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Cabazitaxel Versus Topotecan in Patients with Small-Cell Lung Cancer with Progressive Disease During or After First-Line Platinum-Based Chemotherapy

      Introduction:

      Patients with small-cell lung cancer (SCLC) typically respond well to initial chemotherapy. However, relapse invariably occurs, and topotecan, the only approved second-line treatment option, has limited efficacy. Taxanes have activity in SCLC, and cabazitaxel is a second-generation taxane with potential for enhanced activity in chemorefractory malignancies.

      Methods:

      Patients with SCLC who relapsed after initial platinum-based chemotherapy were randomly assigned to receive cabazitaxel 25 mg/m2 every 21 days or topotecan 1.5 mg/m2 on days 1–5 every 21 days. Two patient subgroups, defined by chemosensitive and chemo-resistant/refractory disease, were assessed in combination and separately.

      Results:

      The safety profile of cabazitaxel and topotecan was consistent with previous studies, and despite considerable toxicity in both arms, no new safety concerns were identified. Patients receiving cabazitaxel had inferior progression-free survival compared with topotecan (1.4 versus 3.0 months, respectively; two-sided p < 0.0001; hazard ratio = 2.17, 95% confidence interval = 1.563–3.010), and results were similar in both the chemosensitive and chemorefractory subgroups. No complete responses were observed in either arm, and no partial responses were observed in the cabazitaxel group. The partial response rate in the topotecan arm was 10%. Median overall survival was 5.2 months in the cabazitaxel arm and 6.8 months in the topotecan arm (two-sided p = 0.0125; hazard ratio = 1.57, 95% confidence interval = 1.10–2.25).

      Conclusion:

      Cabazitaxel, a next-generation taxane, had inferior efficacy when compared with standard-dose topotecan in the treatment of relapsed SCLC. Topotecan remains a suboptimal therapy, and continued efforts to develop improved second-line treatments are warranted.

      Key Words

      Small-cell lung cancer (SCLC) constitutes 12%–14% of all lung cancers, and is characterized by a rapid doubling time, a high growth fraction, and early development of systemic metastases.
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      Although several chemotherapies have demonstrated single-agent activity in relapsed SCLC, topotecan is currently considered to be the standard treatment.
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      The first-generation taxanes, docetaxel and paclitaxel, have shown activity as first- or second-line single-agent treatments in SCLC.
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      leading to regulatory approval worldwide. Interestingly, unlike other taxanes, cabazitaxel crosses the blood–brain barrier,
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      which could be therapeutically beneficial in cancers, such as SCLC where brain metastases are common. The paucity of therapeutic options and activity of taxanes in SCLC, the ability of cabazitaxel to cross the blood–brain barrier, and the activity of cabazitaxel in chemorefractory tumors provide a compelling rationale to assess cabazitaxel as a treatment for SCLC.
      This phase II study evaluated the efficacy of cabazitaxel versus topotecan in patients with SCLC that had progressed during or after first-line platinum-based chemotherapy.

      PATIENTS AND METHODS

      Study Population

      Eligible patients had histologically/cytologically documented locally advanced or metastatic SCLC that relapsed during or after first-line platinum-based chemotherapy. Patients were aged greater than or equal to 18 years, had measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1
      • Eisenhauer EA
      • Therasse P
      • Bogaerts J
      • et al.
      New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).
      and an Eastern Cooperative Oncology Group performance status less than or equal to one. Patients were required to have received no more than one prior chemotherapy regimen, and to have adequate hematologic and organ function. Exclusion criteria included: prior topotecan or taxane treatment; prior chemotherapy, radiotherapy (except for bone pain palliation), or surgery within 28 days; treatment with any investigational drug within 30 days; uncontrolled metastases of the central nervous system; known leptomeningeal metastases; other invasive neoplasm requiring ongoing therapy; unresolved adverse event (AE) of grade greater than one (except alopecia) resulting from prior anticancer therapy (according to National Cancer Institute Common Terminology Criteria [NCI CTCAE] v4.03);
      • National Cancer Institute
      Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
      or myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association Class III or IV congestive heart failure, stroke or transient ischemic attack within 6 months before study enrollment.
      The study was conducted according to the Declaration of Helsinki with approval from ethics committees at each institution. Patients provided written informed consent.

