Gemcitabine/carboplatin Arm Research Articles

Gemcitabine plus carboplatin versus gemcitabine plus oxaliplatin in cisplatin-unfit patients with advanced urothelial carcinoma: a randomised phase II study (COACH, KCSG GU10-16)

PurposeGemcitabine–oxaliplatin (GEMOX) demonstrated mild toxicity and promising effectiveness in patients with advanced urothelial cell cancer (UCC). We investigated the activity and safety of first-line GEMOX compared with gemcitabine–carboplatin (GCb) in cisplatin-ineligible patients with advanced UCC. MethodsTreatment-naive, cisplatin-ineligible patients with advanced UCC were randomly assigned to GEMOX (gemcitabine 1000 mg/m2, oxaliplatin 100 mg/m2 on day 1 [D1] every 2 weeks) or GCb (1000 mg/m2 of gemcitabine on D1 and D8 and carboplatin area under the curve of 4.5 mg/mL/min on D1 every 3 weeks). We evaluated the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). ResultsBetween January 2011 and March 2017, 80 patients were enrolled; 39 and 40 patients were allocated to GCb and GEMOX arms, respectively. The ORR was 48.7% in the GCb arm and 55.0% in the GEMOX arm. The median follow-up duration was 37.8 months; the median PFS and OS in the GCb and GEMOX arms were 5.5 months (95% confidence interval [CI], 4.8–6.2) vs. 4.4 months (95% CI, 2.7–6.1) and 9.1 months (95% CI, 5.2–13.0) vs. 11.0 months (95% CI, 6.9–15.0), respectively. ≥Leucopenia, neutropenia and fatigue of ≥ grade III were significantly more common in the GCb arm (26% vs. 3%, P = 0.003; 33% vs. 10%, P = 0.014; 15% vs. 3%, P = 0.012), whereas any-grade neuropathy was more common in the GEMOX arm (8% vs. 60%). ConclusionsGEMOX showed similar efficacy with GCb and a favourable haematologic toxicity profile. GEMOX may be an additional chemotherapy option for patients with UCC ineligible for cisplatin-containing chemotherapy (NCT01487915).

Gemcitabine plus carboplatin versus gemcitabine plus oxaliplatin in cisplatin unfit patients with advanced urothelial carcinoma: A randomized phase II study (COACH, KCSG GU10-16).

4534 Background: We investigated the activity and safety of first-line gemcitabine-oxaliplatin (GemOx) compared with gemcitabine-carboplatin (GCb) in cisplatin-ineligible patients with advanced UCCC. Methods: Treatment naïve, cisplatin-ineligible patients with advanced UCCC were randomly assigned to GemOx [gemcitabine 1,000 mg/m2, oxliplatin 100 mg/m2 on day 1 (D1) every 2 weeks] or GCb (gemcitabine 1,000 mg/m2 on D1 and D8, carboplatin AUCC 4.5 on D1 every 3 weeks) stratified by ECOG performance status (PS) and visceral metastases. The primary endpoint was objective response rate (ORR), and secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: Between January 2011 and Mar 2017, 80 patients were enrolled; 39 patients and 40 patients were allocated to GCb and GemOx arm, respectively. Median age was 72 years (range 46-84) in GCb arm and 72.5 (55-85) in GemOx arm. ECOG PS was 2 in 41% (GCb arm) and 43% (GemOx arm), and median GFR was 45 ml/min (interquartile range 36-56) in GCb and 47 ml/min (37-56) in GemOx arm. ORR were 48.7% and 55.0% in GCb and GemOx, respectively. With a median follow-up duration of 37.8 months, median PFS and OS in GCb and GemOx arm were 5.5 months (95% CI, 4.8-6.2) vs. 4.4 months (95% CI, 2.7-6.1) and 9.1 months (95% CI, 5.2-13.0) vs. 11.0 months (95% CI, 6.9-15.0), respectively. Grade 3 leukopenia, neutropenia and fatigue were significantly more common in GCb arm (26% vs. 3%, p=0.003; 33% vs. 10%, p=0.014; 15% vs. 3%, p=0.057) while any grade neuropathy was more common in GemOx (8% vs. 60%, p<0.001). Conclusions: GemOx has showed comparable efficacy with GCb and favorable hematologic toxicity profile. GemOx may be used as a new option for UCCC patients who are not suitable for platinum-containing chemotherapy. Clinical trial information: NCT01487915.

Gemcitabine-carboplatin (GCb) versus gemcitabine-oxaliplatin (GemOx) in cisplatin un-fit advanced urothelial carcinoma: Randomized phase II study (COACH Study).

