varies according to the histologic diagnosis. That is, the combination of the treatment and the histologic diagnosis affects the efficacy outcome (such as survival). 3. Results

the squamous group, 95.3% of the adenocarcinoma group, 97.8% of the large cell group, and 91.9% of the other histology group. Patients of all four histologic subtypes received a median of 4 cycles of chemotherapy. The percentage of patients receiving the protocol-defined maximum of 6 cycles of study therapy was 36.9% for the squamous group, 36.1% for the adenocarcinoma group, 31.8% for the large cell group, and 29.1% for the other histology group. The relative median dose intensity (% of planned dose that was administered) for patients with squamous histology was 85.5% for gemcitabine, 89.1% for carboplatin, and 98.5% for paclitaxel. The relative median dose intensity for all patients with non-squamous histology combined was 87.9% for gemcitabine, 91.1% for carboplatin, and 98.9% for paclitaxel.

3.1. Patient characteristics Between July 2000 and November 2005, 1135 patients were screened for eligibility/entry into this trial at 105 investigative sites in the United States and randomly assigned to one of three treatments: GCb (N = 379), GP (N = 377), or PCb (N = 379). Within the overall patient population, 202 patients (17.8%) had squamous cell carcinoma, 555 (48.9%) had adenocarcinoma, 45 (4.0%) had large cell carcinoma, and 333 (29.3%) had another histologic type. Table 1 summarizes patient characteristics and assignment to treatment by histology. Most variables, including age, gender, performance status, ethnicity, and disease stage, were balanced across histologic subgroups. The rate of BM, however, was greater among patients with non-squamous histology compared with squamous histology (19.3% versus 6.9%, P < 0.0001). The distribution of histologic subtypes was uniform across treatment groups. 3.2. Dose administration Study therapy was administered to 1077 patients (94.9%) of the 1135 who were randomly assigned to a study treatment. This group comprised the safety analysis population and included 98.0% of

3.3. Efficacy Primary efficacy outcomes by histologic subtype are shown in Table 2. Using four-category classifications of histology, RRs for squamous (35.1%) and large cell carcinoma (46.7%) were significantly greater compared with adenocarcinoma (27.4%; pairwise P-values for comparisons = 0.05 and 0.01, respectively). Using twocategory classifications of histology, the RR for squamous patients was greater than non-squamous (35.1% versus 27.8%, P = 0.04). Median follow-up for all patients was 8.2 months, and censorship was 8.9% for OS and 7.1% for TTP. Median survival was 9.5 months (95% confidence interval [CI]: 7.6, 10.6) for squamous, 8.7 months (95% CI: 7.8, 9.9) for adenocarcinoma, 7.7 months (95% CI: 5.4, 9.4) for large cell, and 7.9 months (95% CI: 7.1, 8.9) for other histologic types. Median TTP was 5.0 months (95% CI: 4.3, 5.6) for squamous, 4.9 months (95% CI: 4.3, 5.4) for adenocarcinoma, 3.9 months (95% CI: 2.8, 5.9) for large cell, and 3.9 months (95% CI: 3.4, 4.6) for other histologic types. Log-rank P-values for comparisons indicated that differences in OS and TTP were not statistically significant across either two-category or four-category classifications of histology. Curves for OS and TTP by two-category and

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Table 2 Analysis of efficacy parameters by histology. Variable

Objective response, n (%) Complete response Partial response Stable disease Progressive disease Unknown/not done Response rate (CR + PR), n (%) (95% CI) Disease control rate (CR + PR + SD), n (%) (95% CI) Overall survival (OS) Events, n Censored, n (%) Median, months (95% CI) 1 year, % (95% CI) 2 year, % (95% CI) 3 year, % (95% CI) Time to progression (TTP) Events, n Censored, n (%) Median TTP, months (95% CI)

Squamous (N = 202)

Adenocarcinoma (N = 555)

Large cell (N = 45)

Other (N = 333)

All nonsquamous (N = 933)

1 (0.5) 70 (34.7) 65 (32.2) 36 (17.8) 30 (14.9) 71 (35.1) (28.6, 42.2) 136 (67.3) (60.4, 73.7)

6 (1.1) 146 (26.3) 203 (36.6) 107 (19.3) 93 (16.8) 152 (27.4) (23.7, 31.3) 355 (64.0) (59.8, 68.0)

2 (4.4) 19 (42.2) 8 (17.8) 10 (22.2) 6 (13.3) 21 (46.7) (31.7, 62.1) 29 (64.4) (48.8, 78.1)