      Study Design

      This was a phase II, open-label study (ARD12166; NCT01500720, ClinicalTrials.gov). Patients were randomly assigned (1:1) to receive cabazitaxel or topotecan. Patients were divided evenly into two subgroups depending on whether their disease had progressed (by RECIST 1.1) either greater than or equal to 90 days after completing first-line chemotherapy (chemosensitive subgroup) or during or up to 90 days after completing first-line chemotherapy (chemorefractory subgroup). Patients were also stratified by the presence of brain metastases and serum lactate dehydrogenase (LDH) concentration.
      The primary endpoint was PFS, defined as time from randomization to documented tumor progression or death from any cause, whichever came first. Secondary endpoints included disease progression-free rate at week 12, response rate, duration of response, OS, and safety. Progression and response were defined per RECIST 1.1.

      Study Treatment

      Cabazitaxel 25 mg/m2 was administered as a 1-hour intravenous (IV) infusion on day 1 every 21 days. Topotecan 1.5 mg/m2 was administered as a 30-minute IV infusion on days 1–5 every 21 days. For cabazitaxel, premedication included an antihistamine (dexchlorpheniramine 5 mg, diphenhydramine 25 mg, or equivalent), a steroid (dexamethasone 8 mg or equivalent) and an H2 antagonist (ranitidine 50 mg or equivalent). Premedications were administered by IV infusion at least 30 minutes before each cabazitaxel dose. If IV antihistamines were not available, premedication for hypersensitivity could be administered per local practice. Antiemetic prophylaxis with ondansetron, granisetron or dolasetron, or per local practice for topotecan, was permitted. Supportive care with granulocyte colony-stimulating factor (G-CSF) could be considered in both treatment arms, in accordance with ASCO guidelines.
      • Smith TJ
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      • Lyman GH
      • et al.
      2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline.

      Safety Assessments

      The safety population was defined as all randomized patients who received at least one dose of cabazitaxel or topotecan during the treatment period. Patients had a full health evaluation before treatment initiation. On-study safety assessments included: physical examinations, AE monitoring, hematology, blood chemistry, coagulation and urine analysis, and 12-lead electrocardiograms. AEs and laboratory data were graded using NCI CTCAE v4.03.17 Safety assessments were also performed within 22–30 days after the final dose of study treatment. In the follow-up period, ongoing serious and treatment-related AEs and concomitant medications were monitored until recovery from the AE or stabilization of the patient’s condition.

      Efficacy Assessments

      The intent-to-treat population was defined as all randomized patients according to treatment arm. Tumors were assessed at baseline and every 6 weeks during treatment using abdominal and chest computerized tomography or magnetic resonance imaging. Brain computerized tomography or magnetic resonance imaging was performed every 6 weeks to follow metastases found at baseline or if new lesions were suspected. If study treatment was discontinued before disease progression, tumor assessments continued every 6 weeks until radiological progression or study cut-off, whichever came first. For imaging reviews, the same processes and technology (MEDIAN Technologies) were used at the investigator sites, and centrally.

      Statistical Analysis

      PFS, OS, and duration of response in the cabazitaxel and topotecan arms were compared using log-rank tests, stratified by brain metastases and LDH level. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were estimated using the Cox proportional hazard model, stratified using the same factors described above. Median PFS and OS and corresponding 95% CIs were calculated using Kaplan–Meier estimates. Progression-free rate at week 12 and response rate were compared between treatment arms using a χ2 test. A logistic regression model was used for additional exploratory analyses. The study sample size was chosen to enable a 30% risk reduction in hazard rate to be detected in the primary endpoint for the treatment arm versus the control arm, assuming a median PFS of 4.0 months in the control arm and 5.7 months in the experimental arm, based on a log-rank test with a one-sided 10% significance level. Based on these assumptions, 172 eligible patients (86 per arm) and 142 PFS events were needed to achieve 80% power for the study.