355 Background: More than half of patients (pts) with advanced urothelial cell carcinoma (UCC) are ineligible for cisplatin because of renal dysfunction or poor performance status. We investigated the activity and safety of first-line gemcitabine-oxaliplatin (GemOx) compared with gemcitabine-carboplatin (GCb) in cisplatin-ineligible pts with advanced UCC. Methods: Treatment naïve, cisplatin-ineligible pts with advanced UCC were randomly assigned to GemOx (gemcitabine 1000 mg/m2, oxliplatin 100 mg/m2 on D1 Q2W) or GCb (gemcitabine 1000 mg/m2 on D1 and 8, carboplatin AUC 4.5 on D1 Q3W) stratified by ECOG performance status (PS) and visceral metastases. The primary endpoint was response rate (RR), and secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: Between May 2013 and Mar 2017, 80 pts were enrolled and 79 pts received at least one dose of chemotherapy (39 pts in GCb; 40 pts in GemOx). Median age was 73 years (47-86) and ECOG PS was 2 in 42% of pts and 60% had visceral metastases. Median GFR was 45 ml/min (range 22-108) in GCb and 47 ml/min (range 15-73) in GemOx arm. With median follow-up duration of 37.8 months, all pts were off study treatments. RR were 48.7% and 55.0% in GCb and GemOx, respectively (p = 0.742). Median PFS and OS in GCb and GemOx arm were 5.5 months (95% CI, 4.8-6.2) vs. 4.4 months (95% CI, 2.7-6.1) [HR GemOx/GCb 0.92; p = 0.756] and 9.1 months (95% CI, 5.2-13.0) vs. 11.0 months (95% CI, 6.9-15.0) [HR 0.72; p = 0.194], respectively. The median cycle was 6 (1-10) in GCb and 7 (1-12) in GemOx. Grade 3 leukopenia, neutropenia and fatigue were more common in GCb arm (25.6% vs. 2.5%, p = 0.003; 33.3% vs. 10.0%, p = 0.014; 15.4% vs. 0%, p = 0.012). Dose delay and reduction in GCb and GemOx group were needed in 46.2%, 50.0% and 53.8%, 32.5%, respectively. Salvage chemotherapy after study treatment was offered in 54.3% and 55.9% of patients who experienced PD in GCb and GemOx arm. Conclusions: GemOx has showed comparable efficacy with GCb and favorable hematologic toxicity profile. GemOx may be used as a new option for patients who are not suitable for cisplatin-containing chemotherapy. Clinical trial information: NCT01487915.

A Phase || Trial of First-Line Nab-Paclitaxel/Carboplatin Versus Gemcitabine/Carboplatin in Advanced Squamous Cell Carcinoma of the Lung (Ctong1002)

ABSTRACT Aim: The administration of nab-paclitaxel/carboplatin (nab-PC) as first-line therapy in patients with advanced non-small-cell lung cancer was efficacious and resulted in a significantly improved objective overall response rate (ORR) versus solvent-based PC in a phase ||| trial. Subgroup analysis showed the squamous histology appeared to be a predictive factor to nab-paclitaxel treatment. This phase || trial (NCT01236716; CTONG1002) compared the eficacy and safety of first-line nab-PC wih gemcitabine/carboplatin (GC) in advanced squamous cell carcinoma of the lung. Methods: From November 2010 to June 2013, 127 untreated patients with locally advanced and metastatic squamous cell carcinoma of the lung were randomly assigned 1:1 to receive first-line nab-PC (nab-P, 135mg/m2, d1,d8, q3w; C, AUC = 5, d1, q3w) or GC (G, 1250mg/m2, d1, d8, q3w; C, AUC = 5, d1, q3w ). The primary endpoint was ORR. The secondary endpoints were progression-free survival (PFS), overall survival (OS), safety and quality of life (QoL). Results: There were 110 cases evaluable for ORR (nab-PC, 54; GC, 56), 119 evaluable for survival (nab-PC, 57; GC, 62) and 124 evaluable for safety (nab-PC, 59; GC, 65), respectively. ORR was 46.3% (25/54) for the nab-PC arm and 30.4% (17/56) for the GC arm respectively, p = 0.085. There was an approximately 18.8% improvement in PFS (median, 5.7 v 4.8 months; hazard ratio [HR], 0.907; 95%CI, 0.588 to 1.399; p = 0.657) in the nab-PC arm versus the GC arm. OS was not significantly different between the two arms (median, 11.9 v 14.4 months; HR, 1.010; 95%CI, 0.640 to 1.590; p = 0.970). Significant grade ≥3 leucopenia (41.7% v 17.2%, p Conclusions: First-line nab-PC in advanced squamous cell carcinoma of the lung was efficacious and resulted in a marginally improved ORR versus GC, but not achieving the primary endpoint. There was no significant difference in terms of survival and QoL between the two arms. The overall adverse events of nab-PC were manageable though more leucopenia and neutropenia were observed in nab-PC arm than with GC. Disclosure: All authors have declared no conflicts of interest.

Prognostics factors in previously untreated urothelial cancer patients ineligible for cisplatin-based chemotherapy: An external validation of the Bajorin risk groups.