4 (1.2) 82 (24.6) 108 (32.4) 76 (22.8) 63 (18.9) 86 (25.8) (21.2, 30.9) 194 (58.3) (52.8, 63.6)

12 (1.3) 247 (26.5) 319 (34.2) 193 (20.7) 162 (17.4) 259 (27.8) (24.9, 30.8) 578 (62.0) (58.7, 65.1)

185 17 (8.4) 9.5 (7.6, 10.6) 36.5 (29.9, 43.2) 12.2 (7.6, 16.8) 7.4 (3.4, 11.4)

498 57 (10.3) 8.7 (7.8, 9.9) 37.5 (33.4, 41.6) 13.6 (10.6, 16.6) 7.5 (5.1, 10.0)

44 2 (4.4) 7.7 (5.4, 9.4) 28.9 (15.6, 42.1) 8.9 (0.6, 17.2) 2.2 (0.0, 6.5)

307 26 (7.8) 7.9 (7.1, 8.9) 31.4 (26.4, 36.5) 12.6 (8.9, 16.4) 3.5 (1.2, 5.8)

1043 101 (10.8) 8.3 (7.7, 9.1) 34.9 (31.8, 38.0) 13.0 (10.7, 15.3) 5.8 (4.1, 7.5)

190 12 (5.9) 5.0 (4.3, 5.6)

50 505 (91.0) 4.9 (4.3, 5.4)

44 1 (2.2) 3.9 (2.8, 5.9)

315 18 (5.4) 3.9 (3.4, 4.6)

864 69 (7.4) 4.4 (4.2, 5.0)

Abbreviations: CI = confidence interval; CR = complete response; GCb = gemcitabine + carboplatin; GP = gemcitabine + paclitaxel; N = number of patients; n = number in group; PCb = paclitaxel + carboplatin; PR = partial response; SD = stable disease.

Table 3 Regression analyses with treatment-by-histology interaction effect. Histology subgroup

n

Response rate, % (95% CI)

Cofactor adjusted OR (95% CI)

P-value for OR

Treatment × histology interaction P-value

Squamous Gemcitabine/carboplatin Gemcitabine/paclitaxel Paclitaxel/carboplatin

67 74 61

25.4 (15.5, 37.5) 35.1 (24.4, 47.1) 45.9 (33.1, 59.2)

0.40 (0.18, 0.88) 0.65 (0.31, 1.33) 1.0 (Reference)

0.02 0.24 Reference

0.04 comparing gemcitabine/carboplatin and paclitaxel/carboplatin

Non-squamous Gemcitabine/carboplatin Gemcitabine/paclitaxel Paclitaxel/carboplatin

312 303 318

25.32 (20.6, 30.5) 31.35 (26.2, 36.9) 26.73 (22.0, 32.0)

0.93 (0.65, 1.34) 1.25 (0.88, 1.77) 1.0 (Reference)

0.71 0.22 Reference

0.08 comparing gemcitabine/paclitaxel and paclitaxel/carboplatin

Histology subgroup

n

Median survival, months (95% CI)

Cofactor adjusted HR (95% CI)

P-value for HR

Treatment × histology interaction P-value

Squamous Gemcitabine/carboplatin Gemcitabine/paclitaxel Paclitaxel/carboplatin

67 74 61

6.6 (5.1, 9.5) 10.2 (7.7, 13.7) 10.3 (8.7, 12.0)

1.36 (0.93, 1.99) 1.08 (0.75, 1.55) 1.0 (Reference)

0.11 0.67 Reference

0.04 comparing gemcitabine/carboplatin and paclitaxel/carboplatin

Non-squamous Gemcitabine/carboplatin Gemcitabine/paclitaxel Paclitaxel/carboplatin

312 303 318

8.2 (7.3, 9.5) 8.4 (7.2, 9.8) 8.3 (7.3, 9.8)

0.96 (0.81, 1.13) 0.97 (0.82, 1.14) 1.0 (Reference)

0.61 0.70 Reference

0.40 comparing gemcitabine/paclitaxel and paclitaxel/carboplatin

Cofactor adjusted HR (95% CI)

P-value for HR

Treatment × histology interaction P-value

Histology subgroup

n

Median TTP, months (95% CI)

Squamous Gemcitabine/carboplatin Gemcitabine/paclitaxel Paclitaxel/carboplatin

67 74 61

4.3 (3.8, 5.1) 5.0 (3.9, 6.6) 5.7 (4.6, 6.9)

1.33 (0.91, 1.94) 1.17 (0.82, 1.67) 1.0 (Reference)

0.14 0.38 Reference

0.07 comparing gemcitabine/carboplatin and paclitaxel/carboplatin

Non-squamous Gemcitabine/carboplatin Gemcitabine/paclitaxel Paclitaxel/carboplatin

312 303 318

4.4 (3.8, 5.3) 4.4 (3.7, 5.4) 4.4 (3.9, 5.1)

0.92 (0.78, 1.08) 0.95 (0.80, 1.12) 1.0 (Reference)

0.312 0.539 Reference

0.26 comparing gemcitabine/paclitaxel and paclitaxel/carboplatin

Abbreviations: HR = hazard ratio, OR = odds ratio.

