ORIGINAL ARTICLE
`
`Randomized Multicenter Phase II Study of Larotaxel
`(XRP9881) in Combination with Cisplatin or Gemcitabine
`as First-Line Chemotherapy in Nonirradiable Stage IIIB or
`Stage IV Non-small Cell Lung Cancer
`
`Petr Zatloukal, MD,* Radj Gervais, MD,† Johan Vansteenkiste, MD, PhD,‡ Le´on Bosquee, MD,§
`Christiana Sessa, MD,储 Etienne Brain, MD, PhD,¶ Eric Dansin, MD,# Thierry Urban, MD, PhD,**
`Nadine Dohollou, MD,†† Miche`le Besenval, MD,‡‡ and Elisabeth Quoix, MD§§
`
`Introduction: This randomized phase II study investigated the
`efficacy and safety of a new taxane, larotaxel (XRP9881), in com-
`bination with either cisplatin or gemcitabine in the first-line treat-
`ment of patients with nonirradiable stage IIIB or stage IV non-small
`cell lung cancer to select the combination having the most promising
`antitumor activity.
`Methods: Patients received either larotaxel (50 mg/m2) as a 1-hour
`infusion, followed by a 1-hour infusion of cisplatin (75 mg/m2),
`every 3 weeks (arm A), or gemcitabine (800 mg/m2) as a 30 minute
`infusion, on days 1 and 8, and larotaxel (60 mg/m2) as a 1-hour
`infusion, on day 8 (following gemcitabine), every 3 weeks (arm B).
`The primary end point was the objective response rate (per-protocol
`population).
`Results: Thirty-two patients were randomized to arm A and 30 to
`arm B. The response rate was higher in arm A compared with arm
`B in both the per-protocol (26.7% versus 18.2%) and intention-to-
`treat (28.1% versus 13.3%) populations. In the intention-to-treat
`population, median progression-free survival for arm A versus arm
`B was 4.7 versus 3.3 months and median overall survival was 8.6
`
`*Department of Pneumology and Thoracic Surgery, 3rd Faculty of Medicine,
`Charles University, Faculty Hospital Bulovka and Postgraduate Medical
`School, Praha, Czech Republic; †Centre Franc¸ois Baclesse, Caen,
`France; ‡Respiratory Oncology Unit (Pulmonology) and Leuven Lung
`Cancer Group, University Hospital Gasthuisberg, Leuven, Belgium;
`§Service de pneumologie, Centre Hospitalier Universitaire, Sart-Tilman,
`Lie`ge, Belgium; 储Ospedale San Giovanni, Bellinzona, Switzerland; ¶De-
`partment of Medical Oncology, Centre Rene´ Huguenin, Saint-Cloud,
`France; #Départment de Cancérologie générale, Centre Oscar Lambret,
`Lille, France; **Service de pneumologie, Centre Hospitalier Universita-
`ire, Angers, France; ††Department of Medical Oncology, Polyclinique
`Bordeaux Nord Aquitaine, Bordeaux, France; ‡‡Sanofi-Aventis, Antony,
`France; and §§Service de pneumologie, University Hospital, Strasbourg,
`France.
`Disclosure: Michèle Besenval is employed by the organization. The other
`authors declare no conflict of interest.
`Address for correspondence: Elisabeth Quoix, MD, Hoˆpital Lyautey, Service
`de Pneumologie, Hoˆpitaux Universitaires de Strasbourg, 1 Place de
`l’Hoˆpital, 67091 Strasbourg cedex, France. E-mail: elisabeth.quoix@
`chru-strasbourg.fr
`Copyright © 2008 by the International Association for the Study of Lung
`Cancer
`ISSN: 1556-0864/08/0308-0894
`
`versus 7.3 months, respectively. Fifty percent of patients in arm A
`and 66.7% in arm B experienced at least one National Cancer
`Institute common toxicity criteria grade 3/4 adverse event and grade
`3/4 neutropenia was observed in 46.9% and 41.4% of patients,
`respectively.
`Conclusions: Both larotaxel combinations were effective and man-
`ageable, however all measured efficacy parameters (response rate,
`progression free survival, and survival) seemed to favor the combi-
`nation with cisplatin.
`
`Key Words: Advanced NSCLC, Combination chemotherapy, First-
`line, Taxane, Larotaxel.
`
`(J Thorac Oncol. 2008;3: 894 –901)
`
`Globally, lung cancer is the most frequently diagnosed
`
`malignancy and the disease remains the most common
`cause of cancer-related death.1 The majority of tumors
`(⬃80%) are non-small cell lung cancers (NSCLCs).2 As a
`consequence of the absence of effective, clinically-validated
`screening procedures, most NSCLCs are locally advanced or
`metastatic at presentation (stage IIIB and IV),3 and therefore
`nonresectable. Treatment for advanced disease may comprise
`chemoradiotherapy (stage IIIB) or chemotherapy (stage IV).4
`Such essentially palliative treatment aims at controlling symp-
`toms, improving quality of life, and lengthening survival.