4529 Background: In patients with urothelial cancer who are unfit for Cisplatin chemotherapy, EORTC phase II/III trial 30986 investigated two carboplatin-based chemotherapy regimens: Gemcitabine/Carboplatin (GC) and Methotrexate/Carboplatin/Vinblastine (M-CAVI). The trial did not show any significant differences in efficacy (response rate, OS, PFS) between the treatments; however the incidence of severe acute toxicity was slightly higher on M-CAVI. We now investigate the prognostic factors for survival. Methods: 238 patients with impaired renal function (Glomerular Filtration Rate (GF) <60 mL/min) or poor performance status (PS 2) were randomized by 29 institutions between GC and M-CAVI. The median follow-up was 4.5 years and, with 218 deaths reported (progression of malignant disease in 72%), the overall survival median was 9.3 months in the GC arm and 8.1 months in the M-CAVI arm. Univariate and multivariate Cox prognostic factor regression models for overall survival were developed on the whole population stratified by treatment arm. Results: In the multivariate analysis, the risk of death significantly increased (p<0.10) with WHO-PS 2, hemoglobin ≤ 12 g/dl (women) or ≤ 13.6 g/dl (men), the presence of visceral metastases and even more with the presence of liver metastases. The risk of death was not influenced by the site of the primary tumour, white blood cell or platelet count. In addition, the prognostic factors had a stronger effect in the M-CAVI arm than in the GC arm. Conclusions: This prognostic factors analysis confirms the Bajorin classification based on visceral metastases and performance status. However, we were also able to show the importance of hemoglobin and that in the patients with visceral metastases, the subgroup of patients with liver metastases had a significantly worse prognosis than the patients with only other visceral metastasis. Clinical trial information: NCT00014274.

MIS2-3 - A Prospective Phase II Study of Induction Erlotinib Therapy in Stage IIIA-N2 Non-Small-Cell Lung Cancer

ABSTRACT Background Stage IIIA NSCLC represents a heterogeneous group of patients with ipsilateral mediastinal (N2) lymph nodes involvement. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide dramatic responses in patients with non-small-cell lung cancer (NSCLC) carrying EGFR mutations. The purpose of this study was to evaluate the role of induction EGFR-TKI therapy in IIIA-N2 NSCLC. Methods Patients with resectable NSCLC of stage IIIA-N2 were assigned to either induction erlotinib arm or gemcitabine/carboplatin(GC) arm based on the EGFR mutations analysis (NCT00600587). Study design Factorial Assignment, non-randomized, safety/efficacy; primary outcome measures: response to induction therapy. Results From January 2008 till June 2011, 24 patients with IIIA-N2 NSCLC diagnosed by mediastinoscopy or PET/CT have been enrolled. Twelve cases with EGFR mutation were assigned to the erlotinib arm (30–42 days), while 12 cases harboring wild-type EGFR received the GC regimen (three cycles). The most common side-effects in the erlotinib arm were rash (90%) and diarrhea (40%). The primary end point of the response rates were 58% (7 of 12) for the erlotinib arm and 33% (4 of 12) for the GC arm (P = 0.49). The pathological N2 complete response rates were 16.7% for the erlotinib arm and 25% for the GC arm (P = 0.64). In the erlotinib arm, the most common failure model was distant metastases (9 of 10), especially brain metastases (3 of 9). The median progression-free survival time was 7 months for the erlotinib arm and 9 months for the GC arm (P = 0.27). The median overall survival was 27.3 months for the erlotinib arm and 23.2 months for the GC arm (P = 0.52). In addition, four cases in the erlotinib arm got partial response to the second EGFR-TKI therapy after progression to erlotinib induction therapy and the following thoractomy. Conclusions Induction erlotinib therapy in IIIA-N2 NSCLC with EGFR activating mutation is a promising strategy. Distance metastases were major failure model. A multicenter, randomized, phase II study evaluating efficacy and safety of erlotinib versus GC as neoadjuvant therapy for stage IIIA-N2 NSCLC patients with EGFR activating mutations (NCT01407822) is currently recruiting participants.

A prospective phase II study of induction erlotinib therapy in stage IIIA-N2 non-small cell lung cancer.

7039 Background: Stage IIIA NSCLC represents a heterogeneous group of patients with ipsilateral mediastinal (N2) lymph nodes involvement. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide dramatic responses in patients with non-small cell lung cancer (NSCLC) carrying EGFR mutations. The purpose of this study is to evaluate the role of induction EGFR-TKI therapy in IIIA-N2 NSCLC. Methods: Patients with resectable NSCLC of stage IIIA-N2 were assigned to either induction erlotinib arm or induction gemcitabine/carboplatin(GC) arm based on the EGFR mutations analysis (NCT00600587) . Study Design: Phase II, factorial Assignment, Safety/Efficacy; Primary outcome measures: Response to Induction Therapy; Estimated enrollment: 5 cases with partial response in the erlotinib arm. Results: From January 2008 till June 2011, 24 patients with IIIA-N2 NSCLC diagnosed by mediastinoscopy or PET/CT have been enrolled. Twelve cases with EGFR mutation were assigned to the erlotinib arm (30-42 days), while 12 cases harboring wild-type EGFR received the GC regimen (3 cycles). The primary end point of the response rates were 58% (7/12) for the erlotinib arm and 33% (4/12) for the GC arm (P=0.49). The pathological N2 complete response rates were 17% for the erlotinib arm and 25% for the GC arm (P=0.64). In the erlotinib arm, the most common failure model after initial therapy was distant metastases (9/10), especially brain metastases (3/9). The median progression free survival time was 7 months for the erlotinib arm and 9 months for the GC arm (P=0.27). The median overall survival was 27 months for the erlotinib arm and 23 months for the GC arm (P=0.52). In addition, four cases in the erlotinib arm got partial response to the 2nd EGFR-TKI therapy after progression to erlotinib induction therapy and the following thoracotomy. Conclusions: Induction erlotinib therapy in IIIA-N2 NSCLC with EGFR activating mutation is a promising strategy. Distance metastases were major failure model. A multicenter, randomized, phase II study evaluating efficacy and safety of erlotinib vs GC as neoadjuvant therapy for stage IIIA-N2 NSCLC patients with EGFR mutations (NCT01407822) is currently recruiting participants.