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Fig. 1. Overall survival among all patients using: a two-category classification of histology (a) and a four-category classification of histology (b).

four-category classification of histology are summarized in Fig. 1a and b. Table 3 summarizes efficacy outcomes by individual strata of treatment groups and histologic subtypes. Among non-squamous patients, no differences in RRs were evident across treatment groups. Among squamous patients, however, treatment with PCb was associated with a greater RR than GCb (P = 0.02). A logistic regression model showed that the effect of treatment on response rates significantly varied according to histologic subtype when comparing PCb and GCb treatment (interaction P-value = 0.04). Examining OS and TTP outcome variables, no significant differences were evident across treatment groups for patients with squamous or non-squamous disease. However, a Cox regression model of OS showed that the effect of treatment significantly varied by histologic subtype for the comparison between PCb and GCb (interaction P-value = 0.04). As shown in Table 3, GCb treatment among squamous patients was associated with the lowest survival of the 6 strata defined by treatment and histology. Curves for OS and TTP by treatment group and two-category classification of histology are summarized in Fig. 2a and b. 3.4. Adverse events Table 4 summarizes grade 3 or 4 toxicity by treatment group for the safety population. As shown, no significant differences were evident in any comparison between hematologic and nonhematologic events by two-category classification of histology. Using four-category classifications of histology (not shown), the

Fig. 2. Overall survival among patients by treatment group for patients with squamous histology (a) and non-squamous histology (b).

only notable significant difference in grade 3 and 4 toxicity was in grade 3 or 4 neutropenia. The incidence of grade 3 or 4 neutropenia was greater among patients with squamous (32.8%), adenocarcinoma (33.5%) or large cell (47.7%) disease compared with other histologic types (24.2%; P for pairwise comparisons = 0.04, 0.005, and 0.002, respectively). 4. Discussion In this trial of commonly used agents for advanced NSCLC, histologic subtype by itself was not prognostic of OS, TTP, or toxicity outcomes. This finding is consistent with previous research suggesting that no histologic subtype of NSCLC has been consistently associated with improved or worsened prognosis [11–13]. However, there were significant differences in RRs across histological subtypes that favored squamous and large cell histologies relative to adenocarcinoma. An unexpected finding from this analysis was that the effect of treatment on OS and RR endpoints varied significantly by histologic type (interaction P-value for both comparisons = 0.04). Therefore, histology was a predictive factor in assessing the benefit of therapy in this trial. For OS, this treatment-by-histology effect was influenced by the numerical difference in OS between squamous patients receiving GCb (6.6 months) and squamous patients receiving PCb (10.3 months). With regard to this finding, however, it should be noted that OS estimates within the squamous subgroup may have been unstable due to the relatively lower sample size of this group relative to the non-squamous subgroup, where sample size was greater and OS estimates were more consistent across

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Table 4 Toxicity according to histology (safety population). Type of toxicity

Hematologic events, n (%) Neutropenia Febrile neutropenia Thromobocytopenia Platelet transfusion Anemia Red blood cell transfusion Transfusion Non-hematologic events, n (%) Hemorrhage Infection Nausea Vomiting Diarrhea Sensory neuropathy Arthralgia (Grade 3 or 4) Alopecia (Grade 2) Any nervous system disorder (Grade 1 to Grade 4)

Squamous histology (N = 198)

Non-squamous histology (N = 879)

Grade 3

Grade 4

Grade 3

Grade 4

35 (17.7) 4 (2.0) 42 (21.2)

30 (15.2) 2 (1.0) 16 (8.1)

143 (16.3) 24 (2.7) 192 (21.8)

129 (14.7) 5 (0.6) 44 (5.0)

0 (0.0)

99 (11.3)

6 (3.0) 18 (9.1)

23 (2.6)

2 (1.0) 11 (5.6)

6 (3.0) 11 (5.6) 10 (5.1) 4 (2.0) 12 (6.1)

3 (0.3) 3 (0.3) 34 (3.9)

