Frank R. Dunphy

Randomized Phase III Trial of Docetaxel Versus Vinorelbine or Ifosfamide in Patients With Advanced Non–Small-Cell Lung Cancer Previously Treated With Platinum-Containing Chemotherapy Regimens

PURPOSE: To confirm the promising phase II results of docetaxel monotherapy, this phase III trial was conducted of chemotherapy for patients with advanced non–small-cell lung cancer (NSCLC) who had previously failed platinum-containing chemotherapy. PATIENTS AND METHODS: A total of 373 patients were randomized to receive either docetaxel 100 mg/m2 (D100) or 75 mg/m2 (D75) versus a control regimen of vinorelbine or ifosfamide (V/I). The three treatment groups were well-balanced for key patient characteristics. RESULTS: Overall response rates were 10.8% with D100 and 6.7% with D75, each significantly higher than the 0.8% response with V/I (P = .001 and P = .036, respectively). Patients who received docetaxel had a longer time to progression (P = .046, by log-rank test) and a greater progression-free survival at 26 weeks (P = .005, by χ2 test). Although overall survival was not significantly different between the three groups, the 1-year survival was significantly greater with D75 than with the control treat...

Head and Neck Cancers

Recent evidence suggests that dysregulated translation and its control significantly contribute to the etiology and pathogenesis of the head and neck cancers, specifically to that of squamous cell carcinoma (HNSCC). eIF4E is one of the most studied components of the translation machinery implicated in the development and progression of HNSCC. It appears that dysregulation of eIF4E levels and activity, namely by the PI3K/AKT/mTOR pathway, plays an important role in the etiology and pathogenesis of HNSCC and correlates with clinical outcomes. In this chapter, we will discuss the role of eIF4E and some other translation factors as they relate to the biology and treatment of HNSCC.

Surveillance for recurrent head and neck cancer using positron emission tomography.

PURPOSE Earlier detection of head and neck cancer recurrence may improve survival. We evaluated the ability of [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) to detect recurrence in a prospective trial using sequential PET scans. PATIENTS AND METHODS Serial posttherapy FDG-PET was prospectively performed in 44 patients with stage III or IV head and neck cancer. PET was performed twice during the first posttreatment year (at 2 and 10 months after therapy) and thereafter as needed. After therapy, patients were grouped, based on tissue biopsies, into those who achieved a complete response (CR) and those who had residual disease (RD). Patients who achieved a CR were further grouped into those without evidence of disease and those who had recurrence by 1 year after completion of therapy. Disease status as determined by physical examination (PE), PET, and correlative imaging was compared. RESULTS Eight patients were lost to follow-up and six had RD after therapy. Of the remaining 30 patients with a CR, 16 had recurrence in the first year after therapy. Five of these 16 patients had recurrence detected by PET only, four by PET and correlative imaging only, five by PE and PET only, and two by PE, correlative imaging, and PET. Only PET detected all recurrences in the first year. PET performed better than correlative imaging (P =.013) or PE (P =.002) in the detection of recurrence. CONCLUSION PET can detect head and neck tumor recurrence when it may be undetectable by other clinical methods. FDG-PET permits highly accurate detection of head and neck cancer recurrence in the posttherapy period.

Treatment of estrogen receptor-negative or hormonally refractory breast cancer with double high-dose chemotherapy intensification and bone marrow support

We have used high-dose therapy followed by randomization to receive or not receive autologous bone marrow infusion in 58 stage IV breast cancer patients (all were estrogen receptor-negative [ER-] or primary hormonal refractory). Patients received a median of four courses of induction chemotherapy and if stable or responding received two courses of intensive therapy with cyclophosphamide 4.5 to 5.25 g/m2, etoposide 750 to 1,200 mg/m2, and cisplatin 120 to 180 mg/m2 (CVP). The complete remission (CR) rate after completion of the induction and intensive phases was 55%. Median progression-free interval from induction is 57 weeks with a projected 2-year progression-free survival of approximately 25%. Six of seven patients followed for greater than 2 years are still progression-free. Three favorable features predicted for improved progression-free survival are the following: (1) absent liver involvement, (2) absent soft tissue involvement, and (3) less than or equal to two disease sites (P values of .001, .013, and .048, respectively). Hormonal and menopausal status did not predict for progression-free survival. Major toxicities were infectious secondary to neutropenia, with a 93% incidence of fever and a 38% incidence of sepsis. The treatment-related mortality rate was 9%, with three infectious, one coronary, and one late hemorrhage-related death of unknown cause. Longer follow-up is still needed to truly evaluate the possibility of long-term disease-free survival, but further studies of this approach to high-dose intensification in poor prognostic groups of stage IV breast cancer appear warranted.

Evaluation of chemotherapy response in patients with advanced head and neck cancer using [F-18]fluorodeoxyglucose positron emission tomography

[F‐18]Fluorodeoxyglucose (FDG)‐positron emission tomography (PET) can measure the metabolic activity of tissues; FDG‐PET may be able to predict response to chemotherapy by identifying changes in tumor metabolism. Measurement of response to treatment may help improve survival in the management of advanced head and neck cancer. We evaluated this particular use of FDG‐PET in patients participating in a neoadjuvant organ‐preservation protocol using taxol and carboplatin and compared pathologic response after chemotherapy with changes in tumor metabolism measured by FDG‐PET.

Head and neck cancers, version 1.2015 featured updates to the NCCN guidelines

These NCCN Guidelines Insights focus on nutrition and supportive care for patients with head and neck cancers. This topic was a recent addition to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers. The NCCN Guidelines Insights focus on major updates to the NCCN Guidelines and discuss the new updates in greater detail. The complete version of the NCCN Guidelines for Head and Neck Cancers is available on the NCCN Web site (NCCN.org).