Randomized Phase II/III Trial Assessing Gemcitabine/Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer Who Are Unfit for Cisplatin-Based Chemotherapy: EORTC Study 30986

This is the first randomized phase II/III trial comparing two carboplatin-based chemotherapy regimens in patients with urothelial cancer who are ineligible ("unfit") for cisplatin chemotherapy. The primary objective of the phase III part of this study was to compare the overall survival (OS) of chemotherapy-naive patients with measurable disease and an impaired renal function (glomerular filtration rate < 60 but > 30 mL/min) and/or performance score of 2 who were randomly assigned to receive either gemcitabine/carboplatin (GC) or methotrexate/carboplatin/vinblastine (M-CAVI). To detect an increase of 50% in median survival with GC compared with M-CAVI (13.5 v 9 months) based on a two-sided log-rank test at error rates α = .05 and β = .20, 225 patients were required. Secondary end points were overall response rate (ORR), progression-free survival (PFS), toxicity, and quality of life. In all, 238 patients were randomly assigned by 29 institutions over a period of 7 years. The median follow-up was 4.5 years. Best ORRs were 41.2% (36.1% confirmed response) for patients receiving GC versus 30.3% (21.0% confirmed response) for patients receiving M-CAVI (P = .08). Median OS was 9.3 months in the GC arm and 8.1 months in the M-CAVI arm (P = .64). There was no difference in PFS (P = .78) between the two arms. Severe acute toxicity (death, grade 4 thrombocytopenia with bleeding, grade 3 or 4 renal toxicity, neutropenic fever, or mucositis) was observed in 9.3% of patients receiving GC and 21.2% of patients receiving M-CAVI. There were no significant differences in efficacy between the two treatment groups. The incidence of severe acute toxicities was higher for those receiving M-CAVI.

Induction erlotinib or gemcitabine/carboplatin factorial assignment therapy in stage IIIA-N2 non-small cell lung cancer.

e17512 Background: Stage IIIA-N2 NSCLC represents a heterogeneous group of patients with ipsilateral mediastinal lymph nodes involvement. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) may provide dramatic responses in patients with non-small cell lung cancer (NSCLC) carrying EGFR mutations. The purpose of this study is to evaluate the role of induction EGFR-TKI therapy in IIIA-N2 NSCLC. Methods: A Phase II trial conferring induction erlotinib therapy is currently recruiting participants (NCT00600587). Patients with resectable NSCLC of stage IIIA-N2 were assigned to either induction erlotinib arm or induction gemcitabine/carboplatin (GC) arm based on the EGFR mutations analysis. Results: From January 2008 till now, 21 patients with IIIA-N2 NSCLC diagnosed by mediastinoscopy or PET/CT have been enrolled. Ten cases with EGFR mutation were assigned to the erlotinib arm, while 11 cases harboring wild-type EGFR received the GC regimen. In the erlotinib arm, one case suffered from postoperative bleeding, and another case suffered from acute radiotherapy-induced pneumonitis which led to death. In the GC arm, three cases suffered from grade IV thrombocytopenia, among which two cases received transfusion. In the 19 cases with full data up till now, the response rates were 66.7% (6/9) for the erlotinib arm and 40% (4/10) for the GC arm (P=0.31). The pathological N2 complete response rates were 22.2% (2/9) for the erlotinib arm and 30% (3/10) for the GC arm (P=1.0). Five cases received complete resection in the erlotinib arm, while 6 cases received complete resection in the GC arm. In the erlotinib arm, the most common failure model after initial therapy was distant metastases (5/7), especially brain metastases (3/7). The median progression free survival time was 236 days for the erlotinib arm and 271 days for the GC arm (P=0.27). In addition, two cases in the erlotinib arm got partial response to gefitinib therapy after progression to erlotinib induction therapy and the following complete resection. Conclusions: Induction erlotinib therapy in IIIA-N2 NSCLC with EGFR activating mutation is a promising strategy. Brain metastases were major failure model.

Induction erlotinib therapy in stage IIIA-N2 non-small cell lung cancer.