`A number of cytotoxic agents have been shown to be
`effective as first-line treatments for NSCLC. Currently, pa-
`tients with good performance status will commonly receive a
`doublet comprising a platinum analogue (cisplatin or carbo-
`platin) combined with a third-generation cytotoxic agent
`(gemcitabine, vinorelbine, or a taxane). Various combina-
`tions seem to be essentially equally effective,5,6 with differ-
`ences between regimens primarily limited to their side
`effect profiles.7,8 Nonplatinum-based doublets, especially
`gemcitabine plus a taxane have been developed in an
`attempt
`to overcome cisplatin-associated toxicities. Re-
`sults available at time of this study led to the recommen-
`dation by American Society of Clinical Oncology in 2003
`of their use as an alternative to platinum-based doublets.4
`
`894
`
`Journal of Thoracic Oncology (cid:127) Volume 3, Number 8, August 2008
`
`AVENTIS EXHIBIT 2045
`Mylan v. Aventis, IPR2016-00712
`
`

`
`Journal of Thoracic Oncology (cid:127) Volume 3, Number 8, August 2008
`
`Larotaxel in First-Line Treatment of NSCLC
`
`The taxanes, paclitaxel and docetaxel, are both effec-
`tive and approved in combination with platinum in first-line
`NSCLC therapy.9 Docetaxel is also approved as a single
`agent for second-line treatment. There is however a need to
`increase the effectiveness of such compounds in relation to
`increasing cytotoxicity in taxane-resistant tumors and de-
`creasing systemic toxicity.10 Larotaxel (XRP9881) is a novel
`semi-synthetic taxane compound that seems to be a potent
`microtubule stabilizer, blocking tubulin disassembly and
`thereby inhibiting mitosis. The drug efflux pump, P-glyco-
`protein 1 (encoded by the multidrug resistance gene, ABCB1),
`which is commonly overexpressed in tumors, may play a key
`role in taxane resistance. Larotaxel has a much lower affinity
`for P-glycoprotein 1 than docetaxel and was shown to be
`active in cell lines resistant to doxorubicin, vinblastine, pac-
`litaxel, and docetaxel. In addition, this compound seems to
`cross the blood-brain barrier.11
`Several phase I studies have explored different sched-
`ules of administration of larotaxel as a single agent and have
`recommended dose levels for phase II studies of 60 and 90
`mg/m2 for the every 3 weeks regimen.11–15 Hematologic
`toxicity was the main dose-limiting toxicity in all the tested
`regimens. Other nonhematologic toxicities characteristically
`associated with taxanes, such as alopecia, gastrointestinal
`effects, neurosensory disorders, hypersensitivity reactions,
`skin disorders, and fluid retention were generally mild or
`moderate. Objective responses were observed in several tu-
`mor types. Of particular interest, Sessa and colleagues noted
`responses in three NSCLC patients. In one case, a response
`was seen in both the patient’s primary tumor and also asso-
`ciated brain metastases.11 This study provided a rational basis
`for the further testing of larotaxel
`in advanced NSCLC
`patients.
`A preliminary three-arm phase I study investigated
`larotaxel in combination with cisplatin, gemcitabine, or vi-
`norelbine. The recommended doses for the combination of
`larotaxel and cisplatin were 50 and 75 mg/m2, respectively
`and for larotaxel and gemcitabine; 60 and 800 mg/m2, re-
`spectively. However, larotaxel combined with vinorelbine
`showed poor tolerability, even at the lowest doses tested, and
`so this combination was rejected for phase II development
`(manuscript in preparation). Using response rate as the pri-
`mary efficacy measure, the current phase II study was de-
`signed to investigate whether cisplatin or gemcitabine was the
`most appropriate partner for larotaxel in patients with che-
`motherapy naive advanced NSCLC.
`
`PATIENTS AND METHODS
`Major Eligibility Criteria
`Chemotherapy naive patients were eligible for inclu-
`sion if they had histologically or cytologically-confirmed
`nonirradiable stage IIIB or stage IV NSCLC and were ⱖ18
`and ⱕ75 years of age, with a life expectancy of at least 12
`weeks and an Eastern Cooperative Oncology Group perfor-
`mance status of 0 to 2. They were not to have received
`surgery for NSCLC within the previous 4 weeks (excluding
`simple surgery for diagnosis or to implant a venous access
`device) and required adequate hematologic (neutrophils
`
`⬎2 ⫻109/l, platelet count ⬎100 ⫻109/l), renal (creatinine
`within upper normal limits or if borderline, with a creatinine
`clearance ⬎60 mL/min), and hepatic (total bilirubin within
`normal limits, serum aspartate aminotransferase/alanine ami-
`notransferase and alkaline phosphatase ⱕ2.5 times the upper
`limits of normal or aspartate aminotransferase/alanine ami-
`notransferase ⱕ1.5 times associated with alkaline phospha-
`tase ⱕ5 times the upper limits of normal) function. Patients
`were required to have at least one measurable lesion accord-
`ing to response evaluation criteria in solid tumors criteria.16
`The study was conducted in accordance with the declaration
`of Helsinki and written informed patient consent was ob-
`tained before the implementation of any study-related proce-
`dures.
