Nab-Paclitaxel plus Gemcitabine and FOLFOX in Metastatic Pancreatic Cancer.

BACKGROUND: Sequential nab-paclitaxel plus gemcitabine followed by modified FOLFOX-6 (oxaliplatin, leucovorin, and 5-fluorouracil) (nab-P/Gem-mFOLFOX) showed a good safety and clinical profile in metastatic pancreatic ductal adenocarcinoma (mPDAC) in the phase I SEQUENCE trial. METHODS: The safety and efficacy of sequential nab-P/Gem-mFOLFOX was compared with standard nab-paclitaxel plus gemcitabine (nab-P/Gem) as first-line treatment in a multi-institutional, randomized, open-label, phase II trial in patients with untreated mPDAC. We randomly assigned patients in a 1:1 ratio to receive nab-P/Gem on days 1, 8, and 15 followed by mFOLFOX on day 29 of a 6-week cycle (experimental group) or nab-P/Gem on days 1, 8, and 15 of a 4-week cycle (control group). The primary end point was the 12-month overall survival rate. RESULTS: A total of 157 patients were randomly assigned: 78 to nab-P/Gem-mFOLFOX and 79 to nab-P/Gem. Patients receiving nab-P/Gem-mFOLFOX had a 12-month overall survival of 55.3% (95% confidence interval [CI], 44.2 to 66.5) versus 35.4% (95% CI, 24.9 to 46) in the control group (P=0.02). Similarly, the 24-month survival was 22.4% (95% CI, 13 to 31.8) with nab-P/Gem-mFOLFOX versus 7.6% (95% CI, 1.8 to 13.4) with control treatment. The median overall survival was 13.2 months (95% CI, 10.1 to 16.2) with nab-P/Gem-mFOLFOX and 9.7 months (95% CI, 7.5 to 12) with nab-P/Gem (hazard ratio for death, 0.68; 95% CI, 0.48 to 0.95). The safety profile showed a higher incidence of grade 3 or higher neutropenia (35 of 76 vs. 19 of 79 patients, P=0.004), grade 3 or higher thrombocytopenia (18 of 78 vs. 6 of 79 patients, P=0.007), and two treatment-related deaths (2.6%) with nab-P/Gem-mFOLFOX compared with none with control treatment. CONCLUSIONS: Sequential nab-P/Gem-mFOLFOX showed a significantly higher 12-month survival when compared with the standard nab-P/Gem treatment; this came with greater treatment toxicity. (Funded by Celgene; EuCT number, 2014-005350-19; ClinicalTrials.gov number, NCT02504333.)

Gemcitabine-erlotinib versus gemcitabine-erlotinib-capecitabine in the first-line treatment of patients with metastatic pancreatic cancer: Efficacy and safety results of a phase IIb randomised study from the Spanish TTD Collaborative Group.

BACKGROUND: Gemcitabine and erlotinib have shown a survival benefit in the first-line setting in metastatic pancreatic cancer (mPC). The aim of this study was to assess whether combining capecitabine (C) with gemcitabine + erlotinib (GE) was safe and effective versus GE in patients with mPC. PATIENTS AND METHODS: Previously untreated mPC patients were randomised to receive G (1000 mg/m2, days 1, 8, 15) + E (100 mg/day, days 1-28) + C (1660 mg/m2, days 1-21) or GE, q4 weeks, until progression or unacceptable toxicity. Primary end-point: progression-free survival (PFS); secondary end-points: overall survival (OS), response rate, relationship of rash with PFS/OS and safety. RESULTS: 120 patients were randomised, median age 63 years, ECOG status 0/1/2 33%/58%/8%; median follow-up 16.5 months. Median PFS in the gemcitabine-erlotinib-capecitabine (GEC) and GE arms was 4.3 and 3.8 months, respectively (hazard ratio [HR]: 0.88, 95% confidence interval [CI]: 0.58-1.31; p = 0.52). Median OS in the GEC and GE arms was 6.8 and 7.7 months, respectively (HR: 1.09, 95% CI: 0.72-1.63; p = 0.69). Grade 3/4 neutropenia (GEC 43% versus GE 15%; p = 0.0008) and mucositis (GEC 9% versus GE 0%; p = 0.03) were the only statistically significant differences in grade 3/4 adverse events. PFS and OS were significantly longer in patients with rash (grade ≥1) versus no rash (grade = 0): PFS 5.5 versus 2.0 months (HR = 0.39, 95% CI: 0.26-0.6; p < 0.0001) and OS: 9.5 versus 4.0 months (HR = 0.51, 95% CI: 0.33-0.77; p = 0.0014). CONCLUSION: PFS with GEC was not significantly different to that with GE in patients with mPC. Skin rash strongly predicted erlotinib efficacy. The study was registered with ClinicalTrials.gov: NCT01303029.