      RESULTS

      Patient and Disease Characteristics

      Overall, 179 patients were randomized (Supplementary Figure S1, Supplemental Digital Content, http://links.lww.com/JTO/A848). In the total population, 70% were male, median age was 61 years, and all but one patient had an Eastern Cooperative Oncology Group performance status of 0 or 1 (Table 1). Approximately half of patients (51%) were considered chemosensitive. Most patients (94%) had metastatic disease at study entry, and the most frequent metastatic sites were lung, lymph node, and liver. Brain metastases were present in 28% of patients. Median time from initial diagnosis to study treatment was 8.6 months. Patient demographics and baseline disease characteristics were balanced across treatment groups.
      TABLE 1Patient Demographics and Baseline Disease Characteristics by Treatment Arm in the Overall Population and in Chemorefractory and Chemosensitive Subgroups
      Overall PopulationChemorefractory SubgroupChemosensitive Subgroup
      Cabazitaxel (n = 90)Topotecan (n = 89)Cabazitaxel (n = 45)Topotecan (n = 43)Cabazitaxel (n = 45)Topotecan (n = 46)
      Median age, years (range)60 (37–82)62 (27–80)58 (37–76)60 (27–80)62 (40–82)65 (33–80)
      ECOG PS, n (%)
       ≤190 (100)88 (98.9)45 (100)43 (100)45 (100)45 (97.8)
       201 (1.1)0001 (2.2)
      Patient subgroup, n (%)
       Chemorefractory45 (50.0)43 (48.3)45 (100)43 (100)00
       Chemosensitive45 (50.0)46 (51.7)0045 (100)46 (100)
      LDH concentration, n (%)
       ≤ULN46 (51.1)46 (51.7)18 (40.0)17 (39.5)28 (62.2)29 (63.0)
       >ULN44 (48.9)43 (48.3)27 (60.0)26 (60.5)17 (37.8)17 (37.0)
      Median time from initial diagnosis to study treatment, months (range)
      Patients with available data: total population, cabazitaxel n = 89 and topotecan n = 88; chemosensitive subgroup, cabazitaxel n = 44 and topotecan n = 45. ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; ULN, upper limit of normal.
      8.7 (3–56)8.5 (3–36)6.8 (3–56)7.1 (3–17)10.7 (5–22)10.5 (5–36)
      Extent of disease at study entry, n (%)
       Metastatic87 (96.7)81 (91.0)44 (97.8)41 (95.3)43 (95.6)40 (87.0)
       Locoregional3 (3.3)8 (9.0)1 (2.2)2 (4.7)2 (4.4)6 (13.0)
      Number of organs involved at baseline, n (%)
       1–346 (51.1)35 (39.3)21 (46.7)13 (30.2)25 (55.6)22 (47.8)
       4–538 (42.2)45 (50.6)19 (42.2)25 (58.1)19 (42.2)20 (43.5)
       6–86 (6.7)9 (10.1)5 (11.1)5 (11.6)1 (2.2)4 (8.7)
      Brain metastases, n (%)25 (27.8)25 (28.1)13 (28.9)12 (27.9)12 (26.7)13 (28.3)
      Other most common sites of metastasis, n (%)
       Lung88 (97.8)83 (93.3)44 (97.8)39 (90.7)44 (97.8)44 (95.7)
       Lymph node76 (84.4)76 (85.4)39 (86.7)39 (90.7)37 (82.2)37 (80.4)
       Liver43 (47.8)45 (50.6)24 (53.3)24 (55.8)19 (42.2)21 (45.7)
       Bone28 (31.1)34 (38.2)18 (40.0)19 (44.2)10 (22.2)15 (32.6)
       Adrenal gland24 (26.7)26 (29.2)8 (17.8)14 (32.6)16 (35.6)12 (26.1)
      a Patients with available data: total population, cabazitaxel n = 89 and topotecan n = 88; chemosensitive subgroup, cabazitaxel n = 44 and topotecan n = 45. ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; ULN, upper limit of normal.