`Main exclusion criteria were: a prior history of cancer
`(excluding basal cell skin or in situ disease); symptomatic
`brain or leptomeningeal metastases; hypercalcemia (⬎2.8
`mmol/l); peripheral neuropathy ⬎ grade 1; another serious
`comorbid condition; had received prior chemotherapy or
`radiotherapy (except for bone metastases) or were receiving
`another anticancer treatment or experimental drug.
`
`Study Design and Treatments
`This was a multicenter, randomized study conducted in
`11 centers in four countries (France, Belgium, Czech Repub-
`lic and Switzerland). The primary objective was to select the
`combination having the most promising antitumor activity
`(response rate). Patients were randomly assigned centrally
`into two arms. Those in arm A received larotaxel (50 mg/m2)
`as a 1-hour infusion, followed after 30 minutes by a 1-hour
`infusion of cisplatin (75 mg/m2), every 3 weeks. Patients in
`arm B received gemcitabine (800 mg/m2) as a 30 minute
`infusion, on days 1 and 8, and larotaxel (60 mg/m2) as a
`1-hour infusion, on day 8 (following gemcitabine, with no
`interval), every 3 weeks. Administration of larotaxel on day
`8 in this arm was selected to match docetaxel/gemcitabine
`NSCLC schedules, which have been designed to avoid do-
`cetaxel-induced neutropenia (which generally occurs 5 to 8
`days after administration) causing a delay in the day 8
`administration of gemcitabine.17 All patients in arm A re-
`ceived a setron (ondansetron or alternative) as a prophylactic
`antiemetic premedication from cycle 1. Patients in this arm
`were to be adequately hydrated to avoid the nephrotoxicity
`secondary to cisplatin administration. No prophylactic anti-
`emetic drugs were allowed during the first cycle for patients
`in arm B. In subsequent cycles,
`in the case of nausea/
`vomiting, patients could receive preventive antiemetic treat-
`ment in compliance with the standard protocol of the center.
`Prophylaxis with dexamethasone was given (16 mg the day
`before, 24 mg the day of, and 16 mg the day after larotaxel
`administration).
`Adverse events (AEs) were graded according to Na-
`tional Cancer Institute-Common Toxicity Criteria Version 2.
`In the event of long lasting AEs, the cycle could be extended
`for 1 week. No dose reduction was permitted for arm A and
`if such toxicity did not resolve by day 28, the patient was to
`discontinue the study treatment. For arm B, in the case of
`severe toxicity related to larotaxel or gemcitabine, a dose
`reduction to 50 and/or 650 mg/m2, respectively, was allowed.
`
`Copyright © 2008 by the International Association for the Study of Lung Cancer
`
`895
`
`

`
`Zatloukal et al.
`
`Journal of Thoracic Oncology (cid:127) Volume 3, Number 8, August 2008
`
`The interval between day 1 of 2 consecutive cycles could be
`extended to 5 weeks for nondrug-related AEs, but only once
`during the study. Treatment was continued until disease
`progression, unacceptable toxicity, or the withdrawal of pa-
`tient consent.
`
`Evaluations Before and During Therapy
`Within 7 days before first study drug administration,
`medical history (including NSCLC histology/cytology, prior
`surgery other than for cancer, concurrent illness, prior med-
`ications, history of allergy) was recorded and a physical
`examination (height, weight, Eastern Cooperative Oncology
`Group performance status, vital signs) carried out. Standard
`hematologic and biochemical analyses and an evaluation of
`existing signs and symptoms were also completed. Within 4
`weeks before treatment a cardiologic examination and radio-
`logic scanning of the chest (x-ray or computed tomography;
`CT), abdomen (CT), brain (CT or magnetic resonance imag-
`ing) and when indicated, bone (scan or x-ray) were carried
`out, encompassing all target and nontarget (when indicated)
`lesions. During the study, a physical examination was carried
`out immediately before treatment, on day 1 of each cycle.
`Toxicity was evaluated weekly. Hematologic assessments
`were carried out every week, or every other day in the case of
`grade four neutropenia or thrombopenia (arm B) until recov-
`ery to grade ⱕ3 or ⬍3, respectively. Radiologic assessment
`of the chest and abdomen and all target and nontarget lesions
`was performed every 2 cycles (6 weeks) using the same
`method as the baseline evaluation.
