Wilfried Eberhardt

Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.

BACKGROUND Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population. METHODS We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. RESULTS The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel (P=0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group. CONCLUSIONS Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. (Funded by Bristol-Myers Squibb; CheckMate 017 ClinicalTrials.gov number, NCT01642004.).

Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial

BACKGROUND Use of cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has the potential to increase survival in patients with advanced non-small-cell lung cancer. We therefore compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced EGFR-positive non-small-cell lung cancer. METHODS In a multinational, multicentre, open-label, phase III trial, chemotherapy-naive patients (>or=18 years) with advanced EGFR-expressing histologically or cytologically proven stage wet IIIB or stage IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio to chemotherapy plus cetuximab or just chemotherapy. Chemotherapy was cisplatin 80 mg/m(2) intravenous infusion on day 1, and vinorelbine 25 mg/m(2) intravenous infusion on days 1 and 8 of every 3-week cycle) for up to six cycles. Cetuximab-at a starting dose of 400 mg/m(2) intravenous infusion over 2 h on day 1, and from day 8 onwards at 250 mg/m(2) over 1 h per week-was continued after the end of chemotherapy until disease progression or unacceptable toxicity had occurred. The primary endpoint was overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00148798. FINDINGS Between October, 2004, and January, 2006, 1125 patients were randomly assigned to chemotherapy plus cetuximab (n=557) or chemotherapy alone (n=568). Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group (median 11.3 months vs 10.1 months; hazard ratio for death 0.871 [95% CI 0.762-0.996]; p=0.044). The main cetuximab-related adverse event was acne-like rash (57 [10%] of 548, grade 3). INTERPRETATION Addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced non-small-cell lung cancer. FUNDING Merck KGaA.

EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study.

BACKGROUND Findings from the phase 3 First-Line ErbituX in lung cancer (FLEX) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone (hazard ratio [HR] 0·871, 95% CI 0·762-0·996; p=0·044) in patients with advanced non-small-cell lung cancer (NSCLC). To define patients benefiting most from cetuximab, we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients. METHODS We used prospectively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0-300. We used response data to select an outcome-based discriminatory threshold immunohistochemistry score for EGFR expression of 200. Treatment outcome was analysed in patients with low (immunohistochemistry score <200) and high (≥200) tumour EGFR expression. The primary endpoint in the FLEX study was overall survival. We analysed patients from the FLEX intention-to-treat (ITT) population. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. FINDINGS Tumour EGFR immunohistochemistry data were available for 1121 of 1125 (99·6%) patients from the FLEX study ITT population. High EGFR expression was scored for 345 (31%) evaluable patients and low for 776 (69%) patients. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group (median 12·0 months [95% CI 10·2-15·2] vs 9·6 months [7·6-10·6]; HR 0·73, 0·58-0·93; p=0·011), with no meaningful increase in side-effects. We recorded no corresponding survival benefit for patients in the low EGFR expression group (median 9·8 months [8·9-12·2] vs 10·3 months [9·2-11·5]; HR 0·99, 0·84-1·16; p=0·88). A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (p=0·044). INTERPRETATION High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC. Assessment of EGFR expression could offer a personalised treatment approach in this setting. FUNDING Merck KGaA.

Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial

BACKGROUND Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET) tyrosine kinases. In a randomised phase 2 study in patients with previously treated non-small-cell lung cancer (NSCLC), adding vandetanib 100 mg to docetaxel significantly improved progression-free survival (PFS) compared with docetaxel alone, including a longer PFS in women. These results supported investigation of the combination in this larger, definitive phase 3 trial (ZODIAC). METHODS Between May, 2006, and April, 2008, patients with locally advanced or metastatic (stage IIIB-IV) NSCLC after progression following first-line chemotherapy were randomly assigned 1:1 through a third-party interactive voice system to receive vandetanib (100 mg/day) plus docetaxel (75 mg/m(2) intravenously every 21 days; maximum six cycles) or placebo plus docetaxel. The primary objective was comparison of PFS between the two groups in the intention-to-treat population. Women were a coprimary analysis population. This study has been completed and is registered with ClinicalTrials.gov, number NCT00312377. FINDINGS 1391 patients received vandetanib plus docetaxel (n=694 [197 women]) or placebo plus docetaxel (n=697 [224 women]). Vandetanib plus docetaxel led to a significant improvement in PFS versus placebo plus docetaxel (hazard ratio [HR] 0.79, 97.58% CI 0.70-0.90; p<0.0001); median PFS was 4.0 months in the vandetanib group versus 3.2 months in placebo group. A similar improvement in PFS with vandetanib plus docetaxel versus placebo plus docetaxel was seen in women (HR 0.79, 0.62-1.00, p=0.024); median PFS was 4.6 months in the vandetanib group versus 4.2 months in the placebo group. Among grade 3 or higher adverse events, rash (63/689 [9%] vs 7/690 [1%]), neutropenia (199/689 [29%] vs 164/690 [24%]), leukopenia (99/689 [14%] vs 77/690 [11%]), and febrile neutropenia (61/689 [9%] vs 48/690 [7%]) were more common with vandetanib plus docetaxel than with placebo plus docetaxel. The most common serious adverse event was febrile neutropenia (46/689 [7%] in the vandetanib group vs 38/690 [6%] in the placebo group). INTERPRETATION The addition of vandetanib to docetaxel provides a significant improvement in PFS in patients with advanced NSCLC after progression following first-line therapy.

Preoperative chemotherapy followed by concurrent chemoradiation therapy based on hyperfractionated accelerated radiotherapy and definitive surgery in locally advanced non-small-cell lung cancer: mature results of a phase II trial.

PURPOSE To evaluate the feasibility and efficacy of an intensive multimodality approach with combination chemotherapy, hyperfractionated accelerated chemoradiotherapy, and definitive surgery in prognostically unfavorable subgroups of locally advanced non-small-cell lung cancer stages IIIA and IIIB (LAD-NSCLC). PATIENTS AND METHODS Following staging, including mediastinoscopy, 94 patients with inoperable LAD-NSCLC were treated preoperatively with chemotherapy (three courses of split-dose cisplatin and etoposide [PE]) followed by concurrent chemoradiotherapy (one course of PE combined with 45 Gy hyperfractionated accelerated radiotherapy). After repeat mediastinoscopy, patients underwent surgery 4 weeks postradiation. RESULTS Of 94 consecutive patients (52 stage IIIA [> or = two lymph node levels involved] and 42 stage IIIB [no pleural effusion, no supraclavicular nodes]), 62 (66%) completed induction and underwent surgery. Complete resection (R0) was achieved in 50 (53% of all patients) and pathologic complete response (PCR) in 24 (26%). After a median follow-up of 43 months, the median survival time was 20 months for IIIA, 18 months for IIIB, and 42 months for R0 patients. Calculated survival rates at 4 years were 31%, 26%, and 46%. Two patients died of sepsis preoperatively and four died postoperatively of pleural empyema (n = 1), stump insufficiency (n = 2), and cardiac failure (n = 1). Other toxicities were acceptable-mainly hematologic during chemotherapy or chemoradiotherapy and esophagitis during chemoradiotherapy. CONCLUSION This intensive multimodality treatment is feasible and demonstrates high efficacy in prognostically unfavorable LAD-NSCLC subgroups with high R0 rates and improved long-term survival compared with historical controls

Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial

BACKGROUND Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. METHODS The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4-12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 μg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m(2) (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188. FINDINGS From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25.6 months (95% CI 22.5-29.2) with tecemotide versus 22.3 months (19.6-25.5) with placebo (adjusted HR 0.88, 0.75-1.03; p=0.123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30.8 months (95% CI 25.6-36.8) compared with 20.6 months (17.4-23.9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0.78, 0.64-0.95; p=0.016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19.4 months [95% CI 17.6-23.1] vs 24.6 months [18.8-33.0], respectively; adjusted HR 1.12, 0.87-1.44; p=0.38). Grade 3-4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 [5%] of 1024 patients in the tecemotide group vs 21 [4%] of 477 patients in the placebo group), metastases to central nervous system (29 [3%] vs 6 [1%]), and pneumonia (23 [2%] vs 12 [3%]). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 [3%] in the tecemotide group vs 14 [3%] in the placebo group), dyspnoea (29 [3%] vs 13 [3%]), and metastases to central nervous system (32 [3%] vs 9 [2%]). Serious immune-related adverse events did not differ between groups. INTERPRETATION We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. FUNDING Merck KGaA (Darmstadt, Germany).

Value of 18F-Fluoro-2-Deoxy-d-Glucose-Positron Emission Tomography/Computed Tomography in Non–Small-Cell Lung Cancer for Prediction of Pathologic Response and Times to Relapse after Neoadjuvant Chemoradiotherapy

Purpose: To determine the value of combined positron emission tomography/computed tomography (PET/CT) during induction chemotherapy (CTx) followed by chemoradiotherapy (CTx/RTx) for non–small-cell lung cancer to predict histopathologic response in primary tumor and mediastinum and prognosis of the patient. Experimental Design: Fifty consecutive patients with locally advanced non–small-cell lung cancer received induction therapy and, if considered resectable, proceeded to surgery (37 of 50 patients). Patients had at least two repeated 18F-2-fluoro-2-deoxy-d-glucose (FDG)-PET/CT scans either before treatment (t0) or after induction CTx (t1) or CTx/RTx (t2). Variables from the PET/CT studies [e.g., lesion volume and corrected maximum standardized glucose uptake values (SUVmax,corr)] were correlated with histopathologic response (graded as 3, 2b, or 2a: 0%, >0-10%, or >10% residual tumor cells) and times to failure. Results: Primary tumors showed a percentage decrease in SUVmax,corr during induction significantly larger in grade 2b/3 than in grade 2a responding tumors (67% versus 34% at t1, 73% versus 49% at t2; both P < 0.005). SUVmax,corr at t2 was significantly correlated with histopathologic response in tumors smaller than the median volume (7.5 cm3; r = −0.54, P = 0.02). In the mediastinal lymph nodes, SUVmax,corr values at t2 predicted an ypN0 status with a sensitivity and specificity of 73% and 89%, respectively (SUVmax,corr threshold of 4.1, r = −0.54, P = 0.0005). Freedom from extracerebral relapse was significantly better in grade 2b/3 patients (86% at 16 months versus 20% in 2a responders; P = 0.003) and in patients with a greater percentage decrease in SUVmax,corr in the primary tumor at t2 in relation to t0 than in patients with lesser response (83% at 16 months versus 43%; P = 0.03 for cutoff points between 0.45 and 0.55). Conclusions: SUVmax,corr values from two serial PET/CT scans, before and after three chemotherapy cycles or later, allow prediction of histopathologic response in the primary tumor and mediastinal lymph nodes and have prognostic value.

Randomized Phase II Study of Vandetanib Alone or With Paclitaxel and Carboplatin as First-Line Treatment for Advanced Non–Small-Cell Lung Cancer

PURPOSE Vandetanib is a once-daily, oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. The antitumor activity of vandetanib monotherapy or vandetanib with paclitaxel and carboplatin (VPC) was compared with paclitaxel and carboplatin (PC) in previously untreated patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS All NSCLC histologies and previously treated CNS metastases were permitted in this partially blinded, placebo-controlled, randomized phase II study. Patients were randomly assigned 2:1:1 to receive vandetanib, VPC, or PC. Progression-free survival (PFS) was the primary end point, and the study was powered to detect a reduced risk of progression with VPC versus PC (hazard ratio = 0.70; one-sided P < .2) and to demonstrate noninferiority for vandetanib versus PC. Overall survival was a secondary assessment. RESULTS The risk of progression was reduced for patients receiving VPC (n = 56) versus PC (n = 52; hazard ratio = 0.76, one-sided P = .098); median PFS was 24 weeks (VPC) and 23 weeks (PC). The vandetanib monotherapy arm (n = 73) was discontinued after a planned interim PFS analysis met the criterion for discontinuation (hazard ratio > 1.33 v PC). Overall survival was not significantly different between patients receiving VPC or PC. Rash, diarrhea, and hypertension were common adverse events; no pulmonary or CNS hemorrhage events required intervention. CONCLUSION VPC could be safely administered to patients with NSCLC, including those with squamous cell histology and treated brain metastases. Compared with the PC control arm, patients receiving VPC had longer PFS, meeting the prespecified study end point, whereas those receiving vandetanib monotherapy had shorter PFS.