      Treatment Exposure

      Ninety and 89 patients were randomly assigned to receive cabazitaxel or topotecan, of which 89 and 88 patients received treatment, respectively. The median number of treatment cycles with cabazitaxel or topotecan, respectively, was 2.0 versus 4.0 in the overall group, 2.0 versus 3.0 in the chemorefractory subgroup, and 2.5 versus 4.0 in the chemosensitive subgroup (Supplementary Table S1, SDC, http://links.lww.com/JTO/A848). Dose delays (study dose given later than 3 days after the scheduled time in any cycle) were required by 12 patients (13%) who received cabazitaxel, compared with 45 patients (51%) who received topotecan. Dose reductions were required by 18 patients (20%) who received cabazitaxel, compared with 33 patients (38%) who received topotecan. Among treated patients, cabazitaxel or topotecan was discontinued by 88 patients (99%) and 87 patients (99%), respectively, and the most frequent reasons for discontinuation in both arms were disease progression (cabazitaxel, 79%; topotecan, 57%) and AE (cabazitaxel, 16%; topotecan, 27%).

      Survival

      Median PFS was 1.4 months in the cabazitaxel arm versus 3.0 months in the topotecan arm (HR = 2.17, 95% CI = 1.563–3.010; two-sided p < 0.0001). Results were similar in both the chemosensitive and chemorefractory subgroups (Fig. 1). The progression-free rates at week 12 for cabazitaxel and topotecan were, respectively, 19% versus 53% in the overall group (p < 0.0001), 29% versus 63% in the chemosensitive subgroup (p = 0.0011), and 9% versus 42% in the chemorefractory subgroup (p = 0.0004).
      Figure thumbnail gr1
      FIGURE 1PFS. A, Intent-to-treat population. B, Chemorefractory subgroup. C, Chemosensitive subgroup. CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.
      Median OS in the total population was 5.2 months with cabazitaxel versus 6.8 months with topotecan (HR = 1.57, 95% CI = 1.10–2.25; two-sided p = 0.0125), and trends were similar in the chemosensitive and chemorefractory subgroups (Fig. 2).
      Figure thumbnail gr2
      FIGURE 2OS. A, Intent-to-treat population. B, Chemorefractory subgroup. C, Chemosensitive subgroup. CI, confidence interval; HR, hazard ratio; OS, overall survival.
      Potential heterogeneity of the treatment effect was analyzed in a subgroup analysis of PFS and OS. A subgroup effect on both PFS and OS trended toward topotecan for most factors tested (Fig. 3).
      Figure thumbnail gr3
      FIGURE 3Subgroup analysis of PFS and OS in patients treated with cabazitaxel or topotecan. Overall Cox model was stratified for brain metastases and lactate dehydrogenase (LDH) level, as specified at randomization. Cox models for subgroups were not stratified. CI, confidence interval; ITT, intent-to-treat; ULN, upper limit of normal; PFS, progression-free survival; OS, overall survival; cbz, cabazitaxel; top, topotecan.