TPS284 Background: Stage IIIA non-small cell lung cancer (NSCLC) is seen in a relatively heterogeneous group of patients with ipsilateral mediastinal (N2) lymph node involvement. The relative roles of different treatment modalities are not clear. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) may result in dramatic responses in patients with pulmonary adenocarcinoma carrying EGFR activating mutations. In case reports, the efficacy of perioperative EGFR-TKI therapy in patients with locally advanced NSCLC harboring EGFR gene mutations was satisfactory. Although no prospective data support the use of EGFR-TKIs as induction therapy in stage IIIA-N2 NSCLC, their low toxicity profile and the possibility of a rapid tumor response suggests that prospective trials are required. Therefore, this study evaluated the value of induction erlotinib therapy in IIIA-N2 NSCLC selected by EGFR gene analysis and explored a new treatment strategy for this subset. Erlotinib specifically targets the EGFR TK domain, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor. Methods: A two-stage phase II trial of induction EGFR-TKI therapy is currently recruiting participants (ClinicalTrials.gov identifier: NCT00600587). Patients with resectable stage IIIA-N2 NSCLC confirmed by mediastinoscopy or PET/CT were assigned to the induction erlotinib therapy arm (150 mg erlotinib taken once daily and continued uninterrupted for 42 d before evaluation and thoracotomy/radiotherapy) or the induction gemcitabine/carboplatin (GC) arm based on the EGFR mutation analysis. Study type: Interventional. Study Design: Active control, factorial assignment, nonrandomized, open label, safety/efficacy study, treatment. Primary outcome measures: Response to induction therapy, disease-free survival. Estimated enrollment: Fifteen cases in the erlotinib arm are needed in the first stage, and 46 cases in the second stage. At present, six patients have been assigned to the induction erlotinib therapy arm and seven to the induction GC arm. No significant financial relationships to disclose.

A randomized phase II study of gemcitabine (G) vs gemcitabine/carboplatin (GC) as consolidation therapy to concurrent chemoradiotherapy (CRT) for stage III non-small cell lung cancer (NSCLC): A Lung Cancer Research Group (LCRG) study

7559 Background: Consolidation chemotherapy following concurrent CRT may improve systemic control and possibly prolong survival of pt with stage III NSCLC. Phase II study using docetaxel showed promising result but subsequent phase III study was negative. We explored the role of single agent gemcitabine (G) and combination with carboplatin (C) as consolidation chemotherapy. Methods: Study was conducted by Asian mutli-center group. Eligible criteria: stage IIIA/B, histologic/cytologic confirmed NSCLC, completed concurrent CRT according to preset cisplatin and RT doses, attained CR/PR/SD from CRT, randomized within 6 weeks from last day of CRT, ECOG 0–1, adequate organ function, no brain met. Exclusion: unresolved radiation pneumonitis/esophagitis. Randomized to G at 1250mg/m2 day 1,8 q21d x3 or G at same dose plus C at 5 x AUC at day 1 x3. Primary and 2nd end points are 2-yr survival rate, median survival and toxicity, respectively. Sample size was estimated to detect a 15% difference in 2 yrs survival rate. Results: Between 3/04 and 6/06 we screened 111 pts and enrolled 61. 10 pts were excluded because of unresolved pneumonitis/esophagitis. Pt characteristics are similar between 2 arms.(Table) Median age: 56. Dose of RT/cisplatin during CRT were similar. 3 pts in G arm skipped day 8 G while 10 in GC arm (p=0.16). 3 pt and 2 pt attained higher response status during G and GC respectively, while 3 and 4 pt progressed. Survival outcomes are similar. More hematologic toxicity in GC arm (G3/4 Anemia 3 v 44%; Neutro 25 v 51%; Plat 15.6 v 31%) 5 out of 61 pt had grade 3/4 post gemcitabine radiation pneumonitis and all 5 are from G arm. Conclusion: It is feasible to give G-based consolidation chemotherapy in selected patients after concurrent CRT. Combination therapy with platinum did not improve survival but it added to myelotoxicity. “Re-call” radiation pneumonitis by gemcitabine is relatively uncommon. Patient Characteristics and Primary Efficacy G (n=32) GC (n-29) p M/F 29/3 26/3 IIIA/IIIB 5/27 7/22 0.4 Adenocarcinoma/Non-adenocinoma 15/17 13/16 0.87 Median # of cycles 2 2 0.84 2 yr survival rate 46.3% 42.2% 0.89 1 yr progression free rate 34.4% 38.7% 0.53 Median survival 1.78 yr 1.75 yr 0.98 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Abraxis, AstraZeneca, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, Roche AstraZeneca, Eli Lilly, Merck, Novartis, Pfizer, Roche Bayer, Novartis

PD4-2-4: Outcome of patients with WHO performance status 2 in a randomized trial comparing vinorelbine/carboplatin with gemcitabine/carboplatin in advanced NSCLC