`
`Statistical Methods and Considerations
`The intention-to-treat (ITT) population comprised all
`randomized patients. The per-protocol population (PPP) was
`defined as a subset of the treated population: patients had to
`be eligible, evaluable for response, and without any major
`protocol deviations during the course of the study. The safety
`population was the treated population, defined as all patients
`who had been administered at least one (even incomplete)
`infusion of one study drug.
`The primary objective was to rank the activity of the
`two test regimens using the Simon design.18 An independent
`External Response Review Committee reviewed radiologic
`assessments to evaluate the best
`tumor response and to
`establish the date of progression (response evaluation criteria
`in solid tumors16). The primary efficacy variable was the
`objective response rate for the PPP, as assessed by the
`External Response Review Committee and as defined by
`the percentage of patients achieving a confirmed complete
`(CR) or partial (PR) response (CR ⫹ PR). Twenty-one pa-
`tients/arm were to be included. Taking into account a likely
`rate of exclusion from the PPP of 10%, 23 patients/arm were
`to be enrolled. With this sample size, and assuming that the
`lowest response rate was 10%, there was a probability of 90%
`that the best treatment would be selected, provided that it was
`superior to the other by at least 15%.
`Secondary efficacy variables included: duration of re-
`sponse (DR; defined as the time interval between meeting the
`criteria for a CR or PR and the date of the first documented
`progression or death from any cause), duration of stable
`
`disease (SD) (defined as the time from randomization until
`disease progression or death for patients with SD as best
`overall response), progression-free survival (PFS; defined as
`the time from randomization until disease progression or
`death), and overall survival (OS; defined as the time from
`randomization until death). For DR and PFS evaluations,
`progression or death occurring 84 days or more after the last
`evaluable tumor assessment was censored back to the date of
`that assessment. OS was censored at the date of last contact
`or the cutoff date, whichever came first.
`Categoric variables were summarized by frequency and
`percentage. Ninety five percent confidence intervals [95%]
`were calculated using the Clopper–Pearson exact method,19
`where appropriate. Continuous variables were presented with
`summary statistics (mean, standard deviation, median, range).
`Kaplan–Meier curves20 and estimates21 (median and its 95%
`confidence interval) were used to analyze variables of dura-
`tion and event.
`
`RESULTS
`Patient Demographics
`Sixty-two patients were randomized between 30th July
`2002 and 17th June 2003: 32 to arm A (larotaxel/cisplatin)
`and 30 to arm B (larotaxel/gemcitabine). Patient characteris-
`tics at baseline were generally well balanced between the
`arms, except gender (Table 1). Similarly, baseline tumor
`characteristics were well balanced with only slight differ-
`ences in the interarm frequencies of the number and type of
`organs involved and stage of disease at first diagnosis (Table
`1). The majority of patients had stage IV disease, with
`adenocarcinoma being the most common histologic class.
`Most patients had three or more organs affected.
`
`Treatment Administration
`Thirty-two patients in arm A received a total of 127
`cycles (median 4, range 1– 8) and 30 patients in arm B
`received a total 116 cycles (median 4, range 1– 6). Table 2
`summarizes drug exposure. Reflecting the absence of proto-
`col-permitted dose reduction in arm A, the relative dose
`intensity was 0.98 for both larotaxel and cisplatin. In arm B,
`28 of 30 patients received larotaxel, with 2 discontinuing
`treatment immediately after the first gemcitabine infusion
`(day 1) following, in 1 case, grade 4 supraventricular arrhyth-
`mia and in 1 case, pulmonary embolism (neither considered
`related to study treatment). The relative dose intensity in this
`arm for larotaxel was 0.94 and for gemcitabine was 0.93, with
`these intensities demonstrating the feasibility of the combi-
`nation. Although not allowed, 1 (3.1%) patient (1 cycle,