Vandetanib Versus Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer: Results From a Two-Part, Double-Blind, Randomized Phase II Study

PURPOSE Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) signaling. In this two-part phase II study, the efficacy and safety of vandetanib was compared with that of gefitinib, an inhibitor of EGFR signaling. PATIENTS AND METHODS Patients (N = 168) with locally advanced or metastatic (stage IIIB/IV) non-small-cell lung cancer (NSCLC), after failure of first-line with or without second-line platinum-based chemotherapy, received once-daily vandetanib 300 mg (n = 83) or gefitinib 250 mg (n = 85) until disease progression or evidence of toxicity (part A). After a 4-week washout period, eligible patients had the option to switch to the alternative treatment (part B). Progression-free survival (PFS) was the primary efficacy assessment in part A, which was designed to have a higher than 75% power to detect a 33% prolongation of PFS at a one-sided significance level of .2. RESULTS In part A, vandetanib prolonged PFS compared with gefitinib (hazard ratio = 0.69; 95% CI, 0.50 to 0.96; one-sided P = .013). Patients receiving vandetanib experienced adverse events that were manageable and generally consistent with inhibition of EGFR and VEGFR signaling, including diarrhea, rash, and hypertension. There were no unexpected safety findings with gefitinib. Overall survival, a secondary assessment, was not significantly different between patients initially randomly assigned to either vandetanib or gefitinib. CONCLUSION The primary efficacy objective was achieved, with vandetanib demonstrating a significant prolongation of PFS versus gefitinib. Vandetanib 300 mg/d is currently being evaluated as a monotherapy in two randomized phase III studies in advanced NSCLC.

Prophylactic Cranial Irradiation in Locally Advanced Non–Small-Cell Lung Cancer After Multimodality Treatment: Long-Term Follow-Up and Investigations of Late Neuropsychologic Effects

PURPOSE Relapse pattern and late toxicities in long-term survivors were analyzed after the introduction of prophylactic cranial irradiation (PCI) into a phase II trial on trimodality treatment of locally advanced (LAD) non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Seventy-five patients with stage IIIA(N2)/IIIB NSCLC were treated with induction chemotherapy, preoperative radiochemotherapy, and surgery. PCI was routinely offered during the second period of study accrual. Patients were given a total radiation dose of 30 Gy (2 Gy per daily fraction) over a 3-week period starting 1 day after the last chemotherapy cycle. RESULTS Introduction of PCI reduced the rate of brain metastases as first site of relapse from 30% to 8% at 4 years (P =.005) and that of overall brain relapse from 54% to 13% (P <.0001). The effect of PCI was also observed in the good-prognosis subgroup of 47 patients who had a partial response or complete response to induction chemotherapy, with a reduction of brain relapse as first failure from 23% to 0% at 4 years (P =.01). Neuropsychologic testing revealed impairments in attention and visual memory in long-term survivors who received PCI as well as in those who did not receive PCI. T2-weighted magnetic resonance imaging revealed white matter abnormalities of higher grades in patients who received PCI than in those who did not. CONCLUSION PCI at a moderate dose reduced brain metastases in LAD-NSCLC to a clinically significant extent, comparable to that in limited-disease small-cell lung cancer. Late toxicity to normal brain was acceptable. This study supports the use of PCI within intense protocols for LAD-NSCLC, particularly in patients with favorable prognostic factors.