Outcome of patients with WHO performance status 2 in a randomized trial comparing vinorelbine/carboplatin with gemcitabine/carboplatin in advanced NSCLC Helbekkmo, Nina1,6 Aaseboe, Ulf2,6 Sundstrom, Stein H.3 Plessen, Christian v.4,6 Brunsvig, Paal F.5 Bremnes, Roy M.6,7 1 Dept. of Oncology, Universital Hospital of Northern Norway and Institute of Clinical Medicine, University of Tromsoe, Tromsoe, Norway 2 Dept of Pulmonology, University Hospital of Northern Norway, Tromsoe, Norway 3 Dept of Oncology, St. Olavs University Hospital, Trondheim, Norway 4 Dept of Thoracic Medicine, Haukeland University Hospital and Institute of Medicine, University of Bergen, Bergen, Norway 5 Dept of Oncology, Rikshospitalet-Radiumhospitalet, Oslo, Norway 6 Institute of Clinical Medicine, University of Tromso, Tromsoe, Norway 7 Dept of Oncology, University Hospital of Northern Norway, Tromsoe, Norway Background: In a national multicenter phase III study in stage IIIB and IV NSCLC patients, comparison of three cycles of vinorelbine/carboplatin (VC) to three cycles of gemcitabine/carboplatin (GC) concluded with equal survival in the two treatment arms. Hematological toxicity requiring interventions was more frequent in the GC arm but significant differences in quality of life (QOL) were not revealed. PS2 is the most powerful predictor of survival in patients with advanced NSCLC. Since single drug or combination chemotherapy to PS2 patients with advanced NSCLC still is controversial, outcomes following 2-drug combination treatment in this subpopulation were explored. Methods: In the main study of 432 randomized patients, median age was 67 years, 20% were ≥ 75 years old, 71% had stage IV disease and 28% PS 2. The PS2 subpopulation consisted of 123 patients, 62 in the VC and 61 in the GC arm. The total PS2 group and subgroups according to treatment were analyzed with respect to survival, QOL, and toxicity including required interventions. The PS2 group was then compared to PS0/1 with respect to the same variables. Results: Follow-up time was minimum two years. Baseline characteristics were well balanced between PS2 and PS0/1. Planned treatment (three cycles) was completed in 68 % of PS2 versus 85% of PS0/1 patients (p<0.01), and reasons for drop-out were similar in the two subgroups. Median, 1-year and 2-year survival was lower in the PS2 group, 4.5 vs. 8.9 months, 10 % vs. 37 % and 2 % vs. 8.5 %, respectively (p<0.01). Patients with PS2 received significantly less palliative radiotherapy and second-line chemotherapy than the PS0/1 patients. Compared to PS0/1, PS2 patients had lower mean hemoglobin (p<0.01), more need of blood transfusions (p<.01), and more registered hospital admissions due to side effects (p=0.02). Regarding QOL, PS2 patients had significantly lower compliance regarding questionnaire completion and they had more cancer related symptoms at baseline. But global QOL improved and they achieved clinically meaningful pain relief during and after treatment. Conclusions: As expected, patients with PS2 had shorter survival, more anemia and more admissions due to side-effects. More important is that chemotherapy led to improved QOL also in PS2 patients. PD4-2-5 Cytotoxic Chemotherapy I, Tue, 16:00 17:30

Vinorelbine/carboplatin vs gemcitabine/carboplatin in advanced NSCLC shows similar efficacy, but different impact of toxicity

This randomised phase III study in advanced non-small cell lung cancer (NSCLC) patients was conducted to compare vinorelbine/carboplatin (VC) and gemcitabine/carboplatin (GC) regarding efficacy, health-related quality of life (HRQOL) and toxicity. Chemonaive patients with NSCLC stage IIIB/IV and WHO performance status 0–2 were eligible. No upper age limit was defined. Patients received vinorelbine 25 mg m−2 or gemcitabine 1000 mg m−2 on days 1 and 8 and carboplatin AUC4 on day 1 and three courses with 3-week cycles. HRQOL questionnaires were completed at baseline, before chemotherapy and every 8 weeks until 49 weeks. During 14 months, 432 patients were included (VC, n=218; GC, n=214). Median survival was 7.3 vs 6.4 months, 1-year survival 28 vs 30% and 2-year survival 7 vs 7% in the VC and GC arm, respectively (P=0.89). HRQOL, represented by global QOL, nausea/vomiting, dyspnoea and pain, showed no significant differences. More grade 3–4 anaemia (P<0.01), thrombocytopenia (P<0.01) and transfusions of blood (P<0.01) or platelets (P<0.01) were observed in the GC arm. There was more grade 3–4 leucopoenia (P<0.01) in the VC arm, but the rate of neutropenic infections was the same (P=0.87). In conclusion, overall survival and HRQOL are similar, while grade 3–4 toxicity requiring interventions are less frequent when VC is compared to GC in advanced NSCLC.

Pemetrexed + carboplatin versus gemcitabine + carboplatin in the treatment of stage IIIB/IV non-small cell lung cancer

