Denis Soulières

Multicenter Phase II Study of Erlotinib, an Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck

PURPOSE To determine the efficacy and safety profiles of erlotinib in patients with advanced recurrent and/or metastatic squamous cell cancer of the head and neck (HNSCC). PATIENTS AND METHODS Patients with locally recurrent and/or metastatic HNSCC, regardless of their HER1/EGFR status, were treated with erlotinib at an initial dose of 150 mg daily. Dose reductions or escalations were allowed based on tolerability of erlotinib. RESULTS One-hundred fifteen patients were enrolled onto this study. Forty-seven percent of patients received erlotinib at 150 mg daily throughout the entire study, 6% had dose escalations, and 46% required dose reductions and/or interruptions. Five patients achieved partial responses on study, for an overall objective response rate of 4.3% (95% CI, 1.4% to 9.9%). Disease stabilization was maintained in 44 patients (38.3%) for a median duration of 16.1 weeks. The median progression-free survival was 9.6 weeks (95% CI, 8.1 to 12.1 weeks), and the median overall survival was 6.0 months (95% CI, 4.8 to 7.0 months). Subgroup analyses revealed a significant difference in overall survival favoring patients who developed at least grade 2 skin rashes versus those who did not (P =.045), whereas no difference was detected based on HER1/EGFR expression. Rash and diarrhea were the most common drug-related toxicities, encountered in 79% and 37% of patients, respectively, though the severity was mild to moderate in most cases. CONCLUSION Erlotinib was well tolerated in this heavily pretreated HNSCC population and produced prolonged disease stabilization; hence, further evaluation of its role in this tumor type is warranted.

Randomized Phase IIB Trial of BLP25 Liposome Vaccine in Stage IIIB and IV Non–Small-Cell Lung Cancer

PURPOSE To evaluate the effect of BLP25 liposome vaccine (L-BLP25) on survival and toxicity in patients with stage IIIB and IV non-small-cell lung cancer (NSCLC). Secondary objectives included health-related quality of life (QOL) and immune responses elicited by L-BLP25. PATIENTS AND METHODS Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2 and stable or responding stage IIIB or IV NSCLC after any first-line chemotherapy were prestratified by stage and randomly assigned to either L-BLP25 plus best supportive care (BSC) or BSC alone. Patients in the L-BLP25 arm received a single intravenous dose of cyclophosphamide 300 mg/m2 followed by eight weekly subcutaneous immunizations with L-BLP25 (1,000 microg). Subsequent immunizations were administered at 6-week intervals. RESULTS The survival results indicate a median survival time of 4.4 months longer for patients randomly assigned to the L-BLP25 arm (88 patients) compared with patients assigned to the BSC arm (83 patients; adjusted hazard ratio [HR] = 0.739; 95% CI, 0.509 to 1.073; P = .112). The greatest effect was observed in stage IIIB locoregional (LR) patients, for whom the median survival time for the L-BLP25 arm has not yet been reached compared with 13.3 months for the BSC arm (adjusted HR = 0.524; 95% CI, 0.261 to 1.052; P = .069). No significant toxicity was observed. QOL was maintained longer in patients on the L-BLP25 arm. CONCLUSION L-BLP25 maintenance therapy in patients with advanced NSCLC is feasible with minimal toxicity. The survival difference of 4.4 months observed with the vaccine did not reach statistical significance. In the subgroup of patients with stage IIIB LR disease, a strong trend in 2-year survival in favor of L-BLP25 was observed.

Phase III Study of Gefitinib Compared With Intravenous Methotrexate for Recurrent Squamous Cell Carcinoma of the Head and Neck