      Response

      Overall, 152 patients had measurable lesions present at baseline and were evaluable for tumor response (73 in the cabazitaxel arm, 79 in the topotecan arm). No patient had a complete response. No patient receiving cabazitaxel had a PR, compared with eight PRs (10%) in the topotecan arm (8% and 12% in the chemorefractory and chemosensitive subgroups, respectively). In the overall population, stable disease was recorded as best response in 16 patients (22%), who received cabazitaxel (14% and 29% of chemorefractory and chemosensitive patients, respectively) and 50 patients (63%), who received topotecan (57% and 69% of chemorefractory and chemosensitive patients, respectively; Table 2).
      TABLE 2Objective Tumor Response Rates in the Overall Tumor-Evaluable Population and in Chemorefractory/Chemosensitive Subgroups
      Overall PopulationChemorefractory SubgroupChemosensitive Subgroup
      Response, n (%)Cabazitaxel (n = 73)Topotecan (n = 79)Cabazitaxel (n = 35)Topotecan (n = 37)Cabazitaxel (n = 38)Topotecan (n = 42)
      Complete response000000
      Partial response08 (10.1)03 (8.1)05 (11.9)
      Stable disease16 (21.9)50 (63.3)5 (14.3)21 (56.8)11 (28.9)29 (69.0)
      Disease progression51 (69.9)18 (22.8)28 (80.0)11 (29.7)23 (60.5)7 (16.7)
      Not evaluable/missing data6 (8.2)3 (3.8)2 (5.7)2 (5.4)4 (10.5)1 (2.4)

      Safety

      In the safety population, 80 cabazitaxel-treated patients (90%) had a treatment-emergent adverse event (TEAE) of any grade, compared with 83 topotecan-treated patients (94%). Grade 3/4 TEAEs occurred in 52 patients (58%) in the cabazitaxel arm, and in 63 patients (72%) in the topotecan arm. In the cabazitaxel arm, the most frequent nonhematologic TEAEs of any grade were fatigue (29%), diarrhea (19%), decreased appetite (18%), and vomiting (18%; Table 3). In the topotecan arm, the most frequent nonhematologic TEAEs of any grade were dyspnea (25%), fatigue (25%), asthenia (20%), and decreased appetite (15%).
      TABLE 3Most Frequently Reported TEAEs (> 10% in Either Arm) in the Safety Population, Irrespective of Relation to Study Treatment, and Hematologic Laboratory Abnormalities
      Cabazitaxel (n = 89)Topotecan (n = 88)
      Any GradeGrade ≥ 3Any GradeGrade ≥ 3
      Any TEAE79 (88.8)52 (58.4)83 (94.3)63 (71.6)
       Fatigue26 (29.2)7 (7.9)22 (25.0)7 (8.0)
       Dyspnea9 (10.1)3 (3.4)22 (25.0)3 (3.4)
       Febrile neutropenia/neutropenic16 (18.0)16 (18.0)21 (23.9)20 (22.7)
       infection/neutropenic sepsis
       Asthenia11 (12.4)2 (2.2)18 (20.5)7 (8.0)
       Diarrhea17 (19.1)2 (2.2)9 (10.2)0
       Decreased appetite16 (18.0)2 (2.2)13 (14.8)1 (1.1)
       Vomiting16 (18.0)1 (1.1)7 (8.0)0
       Nausea14 (15.7)2 (2.2)11 (12.5)0
       Abdominal pain10 (11.2)2 (2.2)3 (3.4)0
       Cough10 (11.2)1 (1.1)8 (9.1)0
       Constipation8 (9.0)09 (10.2)0
       Headache6 (6.7)09 (10.2)0
       Back pain9 (10.1)1 (1.1)5 (5.7)0
      Hematologic laboratory abnormalities.
       Anemia83 (94.3)
      Eighty-eight patients in the cabazitaxel arm had samples available for analysis. TEAE, treatment-emergent adverse events.
      3 (3.4)
      Eighty-eight patients in the cabazitaxel arm had samples available for analysis. TEAE, treatment-emergent adverse events.