7517 Background: A prospective, randomized, multicentre study was conducted to compare pemetrexed + carboplatin (PC) with a standard regimen, gemcitabine + carboplatin (GC). Methods: Chemonaive patients with verified non-small cell lung cancer, stage IIIB (ineligible for curative radiotherapy) or stage IV, WHO performance status (PS) 0–2, adequate hematology and creatinine-clearance &gt; 45 ml/min were eligible. All patients were supplemented with folic acid 0.4 mg OD and vitamin B12 1 mg IM every 9 weeks, from &gt;= 5 days before and through the treatment period. Patients were randomized to receive either pemetrexed 500 mg/m2 + carboplatin AUC=5 (Calvert) day 1 or gemcitabine 1,000 mg/m2 day 1 &amp; 8 + carboplatin AUC=5 (Calvert) day 1. Maximum 4 courses every 3 weeks were given. Primary endpoints: QoL defined as global health status, nausea/vomiting, dyspnea and fatigue - measured by the EORTC QLQ-C30 and LC13 before every cycle and 3 &amp; 11 weeks after the last cycle. Secondary endpoints: Overall survival (OS) and toxicity measured by the CTCAE v3.0. Stratification was done for age (−75 vs +75 years), stage (IIIB vs IV) and PS (0–1 vs 2). 190 evaluable patients in each arm were required to detect a 15% improvement on predefined QoL parameters with an a of 0.05 and β of 0.80. A 15% loss to follow up was expected. Results: 446 patients were included from Apr 05 - Jul 06. The two arms were well balanced with respect to age, sex, stage, PS and histological classification. 436 patients were eligible for the primary QoL-analyses. No statistical significant differences in mean score of the QoL-scales were observed between the arms. So far, 384 patients have been analysed for toxicity. Significantly more patients in the GC arm experienced grade 3–4 thrombocytopenia (48 vs 107, p&lt;0.001), leucopenia (44 vs 89, p&lt;0.001) and granulocytopenia (78 vs 98, p=0.02). No difference in the frequency of neutropenic fever was recorded. More patients in the GC arm received transfusion of platelets (5 vs 19, p=0.02). At present, 291 patients are deceased. We expect to present complete OS analyses for a minimum of 380 patients at the annual meeting. Conclusions: No differences were detected between the two arms with respect to the primary QoL outcome. Patients in the PC arm experienced less toxicity. No significant financial relationships to disclose.

Gemcitabine plus Cisplatin versus Gemcitabine plus Carboplatin as First-Line Chemotherapy in Advanced Transitional Cell Carcinoma of the Urothelium: Results of a Randomized Phase 2 Trial

ObjectivesThis phase 2 randomized study compared the toxicity and assessed the efficacy of gemcitabine–cisplatin (GP) and gemcitabine–carboplatin (GC) in patients with advanced transitional cell carcinoma of the urothelium (TCC), with the main objective to demonstrate a reduction in toxicity of at least 25% in the GC arm. MethodsA total of 110 chemonaive patients (55 per arm) with locally advanced or metastatic TCC received gemcitabine 1250mg/m2 on days 1 and 8 plus cisplatin 70mg/m2 on day 2 (GP) every 3 wk or gemcitabine 1250mg/m2 on days 1 and 8 plus carboplatin AUC 5 on day 2 (GC) every 3 wk for a maximum of six cycles. ResultsNo differences between arms were noted in the overall toxicity profiles and any parameter of toxicity. The most frequent grade 3–4 hematologic toxicity was neutropenia in 34.6% of patients for GP and 45.4% for GC. The most frequent grade 3–4 nonhematologic toxicity was nausea and vomiting (GP: 9.1%; GC: 3.6%). Grade 1–2 nephrotoxicity occurred in 14 GP-treated patients (26.0%) and 9 GC-treated patients (16.3%). Per an intent-to-treat analysis, overall response, evaluated on 80 patients, was 49.1% for GP (CR: 14.5%; PR: 34.5%) and 40.0% for GC (CR: 1.8%; PR: 38.2%). Median time to progression was 8.3 mo for GP and 7.7 mo for GC. Median survival was 12.8 mo and 9.8 mo for GP and GC, respectively. ConclusionsGC has a comparably acceptable toxicity profile compared with that of GP and seems active in patients with TCC.

Gemcitabine/carboplatin (GC) vs. carboplatin (C) in platinum sensitive recurrent ovarian cancer (OVCA). Results of a Gynecologic Cancer Intergroup randomized phase III trial of the AGO OVAR, the NCIC CTG and the EORTC GCG

5005 Background: Most patients (pts) with OVCA relapse. ICON 4 - AGO OVAR 2.2 results suggest combination C-based therapy may be superior to single agent C. GC is a feasible less neurotoxic regimen and thus of interest to evaluate in this setting. Methods: In this phase III trial pts with platinum sensitive recurrent OVCA (≥ 6 months after the end of primary therapy) were randomized to receive C (AUC 4 d1) plus G (1000 mg/m2 d1 and 8) or C (AUC 5 d1) every 3 weeks. The primary objective compared progression free survival (PFS) in both arms. Secondary objectives were response rate (RR) and duration, overall survival (OS), toxicity and quality of life (QoL). Results: From 09/99 and 04/02, 356 pts (178 GC, 178 C) were randomized. Both study arms were well balanced for baseline disease characteristics. Median number of cycles was 6 for GC (0–10) and C (0–9). The weekly dose intensity was 98.2% for C (C arm) and 96.2% for C and 75.6% (92.8% for d 1 and 63.4% for d8) for G (GC arm). Grade 3/4 hematologic toxicities were significant higher in the GC arm (anemia 27.4% of pts. vs. 8.0%, neutropenia 70.3% vs. 12.0%, thrombocytopenia 34.9% vs. 11.4%). G-CSF or GM-CSF was more often used in GC (23.6% of pts. vs. 10.1%) as well as red cell transfusions (37.1% vs. 14.6%). Clinical sequelae were similar between arms: febrile neutropenia (1.1% GC vs. 0% C) and infections (0.6% for both arms). Grade 3/4 non-hematologic toxicities were infrequent in both arms (< 5%), especially for sensory neuropathy (1.1% GC vs. 1.7% C). Overall RR for GC was 47.2% (95% CI: 39.9–54.5%) and 30.9% (95% CI: 24.1–37.7) for C (p= 0.0016). GC pts reported significantly faster palliation of abdominal symptoms as well as significantly improved global QoL. With a median follow up of 13 months, median PFS was 8.6 mo (95%CI: 8.0–9.7) for GC and 5.8 mo (95% CI: 5.2–7.1) for C (HR 0.72 [95% CI: 0.57–0.90], p= 0.0038, e= 311). OS data are immature and this study was not powered to detect differences in OS. Conclusion: The combination of G plus C improves PFS and QoL in platinum sensitive recurrent OVCA patients with acceptable toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb; Eli Lilly Bristol-Myers Squibb; Eli Lilly Eli Lilly