Phase II study of trastuzumab and cisplatin as first-line therapy in patients with HER2-positive advanced gastric or gastroesophageal junction cancer.

INTRODUCTION: HER2 over-expression and/or amplification are present in 9-38% of gastric or gastroesophageal junction (GEJ) cancers and are correlated to poor outcome. We conducted a multicentre phase II trial to evaluate trastuzumab in combination with cisplatin in patients with untreated HER2-positive advanced gastric or GEJ cancer. MATERIALS AND METHODS: Chemo-naïve patients with measurable, non-resectable, advanced or metastatic gastric or GEJ adenocarcinoma, with HER2 over-expression and/or amplification (IHC 3+, or IHC 2+ and FISH+), age ≥18 years, ECOG ≤2, left ventricle ejection fraction ≥50% and adequate organ function were eligible. Treatment consisted of trastuzumab (8 mg/kg on cycle 1 day 1 as loading; 6 mg/kg in subsequent cycles) and cisplatin (75 mg/m(2)), both intravenously on day 1, every 21 days. RESULTS: Twenty-two out of 228 patients (10%) were HER2- positive and were included in this phase II trial. The median age was 66 years and ECOG 0/1 was 41%/59%. The median number of cycles was 4 (range 1-41). The confirmed ORR was 32% and disease control was achieved in 64% of patients. Median time to progression was 5.1 months. Grade 3 adverse events included asthenia (27%), neutropenia (18%), anorexia (14%), diarrhoea (9%) and abdominal pain (9%). There were no grade 4 toxicities or treatment-related deaths. Higher baseline HER extracellular domain (ECD) levels were associated with better outcome in terms of response and survival. CONCLUSIONS: Trastuzumab in combination with cisplatin is an active regimen and has a favourable toxicity profile in advanced HER2-positive gastric or gastroesophageal cancers.

A phase II study of days 1 and 8 combination of docetaxel plus gemcitabine for the second-line treatment of patients with advanced non-small-cell lung cancer and good performance status.

OBJECTIVE: We conducted a phase II trial to evaluate the efficacy and toxicity of a combination consisting of second-line docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. ELIGIBILITY CRITERIA: histologically confirmed advanced NSCLC with progressive disease to platinum-based chemotherapy, ECOG performance status (PS) 0 or 1, and adequate kidney, liver and bone marrow function. Treatment consisted of docetaxel 36 mg/m(2) i.v. over 60 min followed by gemcitabine 1000 mg/m(2) i.v. over 30 min on days 1 and 8 of each 3-week cycle for a planned six cycles or unacceptable toxicity. RESULTS: Of the 52 patients enrolled, 50 were evaluable for response and toxicity. The mean age was 59 years (range 42-79), 46 male and 4 female. Histology subtypes were: adenocarcinoma 26 patients, bronchioloalveolar 1 patient, large cell carcinoma 5 patients, and squamous cell carcinoma 18 patients. Thirty-eight patients had ECOG PS 1 and 12 patients had PS 0. The median number of cycles administered was four (range 2-6). The overall response rate was 28%. The median follow-up was 9 months (range 5-34 months). The median survival time (MST) was 8.2 months (95% CI, 4-12%), and the 1-year survival was 25%. The median progression-free survival was 4.4 months (95% CI, 2-6%). In the Cox regression model, survival was only significantly affected by the PS. The median survival in patients with PS 0 was 17.8 months (95% CI, 18.8-21.8%) compared with a median survival for patients with PS 1 of 6.1 months (95% CI, 4.1-8.2%) (P=0.0057). TOXICITY: three patients had grade 3 anemia, three patients had grade 3 thrombocytopenia, four patients had grade 3 neutropenia and only one patient developed grade 4 febrile neutropenia. Non-hematologic toxicity was also mild; the most frequent was asthenia, with grade 3 in eight patients (16%), and one patient with grade 4. CONCLUSION: This regimen of docetaxel in combination with gemcitabine in advanced second-line NSCLC is an active and safe regimen.

The HLA-B7 allele confers susceptibility to breast cancer in Spanish women.

BACKGROUND: Several HLA alleles are associated with susceptibility or protection in breast cancer. The particular allele varies depending on the geographical region. A study in a small group of Spanish patients using serological methods found an association with HLA-B7. We undertook a larger study in southern Spain using molecular biology techniques. METHODS: Genotype variants of HLA class I and II were typed by PCR-SSP in 132 breast cancer patients and 382 healthy controls. RESULTS: The frequency of the HLA-B7 allele was increased in the patients compared to the controls (P=0.0019; 95% confidence interval, 1.337-3.409, relative risk=2.135). Bonferroni correction of the P showed it was still significant (P(c)=0.0285). CONCLUSIONS: These results support previous suggestions that HLA-B7 is associated with the development of breast cancer in our area.