`0.8%) in arm A did have a dose reduction (larotaxel; cycle 3)
`following anemia. In arm B, 7 (23.3%) patients experienced
`a dose reduction in 9 cycles (7.8%), due to hematologic
`toxicity for two patients, nonhematologic toxicity for three
`patients (diarrhea, nausea, and vomiting); for the two remain-
`ing patients no specific reason was given. Among the 9 cycles
`with dose reduction,
`larotaxel was reduced in eight and
`gemcitabine in one. Eleven patients (34.4%) in arm A and 13
`patients (43.3%) in arm B had a delay in at least 1 cycle. A
`total of 16 (12.6%) cycles were delayed in arm A and 22
`
`896
`
`Copyright © 2008 by the International Association for the Study of Lung Cancer
`
`

`
`Journal of Thoracic Oncology (cid:127) Volume 3, Number 8, August 2008
`
`Larotaxel in First-Line Treatment of NSCLC
`
`TABLE 1. Patient and Disease Characteristics at Baseline
`Arm A
`Arm B
`All Patients
`(N ⴝ 32)
`(N ⴝ 30)
`(N ⴝ 62)
`
`Characteristic
`
`Gender, n (%)
`Male
`Female
`Race, n (%)
`Caucasian
`Age, yr
`Median (range)
`⬍65 yr, n (%)
`ⱖ65 yr, n (%)
`PS before first infusion, n (%)
`Median (range)
`0
`1
`2
`Signs and symptoms at
`baseline, n (%)
`Histology type, n (%)
`Adenocarcinoma
`Large cell carcinoma
`NSCLC undetermined
`Squamous cell carcinoma
`Stage of disease at baseline
`IIIB
`IV
`Measurable disease, n (%)
`Number of organs involved
`1
`2
`3
`4 or more
`Organ involvement, n (%)
`Lung
`Soft tissue (lymph nodes)
`Brain
`Bone
`Adrenal gland
`Liver
`Pleura
`
`21 (65.6)
`11 (34.4)
`
`26 (86.7)
`4 (13.3)
`
`47 (75.8)
`15 (24.2)
`
`32 (100.0)
`
`30 (100.0)
`
`62 (100.0)
`
`57 (43–75)
`21 (65.6)
`11 (34.4)
`
`62 (40–72)
`22 (73.3)
`8 (26.7)
`
`60 (40–75)
`43 (69.4)
`19 (30.6)
`
`1 (0–2)
`9 (28.1)
`20 (62.5)
`3 (9.4)
`27 (84.4)
`
`17 (53.1)
`2 (6.3)
`2 (6.3)
`11 (34.4)
`
`1 (0–2)
`7 (23.3)
`19 (63.3)
`4 (13.3)
`28 (93.3)
`
`15 (50.0)
`4 (13.3)
`—
`11 (36.7)
`
`1 (0–2)
`16 (25.8)
`39 (62.9)
`7 (11.3)
`55 (88.7)
`
`32 (51.6)
`6 (9.7)
`2 (3.2)
`22 (35.5)
`
`5 (15.6)
`27 (84.4)
`32 (100.0)
`
`5 (16.7)
`25 (83.3)
`30 (100.0)
`
`10 (16.1)
`52 (83.9)
`62 (100.0)
`
`1 (3.1)
`12 (37.5)
`13 (40.6)
`6 (18.8)
`
`30 (93.8)
`27 (84.4)
`4 (12.5)
`9 (28.1)
`6 (18.8)
`5 (15.6)
`5 (15.6)
`
`4 (13.3)
`6 (20.0)
`15 (50.0)
`5 (16.7)
`
`24 (80.0)
`22 (73.3)
`6 (20.0)
`5 (16.7)
`8 (26.7)
`7 (23.3)
`6 (20.0)
`
`5 (8.1)
`18 (29.0)
`28 (45.2)
`11 (17.7)
`
`54 (87.1)
`49 (79.0)
`10 (16.1)
`14 (22.6)
`14 (22.6)
`12 (19.4)
`11 (17.7)
`
`Arm A, larotaxel ⫹ cisplatin; Arm B, larotaxel ⫹ gemcitabine; PS, performance
`status; NSCLC, non-small cell lung cancer.
`
`(19.0%) in arm B. The most common reasons for cycle delays
`were other reason (administrative reasons) in arm A and
`hematologic toxicity in arm B. All patients had discontinued
`treatment by the cutoff date of 15th May 2005, with the most
`common reason in both arms being progressive disease,
`followed by no further benefit expected and adverse event.
`Efficacy
`Primary and secondary efficacy data are detailed in
`Table 3. There were no CR. Response rates in the PPP for
`arm A and arm B were 26.7% and 18.2% and for the ITT
`population 28.1% and 13.3%,
`respectively.
`In addition,
`40.0% and 36.4% (PPP), 40.6% and 33.3% (ITT) of patients
`
`respectively had SD. In brain lesions (10 patients), no objec-
`tive responses were observed but stabilization was achieved
`in three of four patients in arm A and one of six in arm B.
`As only 13 patients (including six censored in arm A
`and two in arm B) had an objective response, Kaplan–Meier
`plots for DR were not constructed. The DR ranged between
`1.45⫹ and 20.63⫹ months. Median PFS was similar in arm
`A of the PPP compared with arm B (4.3 versus 4.4 months)
`but a difference of 1.4 months was observed in the ITT
`population (4.7 versus 3.3 months, respectively). In arm B,
`two out of four patients with very short PFS were excluded
`from the PPP (baseline tumor assessment done more than 31
`days before first infusion) and probably explain the difference
`in PFS between ITT and PPP. In the ITT population, median
`OS was 8.6 months in arm A and 7.3 months in arm B (Figure
`1) and the 1-year survival rate was 40.6% in arm A and
`30.0% in arm B.