      87 (98.9)23 (26.1)
       Leukopenia70 (79.5)
      Eighty-eight patients in the cabazitaxel arm had samples available for analysis. TEAE, treatment-emergent adverse events.
      46 (52.3)
      Eighty-eight patients in the cabazitaxel arm had samples available for analysis. TEAE, treatment-emergent adverse events.
      82 (93.2)57 (64.8)
       Neutropenia60 (68.2)
      Eighty-eight patients in the cabazitaxel arm had samples available for analysis. TEAE, treatment-emergent adverse events.
      50 (56.8)
      Eighty-eight patients in the cabazitaxel arm had samples available for analysis. TEAE, treatment-emergent adverse events.
      77 (87.5)69 (78.4)
       Lymphopenia68 (77.3)
      Eighty-eight patients in the cabazitaxel arm had samples available for analysis. TEAE, treatment-emergent adverse events.
      34 (38.6)
      Eighty-eight patients in the cabazitaxel arm had samples available for analysis. TEAE, treatment-emergent adverse events.
      63 (71.6)28 (31.8)
       Thrombocytopenia52 (59.1)
      Eighty-eight patients in the cabazitaxel arm had samples available for analysis. TEAE, treatment-emergent adverse events.
      4 (4.5)
      Eighty-eight patients in the cabazitaxel arm had samples available for analysis. TEAE, treatment-emergent adverse events.
      81 (92.0)40 (45.5)
      a Eighty-eight patients in the cabazitaxel arm had samples available for analysis. TEAE, treatment-emergent adverse events.
      The most frequent hematologic AE was febrile neutropenia/neutropenic infection/neutropenic sepsis (cabazitaxel 18% versus topotecan 24%). The most frequent grade ≥ 3 hematologic laboratory abnormalities with cabazitaxel were neutropenia (57%), leukopenia (52%), and lymphopenia (39%), and with topotecan were neutropenia (78%), leukopenia (65%), and thrombocytopenia (45%; Table 3). G-CSF use was comparable in both treatment arms: therapeutic G-CSF was administered to 25 patients (28%) in the cabazitaxel arm and 23 patients (26%) in the topotecan arm; prophylactic G-GCF was administered to 53 patients (60%) in the cabazitaxel arm and 49 patients (56%) in the topotecan arm.
      In the cabazitaxel arm, 36 patients (40%) experienced a serious TEAE, compared with 41 patients (47%) in the topotecan arm. Grade ≥ 3 serious TEAEs occurred in 35 patients (39%) treated with cabazitaxel, compared with 39 patients (44%) treated with topotecan. The most frequent serious TEAEs of any grade with cabazitaxel were febrile neutropenia/neutropenic infection/neutropenic sepsis (13%), and hyponatremia (3%), and with topotecan were febrile neutropenia/neutropenic infection/neutropenic sepsis (18%), thrombocytopenia (11%), anemia (7%), and pneumonia (7%).
      During the treatment period (from start of treatment until 30 days after the final dose), there were 12 deaths in the cabazitaxel arm and 13 deaths in the topotecan arm, of which five and seven deaths, respectively, were due to an AE. Deaths were considered related to treatment in two patients receiving cabazitaxel (both due to neutropenic infection) and in four patients receiving topotecan (three with febrile neutropenia/neutropenic infection, and one with cardiopulmonary failure).