PURPOSE To compare survival in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) treated with gefitinib 250 or 500 mg/day or standard methotrexate. PATIENTS AND METHODS Four hundred eighty-six patients with recurrent SCCHN were randomly assigned to oral gefitinib 250 mg/day, gefitinib 500 mg/day, or methotrexate 40 mg/m(2) intravenously weekly. Primary end point was overall survival, secondary end points were objective response rate (ORR), safety, symptom improvement, and quality of life (QOL). Exploratory end points included association of efficacy with epidermal growth factor receptor gene copy number and other biomarkers. RESULTS Neither gefitinib 250 nor 500 mg/day improved overall survival compared with methotrexate (hazard ratio [HR], 1.22; 95% CI, 0.95 to 1.57; P = .12; and HR, 1.12; 95% CI, 0.87 to 1.43; P = .39, respectively). In the gefitinib 250 mg/day, 500 mg/day, and methotrexate groups, respectively, median overall survival was 5.6, 6.0, and 6.7 months; ORRs (Response Evaluation Criteria in Solid Tumors) were 2.7%, 7.6% and 3.9%, with no statistically significant difference between either gefitinib arm and methotrexate. No unexpected adverse events were observed, except for tumor hemorrhage-type events with gefitinib (8.9%, gefitinib 250 mg/day; 11.4%, gefitinib 500 mg/day; 1.9%, methotrexate). QOL improvement rates (Functional Assessment of Cancer Therapy-Head & Neck total score) were 13.4%, 18.0%, and 6.0% for gefitinib 250 mg/day, 500 mg/day, and methotrexate, respectively. CONCLUSION In patients with recurrent or metastatic SCCHN, while responses with gefitinib were seen, neither gefitinib 250 nor 500 mg/day improved overall survival compared with methotrexate. With the exception of tumor hemorrhage-type events with gefitinib, the adverse event profiles were generally consistent with those previously observed.

Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study

Objectives/methods:  This 1‐yr prospective phase II trial evaluated the efficacy of deferasirox in regularly transfused patients aged 3–81 yrs with myelodysplastic syndromes (MDS; n = 47), Diamond–Blackfan anaemia (DBA; n = 30), other rare anaemias (n = 22) or β‐thalassaemia (n = 85). Dosage was determined by baseline liver iron concentration (LIC).

Human Papillomavirus and Overall Survival After Progression of Oropharyngeal Squamous Cell Carcinoma

PURPOSE Risk of cancer progression is reduced for patients with human papillomavirus (HPV) -positive oropharynx cancer (OPC) relative to HPV-negative OPC, but it is unknown whether risk of death after progression is similarly reduced. PATIENTS AND METHODS Patients with stage III-IV OPC enrolled onto Radiation Therapy Oncology Group trials 0129 or RTOG 0522 who had known tumor p16 status plus local, regional, and/or distant progression after receiving platinum-based chemoradiotherapy were eligible for a retrospective analysis of the association between tumor p16 status and overall survival (OS) after disease progression. Rates were estimated by Kaplan-Meier method and compared by log-rank; hazard ratios (HRs) were estimated by Cox models. Tests and models were stratified by treatment protocol. RESULTS A total of 181 patients with p16-positive (n = 105) or p16-negative (n = 76) OPC were included in the analysis. Patterns of failure and median time to progression (8.2 v 7.3 months; P = .67) were similar for patients with p16-positive and p16-negative tumors. After a median follow-up period of 4.0 years after disease progression, patients with p16-positive OPC had significantly improved survival rates compared with p16-negative patients (2-year OS, 54.6% v 27.6%; median, 2.6 v 0.8 years; P < .001). p16-positive tumor status (HR, 0.48; 95% CI, 0.31 to 0.74) and receipt of salvage surgery (HR, 0.48; 95% CI; 0.27 to 0.84) reduced risk of death after disease progression whereas distant versus locoregional progression (HR, 1.99; 95% CI, 1.28 to 3.09) increased risk, after adjustment for tumor stage and cigarette pack-years at enrollment. CONCLUSION Tumor HPV status is a strong and independent predictor of OS after disease progression and should be a stratification factor for clinical trials for patients with recurrent or metastatic OPC.

