Ethics approval and consent to participate
This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines of the International Conference on Harmonisation. Informed consent was obtained from all patients prior to study entry. The study received approval from institutional review boards prior to commencement. The trial is registered at ClinicalTrials.gov (NCT02027428).
The approving Institutional Review Boards/Ethics Committees were Bundesinstitut für Arzneimittel und Medizinprodukte, Ethikkommission der Medizinischen Fakultät Heidelberg, Agenzia Italiana del Farmaco, Comitato Etico Campania Nord, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), CEIC Hospital Clinico San Carlos, Health Research Authority, Medicines and Healthcare Products Regulatory Agency, NRES Committee London Surrey Borders, and Quorum Review IRB.
MATERIALS AND METHODS
Patients with stage IIIB or IV, histologically or cytologically confirmed squamous NSCLC measurable by “Response Evaluation Criteria In Solid Tumors” (RECIST) version 1.1 were enrolled in this study. Key eligibility requirements included ≥18 years of age, no prior chemotherapy for metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate hematologic, renal, and liver function. Patients with active brain metastases or preexisting peripheral neuropathy grade ≥2 were excluded.
The Phase III, randomized, open-label, multicenter ABOUND.sqm study is being conducted at ≈120 sites in the United States and the European Union. In the induction part, patients were treated with nab-paclitaxel (ABRAXANE®, albumin-bound paclitaxel) 100 mg/m2 intravenously on days 1, 8, and 15 plus carboplatin area under the curve 6 mg•min/mL intravenously on day 1, every 21 days. After completion of four cycles, patients without progression could continue to the maintenance part of the study in which they would be randomized 2:1 to receive nab-paclitaxel 100 mg/m2 intravenously on days 1 and 8 every 21 days plus best supportive care or best supportive care alone until disease progression. Randomization was stratified by disease stage before four cycles of treatment (IIIB vs IV), response at randomization (complete response/partial response [CR/PR] vs stable disease), and performance status at the end of the induction part (0 vs 1). The primary endpoint of the study is progression-free survival, which was measured from the time the patient was randomized at the start of the maintenance portion to the point of progression during the maintenance portion. Secondary endpoints include overall survival from randomization through the maintenance part, ORR during the induction and maintenance parts, and disease control rate over the entire study. Change in patient-reported QoL during the induction and maintenance parts was a prespecified exploratory endpoint.
The Lung Cancer Symptom Scale (LCSS) and the Euro-QoL-5 Dimensions-5 Levels (EQ-5D-5L) questionnaires were used to measure QoL (Figure S1). In this analysis, per protocol, patient-reported QoL was assessed using the LCSS and EQ-5D-5L during four cycles of treatment on day 1 of each cycle through the end of the induction phase (cycle 5 day 1; prior to maintenance treatment). Patients completed the QoL self-assessments in the clinic using digital tablets.
The LCSS is a validated, disease-specific instrument completed by both patients and observers to measure QoL in patients with lung cancer.15 The patient version of the LCSS consists of eight individual questions about lung cancer symptoms (appetite, fatigue, dyspnea, cough, pain, hemoptysis, overall symptom severity, and normal activities) all measured during the past 24 hours, one global question on QoL, one average total score of the nine questions, and one mean score of the six questions on major lung cancer symptoms. Patients answer each question using a visual analog scale (VAS) of 0 to 100 mm, where 0 = best and 100 = worst to indicate the intensity of a symptom. Figure S1 shows the components of the LCSS scores used in this analysis.
The EQ-5D is a generic instrument designed for self-completion that measures the patient’s health today and comprises the EQ-5D and a VAS for overall QoL.16,17 The EQ-5D includes questions on five dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). The answers to each EQ-5D-5L question are based on five qualitative levels (no problems, slight problems, moderate problems, severe problems, or unable to perform the activity). The EQ-5D-5L global index combines each of the five dimensions as a measure of the patient’s global health state. The VAS records the patient’s self-rated status for overall QoL based on a scale of 0 to 100 where 0 = worst and 100 = best.
Lesion response evaluation
Patients had a radiographic evaluation of lesions at the end of cycles 2 and 4. Patients with a CR or PR (by RECIST version 1.1 during the induction phase per the investigator), or those who experienced progressive disease in either evaluation or stable disease in both evaluations, or those who discontinued before or by the end of cycle 4, were considered lesion-response-evaluable.
This analysis included patients who were lesion-response-evaluable during the induction part of the study with available QoL data from baseline and ≥1 postbaseline visit. A clinically meaningful improvement in LCSS or EQ-5D VAS-scaled questions was defined as ≥1 postbaseline score for a given time point that was ≥10 mm higher than the baseline score.3 For statistical analysis purposes, all scales were aligned so that a positive change from baseline indicated improvement. Changes from baseline LCSS and EQ-5D VAS-scaled items were described by descriptive statistics. The percentages of patients who had a clinically meaningful response, of patients who maintained or improved from baseline in the 5 EQ-5D-5L dimensions, and of patients who had complete resolution of a baseline problem at least once during four cycles of treatment are summarized.
Of the 540 patients planned for enrollment into the induction part of the study, 284 patients had been treated as of September 6a, 2016. Of these 284 patients, 246 patients were lesion-response-evaluable. Of the lesion-response-evaluable patients, the median age was 68 years, and 41% of patients were aged ≥70 years. The majority (67%) of patients had a baseline Eastern Cooperative Oncology Group performance status of 1 (Table 1).
(To view a larger version of Table 1, click here.)
Of the 284 patients treated in the induction part, 251 were treated in cycle ≥2 and were eligible to complete ≥1 postbaseline QoL assessment. Of these, 223 (89%) completed baseline and ≥1 postbaseline assessments.