`
`Safety
`Eight (25.0%) patients in arm A and nine (30.0%)
`patients in arm B experienced grade 3/4 treatment emergent
`adverse events related to study treatment (Table 4). The
`highest incidences of such events (nonhematological) were
`infection (9.4%) and vomiting (6.3%) in arm A, and infection
`(10.0%), diarrhea and allergic reaction (6.7%) in arm B. Of
`note, a similar rate of patients experienced grade 3/4 infection
`related to study treatment. However, more patients experi-
`enced grade 3/4 infection regardless of relationship to study
`treatment (with or without neutropenia) in arm B compared
`with arm A (12.5% in arm A; 26.7% in arm B). Given that the
`excess of infection cases in arm B seemed not to be related to
`treatment, that the patients were randomized to the study
`arms and that there were no obvious imbalances in patient/
`disease characteristics at baseline that might explain this
`excess, this is most likely a chance finding.
`Neutropenia was the most common grade 3/4 hemato-
`logic toxicity in both arms (arm A: 46.9%, arm B: 41.4%),
`with grade 3/4 thrombocytopenia reported for only one pa-
`tient (3.4%) in arm B. Two (6.3%) patients experienced
`febrile neutropenia in arm A (no patients in arm B), and three
`(10.0%) patients experienced neutropenic infection in each
`arm.
`
`The incidence of peripheral neurotoxicity was similar
`in both arms (arm A: 18.8%, arm B: 20.0%) with no patients
`experiencing grade 3. More any grade creatinine increase was
`noted for arm A compared with arm B (37.5% versus 10%).
`However, this was grade 1 in all but two (6.3%) patients
`(grade 2, which subsequently improved to grade 1).
`One patient in arm A (3.1%) and four patients in arm B
`(13.3%) died within 30 days of the last treatment adminis-
`tration (Table 5). Two of the deaths in arm B (6.7%) were
`considered to be related to study treatment: one patient died
`of infection (with concomitant grade 3/4 neutropenia) on day
`11 of the last infusion at cycle 2, and another died of infection
`(with concomitant grade 3/4 neutropenia) on day 7 of the last
`infusion at cycle 1.
`
`Copyright © 2008 by the International Association for the Study of Lung Cancer
`
`897
`
`

`
`Zatloukal et al.
`
`Journal of Thoracic Oncology (cid:127) Volume 3, Number 8, August 2008
`
`TABLE 2.
`
`Exposure to Treatment
`
`Arm A
`
`Arm B
`
`Exposure
`
`Larotaxel
`
`Cisplatin
`
`Larotaxel
`
`Gemcitabine
`
`No. of treated patients
`Cumulative dose, (mg/m2)
`Median (range)
`Actual dose intensity, (mg/m2/wk)
`Median (range)
`Relative dose intensity
`Median (range)
`
`32
`
`32
`
`28
`
`30
`
`200.9 (49.3–397.9)
`
`301.4 (73.9–588.4)
`
`238.0 (59.5–364.9)
`
`6373.3 (767.1–9731.8)
`
`16.3 (14.3–17.4)
`
`24.5 (21.3–25.7)
`
`18.9 (10.9–20.2)
`
`498.3 (255.7–539.9)
`
`0.98 (0.86–1.04)
`
`0.98 (0.85–1.03)
`
`0.94 (0.54–1.01)
`
`0.93 (0.48–1.01)
`
`TABLE 3. Primary and Secondary Efficacy Data in the Per-Protocol and ITT Populations
`PPP
`ITT
`
`Parameter
`
`Arm A (N ⴝ 30)
`
`Arm B (N ⴝ 22)
`
`Arm A (N ⴝ 32)
`
`Arm B (N ⴝ 30)
`
`Response, n (%)
`Complete response (CR)
`Partial response (PR)
`No change/stable disease
`Progressive disease
`Not evaluable
`Overall response rate (CR ⫹ PR)
`关95% CI兴
`Median PFS (mo)
`关95% CI兴
`Median overall survival (mo)
`关95% CI兴
`1-yr survival (mo)
`
`—
`8 (26.7)
`12 (40.0)
`8 (26.7)
`2 (6.7)
`8a (26.7)
`关12.3, 45.9兴
`4.3
`关2.76, 4.96兴
`ND
`
`—
`4 (18.2)
`8 (36.4)
`9 (40.9)
`1 (4.5)
`4 (18.2)
`关5.2, 40.3兴
`4.4
`关1.54, 6.08兴
`ND
`
`—
`9 (28.1)
`13 (40.6)
`8 (25.0)
`2 (6.3)
`9 (28.1)
`关13.7, 46.7兴
`4.7
`关2.92, 6.21兴
`8.6
`关5.39, 16.03兴
`40.6%
`
`—
`4 (13.3)
`10 (33.3)
`10 (33.3)
`6 (20)
`4 (13.3)
`关3.8, 30.7兴
`3.3
`关1.45, 5.42兴
`7.3
`关4.76, 11.07兴
`30.0%
`
`a One patient achieving a response was ineligible for inclusion in the PPP population as a consequence of major protocol deviations at study
`entry (baseline tumor assessment more than 31 d prior to first infusion and previous radiotherapy).