      DISCUSSION

      In the late 1990s, topotecan replaced the cyclophosphamide–doxorubicin–vincristine regimen as standard second-line treatment for SCLC based on its similar efficacy in patients with chemosensitive SCLC (response rate 24%, median OS 25 weeks) and better symptom control.
      • von Pawel J
      • Schiller JH
      • Shepherd FA
      • et al.
      Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.
      Confirmation that topotecan prolonged survival and improved quality of life in patients with relapsed SCLC compared with best supportive care followed in 2006,
      • O'Brien ME
      • Ciuleanu TE
      • Tsekov H
      • et al.
      Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer.
      leading to regulatory approval in this indication.
      • Hurwitz JL
      • McCoy F
      • Scullin P
      • Fennell DA
      New advances in the second-line treatment of small cell lung cancer.
      Since then, however, no other single agent or combination has shown a significant benefit over topotecan. Although amrubicin (an anthracycline) demonstrated superior activity versus topotecan in a phase II trial in Japanese patients, no survival benefit was observed in phase II and III trials performed in Western populations.
      • Inoue A
      • Sugawara S
      • Yamazaki K
      • et al.
      Randomized phase II trial comparing amrubicin with topotecan in patients with previously treated small-cell lung cancer: North Japan Lung Cancer Study Group Trial 0402.
      • Jotte R
      • von Pawel J
      • Spigel DR
      • et al.
      Randomized phase III trial of amrubicin versus topotecan (Topo) as second-line treatment for small cell lung cancer (SCLC).
      • Jotte R
      • Conkling P
      • Reynolds C
      • et al.
      Randomized phase II trial of single-agent amrubicin or topotecan as second-line treatment in patients with small-cell lung cancer sensitive to first-line platinum-based chemotherapy.
      Results from a recent phase III study in Japanese patients suggest that a cisplatin–etoposide–irinotecan regimen is superior to topotecan in relapsed SCLC that is sensitive to first-line treatment, and this regimen has the potential to become standard second-line chemotherapy. However, increased toxicity was noted in the combination arm. To date, these data have been presented only in abstract form, and full publication is awaited.
      • Goto K
      • Ohe Y
      • Seto T
      • et al.
      A randomized phase III study of cisplatin (CDDP), etoposide (ETOP) and irinotecan versus topotecan as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer (SCLC): Japan Clinical Oncology Group study JCOG0605.
      First-generation taxanes have shown modest activity in the treatment of relapsed SCLC. In phase II studies of paclitaxel administered alone or in combination with other agents in patients with previously treated SCLC, overall response rates have ranged from 24–73%.
      • Kakolyris S
      • Mavroudis D
      • Tsavaris N
      • et al.
      Paclitaxel in combination with carboplatin as salvage treatment in refractory small-cell lung cancer (SCLC): A multicenter phase II study.
      • Kosmas C
      • Tsavaris NB
      • Malamos NA
      • Vadiaka M
      • Koufos C
      Phase II study of paclitaxel, ifosfamide, and cisplatin as second-line treatment in relapsed small-cell lung cancer.
      • Sonpavde G
      • Ansari R
      • Walker P
      • et al.
      Phase II study of doxorubicin and paclitaxel as second-line chemotherapy of small-cell lung cancer: A Hoosier Oncology Group Trial.
      • Yamamoto N
      • Tsurutani J
      • Yoshimura N
      • et al.
      Phase II study of weekly paclitaxel for relapsed and refractory small cell lung cancer.
      Similarly, docetaxel treatment in the second-line setting resulted in an overall response rate of 25%,
      • Smyth JF
      • Smith IE
      • Sessa C
      • et al.
      Activity of docetaxel (Taxotere) in small cell lung cancer. The Early Clinical Trials Group of the EORTC.
      although in a trial in patients with limited or extensive-stage disease, a docetaxel/gemcitabine combination was reported to be inactive.
      • Agelaki S
      • Veslemes M
      • Syrigos K
      • Hellenic Oncology Research Group
      • et al.
      A multicenter phase II study of the combination of gemcitabine and docetaxel in previously treated patients with small cell lung cancer.
      However, no taxane-based regimen has emerged as being significantly more effective than established treatments.
      • Hurwitz JL
      • McCoy F
      • Scullin P
      • Fennell DA
      New advances in the second-line treatment of small cell lung cancer.
      Cabazitaxel is a second-generation taxane developed to overcome resistance to first-generation taxanes,
      • Bouchard H
      • Semiond D
      • Risse ML
      • Vrignaud P
      • Fischer J
      • Ganellin R
      • Rotella DP