Gemcitabine/carboplatin (GC) vs. carboplatin (C) in platinum sensitive recurrent ovarian cancer (OVCA). Results of a Gynecologic Cancer Intergroup randomized phase III trial of the AGO OVAR, the NCIC CTG and the EORTC GCG

5005 Background: Most patients (pts) with OVCA relapse. ICON 4 - AGO OVAR 2.2 results suggest combination C-based therapy may be superior to single agent C. GC is a feasible less neurotoxic regimen and thus of interest to evaluate in this setting. Methods: In this phase III trial pts with platinum sensitive recurrent OVCA (≥ 6 months after the end of primary therapy) were randomized to receive C (AUC 4 d1) plus G (1000 mg/m2 d1 and 8) or C (AUC 5 d1) every 3 weeks. The primary objective compared progression free survival (PFS) in both arms. Secondary objectives were response rate (RR) and duration, overall survival (OS), toxicity and quality of life (QoL). Results: From 09/99 and 04/02, 356 pts (178 GC, 178 C) were randomized. Both study arms were well balanced for baseline disease characteristics. Median number of cycles was 6 for GC (0–10) and C (0–9). The weekly dose intensity was 98.2% for C (C arm) and 96.2% for C and 75.6% (92.8% for d 1 and 63.4% for d8) for G (GC arm). Grade 3/4 hematologic toxicities were significant higher in the GC arm (anemia 27.4% of pts. vs. 8.0%, neutropenia 70.3% vs. 12.0%, thrombocytopenia 34.9% vs. 11.4%). G-CSF or GM-CSF was more often used in GC (23.6% of pts. vs. 10.1%) as well as red cell transfusions (37.1% vs. 14.6%). Clinical sequelae were similar between arms: febrile neutropenia (1.1% GC vs. 0% C) and infections (0.6% for both arms). Grade 3/4 non-hematologic toxicities were infrequent in both arms (< 5%), especially for sensory neuropathy (1.1% GC vs. 1.7% C). Overall RR for GC was 47.2% (95% CI: 39.9–54.5%) and 30.9% (95% CI: 24.1–37.7) for C (p= 0.0016). GC pts reported significantly faster palliation of abdominal symptoms as well as significantly improved global QoL. With a median follow up of 13 months, median PFS was 8.6 mo (95%CI: 8.0–9.7) for GC and 5.8 mo (95% CI: 5.2–7.1) for C (HR 0.72 [95% CI: 0.57–0.90], p= 0.0038, e= 311). OS data are immature and this study was not powered to detect differences in OS. Conclusion: The combination of G plus C improves PFS and QoL in platinum sensitive recurrent OVCA patients with acceptable toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb; Eli Lilly Bristol-Myers Squibb; Eli Lilly Eli Lilly

Randomized, multicenter, phase II study of gemcitabine plus cisplatin versus gemcitabine plus carboplatin in patients with advanced non-small cell lung cancer

Background: We conducted a phase II randomized study to assess the efficacy, with response as the primary endpoint, and the toxicity of gemcitabine/cisplatin (GP) and gemcitabine/carboplatin (GC) in patients with advanced non-small cell lung cancer (NSCLC). Methods: Patients were randomized to GP (gemcitabine 1200 mg/m 2, days 1 and 8 plus cisplatin 80 mg/m 2 day 2) or GC (gemcitabine 1200 mg/m 2, days 1 and 8 plus carboplatin AUC=5 day 2). Cycles were repeated every 3 weeks. Results: Sixty-two patients were randomized to GP and 58 to GC. A total of 533 cycles were delivered (264 GP, 269 GC), with a median of four cycles/patient. The objective response rate was 41.9% (95% C.I., 29.6–54.2%) for GP and 31.0% (95% C.I., 18.2–42.8%) for GC ( P=0.29). No significant differences between arms were observed in median survival (10.4 months GP, 10.8 months GC) and median time to progression (5.4 months GP, 5.1 months GC). Both regimens were very well tolerated with no statistical differences between arms in grade 3/4 toxicities. When all toxicity grades were combined, emesis, neuropathy and renal toxicity occurred more frequently on the GP arm ( P<0.005). Conclusions: GC arm did not provide a significant difference in response rate compared with GP arm, with better overall tolerability. Carboplatin could be a valid alternative to cisplatin in the palliative setting.