`PPP, per-protocol population; ITT, intention to treat population; Arm A, larotaxel ⫹ cisplatin; Arm B, larotaxel ⫹ gemcitabine; PFS,
`progression-free survival; ND, not determined; CI, confidence interval.
`
`FIGURE 1. Kaplan–Meier curve for overall sur-
`vival in the ITT population.
`
`898
`
`Copyright © 2008 by the International Association for the Study of Lung Cancer
`
`

`
`Journal of Thoracic Oncology (cid:127) Volume 3, Number 8, August 2008
`
`Larotaxel in First-Line Treatment of NSCLC
`
`TABLE 4. Summary of Adverse Events in Each Study Arm, Treatment Emergent Adverse Events Related to Study Treatment
`by Category and Terms (Reported for ⱖ2 Patients at Grade 3/4 or ⱖ3 Patients at any Grade) and Hematological Toxicity
`Arm A
`Arm B
`(N ⴝ 32)
`(N ⴝ 30)
`
`Adverse Events Summary, N (%)
`
`At least one TEAE regardless of
`relationship to study treatment
`At least one TEAE possibly or
`probably related to study treatment
`At least one grade 3/4 TEAE
`regardless of relationship to
`study treatment
`At least one grade 3/4 TEAE
`possibly or probably related to
`study treatment
`
`Adverse Events: NCI-CTC
`Category/Term, N (%)
`
`Allergy/immunology
`Allergic reaction/hypersensitivity
`Cardiovascular (general)
`Edema
`Constitutional symptoms
`Fatigue
`Fever
`Dermatology
`Alopecia
`Rash/desquamation
`Gastrointestinal
`Anorexia
`Constipation
`Diarrhea
`Nausea
`Stomatitis/pharyngitis
`Vomiting
`Infection
`Infectiona
`Neurology
`Neuropathy sensory
`Pain
`Abdominal pain cramping
`Hematological
`Leukopenia
`Neutropenia
`Anemia
`Thrombocytopenia
`Neutropenic complications
`Febrile neutropenia
`Related neutropenic infection
`Grade 3
`Related neutropenic infection
`Grade 4
`
`30 (93.8)
`
`26 (81.3)
`
`16 (50.0)
`
`8 (25.0)
`
`30 (100.0)
`
`26 (86.7)
`
`20 (66.7)
`
`9 (30.0)
`
`Grade 3/4
`
`Any Grade
`
`Grade 3/4
`
`Any Grade
`
`4 (12.5)
`4 (12.5)
`2 (6.3)
`1 (3.1)
`14 (43.8)
`13 (40.6)
`3 (9.4)
`14 (43.8)
`14 (43.8)
`1 (3.1)
`22 (68.8)
`8 (25.0)
`4 (12.5)
`10 (31.3)
`17 (53.1)
`3 (9.4)
`12 (37.5)
`3 (9.4)
`3 (9.4)
`7 (21.9)
`6 (18.8)
`4 (12.5)
`3 (9.4)
`
`19 (59.4)
`21 (65.6)
`29 (90.6)
`—
`
`—
`—
`—
`—
`2 (6.3)
`1 (3.1)
`—
`—
`—
`—
`3 (9.4)
`—
`—
`1 (3.1)
`—
`—
`2 (6.3)
`3 (9.4)
`3 (9.4)
`—
`—
`—
`—
`
`9 (28.1)
`15 (46.9)
`3 (9.4)
`—
`
`2 (6.3)
`2 (6.3)
`
`1 (3.1)
`
`3 (10.0)
`3 (10.0)
`5 (16.7)
`3 (10.0)
`11 (36.7)
`9 (30.0)
`3 (10.0)
`19 (63.3)
`16 (53.3)
`5 (16.7)
`19 (63.3)
`7 (23.3)
`2 (6.7)
`10 (33.3)
`15 (50.0)
`4 (13.3)
`10 (33.3)
`4 (13.3)
`3 (10.0)
`7 (23.3)
`6 (20.0)
`5 (16.7)
`1 (3.3)
`
`18 (62.1)
`19 (65.5)
`26 (89.7)
`11 (37.9)
`
`2 (6.7)
`2 (6.7)
`—
`—
`—
`—
`—
`—
`—
`—
`3 (10.0)
`—
`—
`2 (6.7)
`1 (3.3)
`—
`1 (3.3)
`3 (10.0)
`3 (10.0)
`—
`—
`1 (3.3)
`—
`
`8 (27.6)
`12 (41.4)
`1 (3.4)
`1 (3.4)
`
`—
`1 (3.3)
`
`2 (6.7)
`
`a Neutropenic infection.
`Arm A, larotaxel ⫹ cisplatin; Arm B, larotaxel ⫹ gemcitabine; NCI-CTC, National Cancer Institute Common Toxicity Criteria; TEAE, treatment emergent adverse event.