Randomized study of growth factors post-peripheral-blood stem-cell transplant: neutrophil recovery is improved with modest clinical benefit.

PURPOSE To evaluate the clinical value of growth factors (GFs) with peripheral-blood stem cells (PBSC) collected following mobilization with GFs, we randomized patients to receive or not to receive GFs following transplant. PATIENTS AND METHODS Thirty-seven patients were apheresed after receiving the combination of granulocyte colony-stimulating factor (G-CSF) with granulocyte-macrophage colony-stimulating factor (GM-CSF) at doses of 10 micrograms/kg/d and 5 micrograms/kg/d, respectively, for 6 days before apheresis and during a median of 4 days of collections. One day after the infusion of autologous marrow and PBSC, patients were randomly assigned to receive no GFs or a combination of G-CSF (7.5 micrograms/kg/d) and GM-CSF (2.5 micrograms/kg/d), both as a 2-hour intravenous (i.v.) infusion twice per day until the neutrophil count was greater than 1,500/microL. RESULTS The median days to recovery to an absolute neutrophil count (ANC) of 100/microL (9 v 11.5, P = .0005), 500/microL (10 v 16, P = .0004), or 1,000/microL (12 v 21, P = .0008) was shortened with the use of GFs, post-PBSC infusion. In addition, the duration of hospitalization was shorter (19 v 21 days, P = .0112) in the arm receiving GFs post-PBSC infusion. There was no significant difference between the two study arms in the duration of fever, documented septic episodes, or RBC or platelet transfusion requirements. CONCLUSION Despite faster neutrophil recovery and shortened duration of hospitalization with GFs administered after PBSC transplantation, the measured clinical variables of febrile days, septic episodes, and transfusion requirements were similar between the study arms. The use of GFs post-PBSC transfusion is associated with a modest clinical benefit.

Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study

BACKGROUND Osimertinib (AZD9291) is an oral, potent, irreversible EGFR tyrosine-kinase inhibitor selective for EGFR tyrosine-kinase inhibitor sensitising mutations, and the EGFR Thr790Met resistance mutation. We assessed the efficacy and safety of osimertinib in patients with EGFR Thr790Met-positive non-small-cell lung cancer (NSCLC), who had progressed after previous therapy with an approved EGFR tyrosine-kinase inhibitor. METHODS In this phase 2, open-label, single-arm study (AURA2), patients aged at least 18 years with centrally confirmed EGFR Thr790Met-positive mutations, locally advanced or metastatic (stage IIIB/IV) NSCLC who progressed on previous EGFR tyrosine-kinase inhibitor therapy received osimertinib 80 mg orally once daily; treatment could continue beyond progression if the investigator observed a clinical benefit. Patients with asymptomatic, stable CNS metastases not requiring steroids were allowed to enrol. The primary endpoint was the proportion of patients achieving an objective response by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the evaluable for response analysis set (ie, all patients who received at least one dose of osimertinib and had measurable disease at baseline according to blinded independent central review). Other endpoints and safety were assessed in all patients receiving at least one osimertinib dose (full analysis set). The study is ongoing and patients are still receiving treatment. This study is registered with ClinicalTrials.gov, number NCT02094261. FINDINGS Between May 20, 2014, and Sept 12, 2014, 472 patients were screened, of whom 210 started osimertinib treatment between June 13, 2014, and Oct 27, 2014; 11 patients were excluded from the evaluable for response analysis set (n=199) due to absence of measurable disease at baseline by blinded independent central review. At data cutoff (Nov 1, 2015), 122 (58%) patients remained on treatment. The median duration of follow-up was 13·0 months (IQR 7·6-14·2). 140 (70%; 95% CI 64-77) of 199 patients achieved an objective response by blinded independent central review: confirmed complete responses were achieved in six (3%) patients and partial responses were achieved in 134 (67%) patients. The most common all-causality grade 3 and 4 adverse events were pulmonary embolism (seven [3%]), prolonged electrocardiogram QT (five [2%]), decreased neutrophil count (four [2%]), anaemia, dyspnoea, hyponatraemia, increased alanine aminotransferase, and thrombocytopenia (three [1%] each). Serious adverse events were reported in 52 (25%) patients, of which 11 (5%) were investigator assessed as possibly treatment-related to osimertinib. Seven deaths were due to adverse events; these were pneumonia (n=2), pneumonia aspiration (n=1), rectal haemorrhage (n=1), dyspnoea (n=1), failure to thrive (n=1), and interstitial lung disease (n=1). The only fatal event assessed as possibly treatment-related by the investigator was due to interstitial lung disease. INTERPRETATION Osimertinib showed clinical activity with manageable side-effects in patients with EGFR Thr790Met-positive NSCLC. Therefore, osimertinib could be a suitable treatment for patients with EGFR Thr790Met-positive disease who have progressed on an EGFR tyrosine-kinase inhibitor. FUNDING AstraZeneca.

Factors predicting long‐term survival for metastatic breast cancer patients treated with high‐dose chemotherapy and bone marrow support

Background. Poor prognosis of Stage IV breast cancer patients have at best a 10% 3‐year survival rate with conventional chemotherapy. Dose‐intensive chemotherapy improved survival rates for some of these patients.

A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)

BACKGROUND KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC. PATIENTS AND METHODS Eligible patients with histologically confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2 : 1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m(2) i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary. RESULTS One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75-1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52-1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). The most frequent adverse events (AEs) in ≥20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia. CONCLUSION Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC. CLINICALTRIALSGOV REGISTRATION NUMBER NCT01362296.