      and has shown comparable antitumor activity to docetaxel in docetaxel-sensitive tumor models and increased potency versus docetaxel in taxane-resistant tumor models.
      • Vrignaud P
      • Sémiond D
      • Lejeune P
      • et al.
      Preclinical antitumor activity of cabazitaxel, a semisynthetic taxane active in taxane-resistant tumors.
      In this study, cabazitaxel failed to demonstrate improved efficacy versus topotecan in patients with SCLC that had progressed during or after first-line platinum-based chemotherapy. In fact, cabazitaxel treatment resulted in a significantly shorter PFS and shorter OS than topotecan. Median OS seen with topotecan in this study (7.2 months) is similar to that reported in previous studies.
      • O'Brien ME
      • Ciuleanu TE
      • Tsekov H
      • et al.
      Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer.
      ,
      • von Pawel J
      • Schiller JH
      • Shepherd FA
      • et al.
      Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.
      Patient and disease characteristics were well balanced between treatment arms. Furthermore, analysis of PFS and OS in patient subgroups, defined by LDH level, presence of brain metastasis, age, global region, stage at diagnosis or number of organs involved, consistently favored topotecan treatment over cabazitaxel, suggesting no heterogeneity of treatment effect. Objective response rates and progression-free rate at week 12 also favored the topotecan arm. It is currently unclear why cabazitaxel treatment resulted in a lower overall response rate compared with single-agent treatment with first generation taxanes in SCLC.
      • Ettinger DS
      • Finkelstein DM
      • Sarma RP
      • Johnson DH
      Phase II study of paclitaxel in patients with extensive-disease small-cell lung cancer: An Eastern Cooperative Oncology Group study.
      • Smyth JF
      • Smith IE
      • Sessa C
      • et al.
      Activity of docetaxel (Taxotere) in small cell lung cancer. The Early Clinical Trials Group of the EORTC.
      • Kirschling RJ
      • Grill JP
      • Marks RS
      • et al.
      Paclitaxel and G-CSF in previously untreated patients with extensive stage small-cell lung cancer: A phase II study of the North Central Cancer Treatment Group.
      ,
      • Yamamoto N
      • Tsurutani J
      • Yoshimura N
      • et al.
      Phase II study of weekly paclitaxel for relapsed and refractory small cell lung cancer.
      In previous studies, frequent cabazitaxel-associated AEs have included hematologic events, such as anemia, leucopenia, and neutropenia, in addition to gastrointestinal disturbances and fatigue.
      • de Bono JS
      • Oudard S
      • Ozguroglu M
      • et al.
      TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial.
      ,
      • Pivot X
      • Koralewski P
      • Hidalgo JL
      • et al.
      A multicenter phase II study of XRP6258 administered as a 1-h i.v. infusion every 3 weeks in taxane-resistant metastatic breast cancer patients.
      ,
      • Diéras V
      • Lortholary A
      • Laurence V
      • et al.
      Cabazitaxel in patients with advanced solid tumours: Results of a Phase I and pharmacokinetic study.
      • Fumoleau P
      • Trigo JM
      • Isambert N
      • Sémiond D
      • Gupta S
      • Campone M
      Phase I dose-finding study of cabazitaxel administered weekly in patients with advanced solid tumours.
      • Mita AC
      • Denis LJ
      • Rowinsky EK
      • et al.
      Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors.
      The safety profile of cabazitaxel in this study was consistent with previous studies and no new safety concerns were identified. However, in this study, the toxicity of both treatments was considerable. The rate of febrile neutropenia/neutropenic infection/neutropenic sepsis was 18% and 24% in the cabazitaxel and topotecan arms, respectively, despite 60% and 56% receiving prophylactic G-CSF. Dose delays and reductions were also common in both arms. Despite the observed survival benefit, treatment with the “traditional” topotecan regimen resulted in four treatment-related deaths, which is certainly a concern for a palliative treatment where the survival benefit is modest.
      Overall, this randomized, phase II study suggests that cabazitaxel 25 mg/m2 administered every 3 weeks, although relatively well tolerated in patients with relapsed SCLC, had inferior efficacy compared with topotecan 1.5 mg/m2 administered on days 1–5 every 3 weeks. Results do not justify further investigation of cabazitaxel treatment in this disease. While it is clear that cabazitaxel is an inferior second-line treatment in patients with SCLC, topotecan remains a suboptimal therapy, and efforts to improve treatment in this setting remain warranted.

      ACKNOWLEDGMENTS

      The authors thank the participating patients and their families. The authors also thank the study investigators, research coordinators, and study sites.

      Supplementary Material

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