`
`DISCUSSION
`Cisplatin is one of the most efficient drugs in NSCLC,
`but requires hyperhydration and induces some cumulative
`toxicities that may be difficult
`to manage such as renal
`impairment, peripheral neuropathy, and ototoxicity. To de-
`
`crease toxicity associated with cisplatin-based doublets, a
`number of studies have investigated whether carboplatin-
`based and nonplatinum combinations including gemcitabine
`instead of cisplatin might confer equivalent efficacy but lower
`toxicity. A first meta-analysis has suggested the superiority of
`
`Copyright © 2008 by the International Association for the Study of Lung Cancer
`
`899
`
`

`
`Zatloukal et al.
`
`Journal of Thoracic Oncology (cid:127) Volume 3, Number 8, August 2008
`
`TABLE 5. Summary of Deaths
`
`Total deaths
`Within 30 d of last administration
`of study treatment
`Malignant disease
`Toxicity from study medication
`Other causesa
`More than 30 d after last
`administration of study
`treatment
`Malignant disease
`Toxicity from study medication
`Other causesb
`
`Arm A
`(N ⴝ 32)
`
`29 (90.6)
`1 (3.1)
`
`—
`—
`1 (3.1)
`28 (87.5)
`
`Arm B
`(N ⴝ 30)
`
`25 (83.3)
`4 (13.3)
`
`1 (3.3)
`2 (6.7)
`1 (3.3)
`21 (70.0)
`
`ALL
`(N ⴝ 62)
`
`54 (87.1)
`5 (8.1)
`
`1 (1.6)
`2 (3.2)
`2 (3.2)
`49 (79.0)
`
`27 (84.4)
`—
`1 (3.1)
`
`21 (70.0)
`—
`—
`
`48 (77.4)
`—
`1 (1.6)
`
`a Other causes, “progression of lung cancer” in arm A and “cerebrovascular event”
`in arm B.
`b Other cause, infection considered as not related to study treatment, occurring on
`day 63 after last study treatment administration.
`
`cisplatin over carboplatin in terms of survival.22 Another
`recent meta-analysis of 11 phase III studies has indicated that
`patients treated with a platinum-based regimen benefited
`from a statistically significant reduction in the risk of death at
`1 year (p ⫽ 0.04) compared with those receiving a nonplati-
`num regimen. This benefit was associated with a significantly
`increased but acceptable risk of severe toxicity.23 Following
`these two meta-analyses, the standard of care in this setting
`therefore remains a cisplatin-based doublet.
`The objective of the current study was to investigate the
`activity and tolerability of a new taxane, larotaxel, combined
`with either cisplatin (arm A) or gemcitabine (arm B) in the
`first-line treatment of NSCLC. The objective response rates
`favored arm A over arm B in both the per-protocol (differ-
`ence of 8.5%) and ITT (difference of 14.8%) populations. In
`addition, with the caution due to the small sample size in both
`arms, the observed median OS time was longer in the ITT
`population for larotaxel combined to cisplatin compared with
`larotaxel combined to gemcitabine by 8.6 and 7.3 months and
`the 1-year survival rate was higher (40.6% versus 30.0%,
`respectively).
`Several phase II and large phase III studies have re-
`ported efficacy data for docetaxel/cisplatin or paclitaxel/
`cisplatin combinations used as first-line treatments for ad-
`vanced NSCLC. Response rates ranged between 17% and
`37%, with median OS lying between 7.4 and 11.3 months and
`1-year survival between 31% and 48%.6,24 –26 Efficacy param-
`eters for larotaxel/cisplatin are therefore included within
`these ranges. However, efficacy parameters for larotaxel/
`gemcitabine generally compare less favorably with the
`taxane/gemcitabine arms of phase II and III first-line NSCLC
`studies, in which response rates were reported to lie between
`20% and 35%, OS between 6.8 and 13 months and 1-year
`survival between 30% and 56%.27–31 Efficacy data in the
`current study therefore favor the combination of larotaxel/
`cisplatin, especially given the meta-analysis data indicating
`that platinum-based doublets may generally be more effective
`than nonplatinum regimens.23
`
`The overall incidence of grade 3/4 toxicities related to
`study treatment was comparable between arms. However,
`grade 3/4 infection, with or without neutropenia was more
`common in arm B including two treatment-related deaths,
`due to neutropenic infection. Levels of neurotoxicity were
`comparable between arms and with no grade 3/4 events
`observed. Severe neurotoxicity seemed to be less common
`than has previously been reported for taxane/cisplatin com-
`binations.6,24,26 Renal toxicity, which was more frequent in
`arm A, was mild (grade 1 or 2) as was edema, which occurred
`in 3% and 10% of patients in arms A and B, respectively. Nail
`changes, characteristically associated with taxane therapy,32
`were not reported for any patient. The safety profile of both
`combinations was considered to be acceptable.
`In summary, although there were some differences in
`the safety profile, with more grade 1/2 renal toxicity with
`larotaxel/cisplatin, and more infection with larotaxel/gemcit-
`abine, this study has