Tremelimumab in Combination with Exemestane in Patients with Advanced Breast Cancer and Treatment-Associated Modulation of Inducible Costimulator Expression on Patient T Cells

Purpose: Tremelimumab is a fully human monoclonal antibody specific for CTL-associated antigen 4 (CTLA4) with single-agent activity in certain tumors but has not been evaluated in patients with breast cancer. Experimental Design: In a phase 1 study, 26 patients with advanced, hormone-responsive breast cancer received tremelimumab (3-10 mg/kg) every 28 days or every 90 days plus exemestane 25 mg daily. The objectives were to determine safety and the maximum tolerated dose (MTD) of tremelimumab with exemestane and, secondarily, to assess tumor response, pharmacokinetics, and immune pharmacodynamics. Results: Most treatment-related adverse events were mild to moderate with the most common being diarrhea (46% of patients), pruritus (42%), constipation (23%), and fatigue (23%). Dose-limiting toxicities were transient serum transaminase elevations (one patient) and diarrhea (four patients). The MTD of tremelimumab with exemestane was 6 mg/kg every 90 days. Among 13 patients treated at the MTD, none developed grade 3 or 4 treatment-related diarrhea. No pharmacokinetic interaction was observed between tremelimumab and exemestane. The best overall response was stable disease for ≥12 weeks in 11 patients (42%). Treatment was associated in most patients with increased peripheral CD4+ and CD8+ T cells expressing inducible costimulator (ICOS) and a marked increase in the ratio of ICOS+ T cells to FoxP3+ regulatory T cells. Conclusions: Tremelimumab plus exemestane is tolerable in patients with hormone-responsive advanced breast cancer. Treatment is associated with increased ICOS+ T cells, which likely signals immune activation secondary to CTL-associated antigen 4 blockade. Clin Cancer Res; 16(13); 3485–94. ©2010 AACR.

Randomized Phase III Trial to Test Accelerated Versus Standard Fractionation in Combination With Concurrent Cisplatin for Head and Neck Carcinomas in the Radiation Therapy Oncology Group 0129 Trial: Long-Term Report of Efficacy and Toxicity

PURPOSE We tested the efficacy and toxicity of cisplatin plus accelerated fractionation with a concomitant boost (AFX-C) versus standard fractionation (SFX) in locally advanced head and neck carcinoma (LA-HNC). PATIENTS AND METHODS Patients had stage III to IV carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Radiation therapy schedules were 70 Gy in 35 fractions over 7 weeks (SFX) or 72 Gy in 42 fractions over 6 weeks (AFX-C). Cisplatin doses were 100 mg/m(2) once every 3 weeks for two (AFX-C) or three (SFX) cycles. Toxicities were scored by using National Cancer Institute Common Toxicity Criteria 2.0 and the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria. Overall survival (OS) and progression-free survival (PFS) rates were estimated by using the Kaplan-Meier method and were compared by using the one-sided log-rank test. Locoregional failure (LRF) and distant metastasis (DM) rates were estimated by using the cumulative incidence method and Grays test. RESULTS In all, 721 of 743 patients were analyzable (361, SFX; 360, AFX-C). At a median follow-up of 7.9 years (range, 0.3 to 10.1 years) for 355 surviving patients, no differences were observed in OS (hazard ratio [HR], 0.96; 95% CI, 0.79 to 1.18; P = .37; 8-year survival, 48% v 48%), PFS (HR, 1.02; 95% CI, 0.84 to 1.24; P = .52; 8-year estimate, 42% v 41%), LRF (HR, 1.08; 95% CI, 0.84 to 1.38; P = .78; 8-year estimate, 37% v 39%), or DM (HR, 0.83; 95% CI, 0.56 to 1.24; P = .16; 8-year estimate, 15% v 13%). For oropharyngeal cancer, p16-positive patients had better OS than p16-negative patients (HR, 0.30; 95% CI, 0.21 to 0.42; P < .001; 8-year survival, 70.9% v 30.2%). There were no statistically significant differences in the grade 3 to 5 acute or late toxicities between the two arms and p-16 status. CONCLUSION When combined with cisplatin, AFX-C neither improved outcome nor increased late toxicity in patients with LA-HNC. Long-term high survival rates in p16-positive patients with oropharyngeal cancer support the ongoing efforts to explore deintensification.