0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

16 (1.8) 54 (6.1) 32 (3.6) 20 (2.3) 54 (6.1)

5 (2.5) 73 (36.9) 108 (54.5)

5 (0.6) 1 (0.1) 1 (0.1) 1 (0.1) 4 (0.5) 18 (2.0) 355 (40.4) 536 (61.0)

P-value for overall comparison

0.611 1.0 0.481 0.807 0.381 0.230 0.323

0.614 0.870 0.421 1.0 0.874 0.595 0.361 0.108

GCb = gemcitabine + carboplatin; GCb = gemcitabine + paclitaxel; PCb = paclitaxel + carboplatin; N = number of patients; n = number in group.

treatments. In fact, OS estimates within the non-squamous subgroup (8.2 months for GCb, 8.4 months for GP, and 8.3 months for PCb) closely resembled OS estimates for the overall trial (7.9 months for GCb, 8.5 months for GP, and 8.7 months for PCb) [27]. Furthermore, with respect to OS, only the treatment-byhistology P-value was significant in the current study. However, the direct comparison of OS between GCb and PCb within the squamous subgroup was not statistically significant (P = 0.11). The first-line, phase III study from Scagliotti et al. comparing pemetrexed/cisplatin with gemcitabine/cisplatin not only produced a significant histology-by-treatment interaction P-value, but also significant P-values for direct comparisons between treatments within histologic subgroups [14]. Furthermore, the numerically lower OS associated with GCb in the squamous compared with the non-squamous group in the current study is at odds with the finding from Scagliotti et al. of the similar OS associated with gemcitabine–cisplatin treatment in squamous (10.8 months) and non-squamous histologies (10.4 months) [14]. Other studies provide more context for the results from the current analysis. A three-arm, phase III study conducted in Italy (N = 607) compared treatment with PCb, gemcitabine/cisplatin, and vinorelbine/cisplatin in chemonaïve advanced NSCLC [9]. That study failed to show any predictive effect of histology or treatmentby-histology interaction [35]. Data from the linked Surveillance, Epidemiology and End Results Program (SEER)-Medicare database evaluated whether histology predicted efficacy outcomes for elderly patients with Stage IIIB/IV NSCLC who were treated with doublet chemotherapy consisting of gemcitabine and a platinum agent or a taxane plus a platinum agent [36]. That study did include a formal treatment-by-histology interaction test and found that histology did not predict any significant differences in OS with either treatment regimen [36]. In a phase III trial, Fidias et al. compared immediate versus delayed docetaxel following first-line treatment with GCb in advanced NSCLC [37]. Among all patients randomly assigned to immediate or delayed docetaxel (N = 308), OS was 10.1 months for squamous patients and 11.8 months for non-squamous patients. While this difference was not statistically significant (P = 0.296), it may be of note that squamous patients had a numerically smaller OS than non-squamous patients (as in the current trial). To date, pemetrexed-cisplatin is the only combination to be approved by the Food and Drug Administration (FDA) for the first-

line treatment of locally advanced or metastatic NSCLC on the basis of a survival differential among non-squamous patients. The current trial did not provide conclusive evidence that survival among the three regimens studied differed within the non-squamous subgroup. In the current study, the toxicity profile of treatment combinations was similar across histologic subtypes, and chemotherapy dose administration also did not vary according to histologic subtype. As noted by Pimentel et al., efficacy differences by histology likely reflect differences in tumor biology across histologic type [38]. In contrast, toxicity of chemotherapy is generally a host phenomenon that is unrelated to tumor biology [38]. In addition to the limitations acknowledged above, interpretation of these results is limited by the retrospective nature of this analysis, the lack of central expert review of histologic classifications, and the lack of any biomarker information. Low tumor expression levels of ribonucleotide reductase subunit M1 (RRM1) and excision-repair cross complementation group 1 (ERCC1) have been shown to be predictive of response to gemcitabine and GCb therapy [39–41]. Unfortunately, a consistent, significant correlation between histologic subtype and RRM1 or ERCC1 has not been established [40,41]. Conflict of interest statement This study was sponsored by Lilly USA, LLC. Co-authors Joseph Treat, Coleman Obasaju, Ruqin Chen, and Matthew Monberg are employees of Lilly USA, LLC. Martin Edelman, Mark Socinski, and Chandra Belani have received honoraria and research funding from Lilly. Acknowledgement This trial was funded by Lilly USA. References [1] Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995;311:899–909. [2] Grilli R, Oxman AD, Julian JA. Chemotherapy for advanced non-small-cell lung cancer: how much benefit is enough? J Clin Oncol 1993;11:1866–72.

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