Phase I/II Trial of Erlotinib and Cisplatin in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: A Princess Margaret Hospital Phase II Consortium and National Cancer Institute of Canada Clinical Trials Group Study

PURPOSE To determine the phase II dose and objective response rate of erlotinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, in combination with cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC). PATIENTS AND METHODS HNSCC patients with no prior chemotherapy and measurable disease were treated in three escalating-dose cohorts of daily continuous oral (PO) erlotinib and intermittent intravenous (IV) cisplatin given every 21 days. The recommended phase II dose (RPTD) was then evaluated in a two-stage trial with a primary end point of objective response rate. RESULTS A total of 51 patients were enrolled. The RPTD was identified as erlotinib 100 mg PO daily and cisplatin 75 mg/m2 IV every 21 days. Forty-five patients were treated at the RPTD, of which 44 and 43 were eligible for toxicity and efficacy evaluations, respectively. The intention-to-treat response rate was 21%, with one complete and eight partial responses (95% CI, 10% to 36%), and disease stabilization was achieved in 21 patients (49%; 95% CI, 33% to 65%). Median progression-free survival was 3.3 months (95% CI, 2.7 to 4.8 months) and median overall survival was 7.9 (95% CI, 5.6 to 9.5) months. The combination was well tolerated, with minimal grade 3 or higher toxicity. Subgroup analysis suggested that patients who developed higher grade skin rashes during cycle 1 had better survival outcomes (P = .034). CONCLUSION This schedule of erlotinib and cisplatin has a favorable toxicity profile and has antitumor activity in HNSCC comparable to standard combination chemotherapy regimens.

Phase II, Open-Label Study Evaluating the Activity of Imatinib in Treating Life-Threatening Malignancies Known to Be Associated with Imatinib-Sensitive Tyrosine Kinases

Purpose: To evaluate the activity of imatinib in treating advanced, life-threatening malignancies expressing one or more imatinib-sensitive tyrosine kinases. Experimental Design: This was a phase II, open-label, single arm study. Patients ≥15 years old with malignancies showing histologic or molecular evidence of expression/activation of imatinib-sensitive tyrosine kinases were enrolled. Patients were treated with 400 or 800 mg/d imatinib for hematologic malignancy and solid tumors, respectively. Treatment was continued until disease progression or unacceptable toxicity. The primary objective was to identify evidence of imatinib activity with tumor response as the primary end point. Results: One hundred eighty-six patients with 40 different malignancies were enrolled (78.5% solid tumors, 21.5% hematologic malignancies). Confirmed response occurred in 8.9% of solid tumor patients (4 complete, 9 partial) and 27.5% of hematologic malignancy patients (8 complete, 3 partial). Notable activity of imatinib was observed in only five tumor types (aggressive fibromatosis, dermatofibrosarcoma protuberans, hypereosinophilic syndrome, myeloproliferative disorders, and systemic mastocytosis). A total of 106 tumors were screened for activating mutations: five KIT mutations and no platelet-derived growth factor receptor mutations were found. One patient with systemic mastocytosis and a partial response to therapy had a novel imatinib-sensitive KIT mutation (D816T). There was no clear relationship between expression or activation of wild-type imatinib-sensitive tyrosine kinases and clinical response. Conclusion: Clinical benefit was largely confined to diseases with known genomic mechanisms of activation of imatinib target kinases. Our results indicate an important role for molecular characterization of tumors to identify patients likely to benefit from imatinib treatment.

Clinical outcomes in non‐small‐cell lung cancer patients with EGFR mutations: pooled analysis

•  Introduction •  Literature review ‐  Molecular biology of EGFR mutations ‐  Clinical characteristics of NSCLC patients with EGFR mutations ‐  Genetic characteristics of EGFR‐mutated tumours ‐  Prognostic significance of NSCLC with EGFR mutations ‐  How do structural changes in EGFR lead to greater sensitivity to EGFR TKIs? •  Methods ‐  Selection criteria ‐  Search strategy ‐  Data extraction and synthesis ‐  Statistical analysis ‐  Sensitivity analysis •  Results ‐  Study characteristics ‐  PFS analysis ‐  Sensitivity analysis ‐  Publication bias •  Discussion •  Conclusions