Larry Leon

Safety and effectiveness of bevacizumab-containing treatment for non-small-cell lung cancer: final results of the ARIES observational cohort study.

Introduction: Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor, was approved by the US Food and Drug Administration for the treatment of advanced non–small-cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel. ARIES (Avastin Regimens: Investigation of Effectiveness and Safety), a prospective observational cohort study, evaluated outcomes in a large, community-based population of patients with first-line NSCLC. Methods: From 2006 to 2009, ARIES enrolled patients with locally advanced or metastatic NSCLC who were eligible for bevacizumab, excluding those with predominantly squamous histology. Patients were required to provide informed consent and to have initiated bevacizumab with chemotherapy within 4 months before enrollment. There were no protocol-defined treatments or assessments. The dosing of bevacizumab and chemotherapy, and the choice of chemotherapy regimen, was at the discretion of the treating physician. Results: ARIES enrolled 1967 patients with first-line NSCLC. At study closure, median follow-up was 12.5 months (range, 0.2–65.5). Median age was 65 years (range, 31–93), and 252 patients (12.8%) identified as never smokers. Median progression-free survival was 6.6 months (95% confidence interval, 6.3–6.9), and median overall survival was 13.0 months (95% confidence interval, 12.2–13.8) with first-line bevacizumab plus chemotherapy. Incidences of bevacizumab-associated adverse events (19.7% overall) were consistent with those in randomized controlled trials of bevacizumab in NSCLC. Conclusion: Results from ARIES demonstrate similar outcomes to randomized controlled trials of bevacizumab when added to standard chemotherapy in a real-world patient population with advanced NSCLC.

Bevacizumab maintenance in patients with advanced non-small-cell lung cancer, clinical patterns, and outcomes in the eastern cooperative oncology group 4599 study: Results of an exploratory analysis

Introduction: The Eastern Cooperative Oncology Group (ECOG) 4599 study showed a significant survival benefit with the use of bevacizumab (BV) in combination with carboplatin and paclitaxel (CP) in comparison with CP chemotherapy alone in patients with previously untreated advanced, metastatic or recurrent non–small-cell lung cancer (NSCLC). Such results were achieved using BV as maintenance therapy until progressive disease. Because current data on single-agent BV maintenance in non–small-cell lung cancer are limited, we present a retrospective analysis of safety and efficacy outcomes for patients who received maintenance BV after induction treatment and the maintenance-eligible population of the control arm in ECOG 4599. Methods: Landmark analyses were conducted in patients in both the CP and CP+BV groups who were alive and progression free through the completion of six cycles + 21 days. The BV maintenance population consisted of patients in the CP+BV arm, who were alive without progressive disease before the start of maintenance (maintenance-nonprogressor population). CP nonprogressors were those patients in the CP-alone arm without progressive disease after six cycles of CP + 21 days. Results: Two hundred and seventeen patients (51%) were alive, progression free, and eligible for maintenance therapy six cycles + 21 days after induction CP+ BV compared with 134 patients (30%) in the CP-alone arm. Postinduction progression-free survival was significantly longer in the BV maintenance group relative to CP nonprogressors (4.4 versus 2.8 months; hazards ratio [HR] 0.64; p < 0.001). One-year overall survival rates were 75% for the BV maintenance group versus 69% in the CP nonprogressor group. Two-year overall survival rates were 34% for the BV maintenance group versus 25% in the CP nonprogressor group. Median postinduction overall survival (OS) was also significantly longer for the BV-maintenance group compared with CP nonprogressors (12.8 versus 11.4 months; HR 0.75; p = 0.030). Within the subgroup having complete response or partial response after induction, the progression-free survival and OS hazard ratio estimates were 0.59 (95% [confidence interval] CI: 0.41–0.84) and 0.78 (95% CI: 0.53–1.14), respectively. In the maintenance setting, BV was associated with a less-than 1% rate of grade 3 or 4 hematological toxicities, no grade 3 or 4 nausea, vomiting or diarrhea, and no grade 5 toxicities. Conclusions: In this retrospective analysis of patients in the ECOG 4599 study, who were alive, progression free, and on-study 21 days after six cycles of induction therapy, significant reductions in HRs for progression (0.64, p < 0.001) and survival (0.75, p = 0.03) were associated with BV treatment during induction and maintenance compared with CP induction therapy alone and suggestive of possible benefit because of bevacizumab maintenance.

Isolating the Role of Bevacizumab in Elderly Patients With Previously Untreated Nonsquamous Non–small Cell Lung Cancer: Secondary Analyses of the Ecog 4599 and Pointbreak Trials

Background:Patient-level data from 2 phase III studies in patients with previously untreated, advanced-stage, nonsquamous non–small cell lung cancer (NSCLC) were pooled to examine outcomes with bevacizumab and chemotherapy based on age. Methods:Data from patients randomized to paclitaxel–carboplatin (PC)+bevacizumab in the Eastern Cooperative Oncology Group 4599 (E4599) and PointBreak studies were pooled and compared with E4599 patients randomized to PC alone. Patients were grouped by age: below 65, 65 to 74, 70 to 74, below 75, and 75 years or above. A multivariable model was used to calculate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) using time-to-event outcomes. Adverse events (AEs) were assessed by age group in each study. Results:The PC+bevacizumab and PC arms comprised 901 and 444 patients, respectively. PC+bevacizumab was associated with significant increases in overall survival relative to PC in patients below 65 years (hazards ratio [HR], 0.75; 95% confidence interval [CI], 0.62-0.89), 65 to 74 years (HR, 0.80; 95% CI, 0.64-1.00), 70 to 74 years (HR, 0.68; 95% CI, 0.48-0.96), and below 75 years (HR, 0.78; 95% CI, 0.68-0.89) but not in those aged 75 years or above (HR, 1.05; 95% CI, 0.70-1.57). Increased incidence of grade ≥3 AEs was reported with PC+bevacizumab versus PC in patients below 75 years (63% vs. 48%; P<0.05) and 75 years or above (81% vs. 56%; P <0.05) in E4599. Conclusions:This analysis suggests that the survival benefits associated with PC+bevacizumab extend to patient subgroups below 75 years with advanced-stage NSCLC; no benefit, however, was observed for bevacizumab-eligible patients who were 75 years or above.

FIR: Efficacy, Safety, and Biomarker Analysis of a Phase II Open-Label Study of Atezolizumab in PD-L1–Selected Patients With NSCLC

Introduction: The FIR phase II study (NCT01846416) evaluated the efficacy and safety of anti–programmed death‐ligand 1 (PD‐L1) atezolizumab in advanced NSCLC selected by tumor cell (TC) or tumor‐infiltrating immune cell (IC) PD‐L1 expression. Methods: Patients with PD‐L1 TC2/3 (PD‐L1 staining on ≥5% of TC) or IC2/3 tumors (PD‐L1 staining on ≥5% of IC; determined by SP142 PD‐L1 immunohistochemistry assay) with paired fresh and archival histology samples were recruited into cohort 1 (chemotherapy‐naive/>6 months between adjuvant chemotherapy and recurrence), cohort 2 (≥ second‐line without brain metastases), or cohort 3 (≥ second‐line with treated brain metastases). Patients received 1200 mg atezolizumab on day 1 (21‐day cycles). Primary endpoint was investigator‐assessed modified Response Evaluation Criteria in Solid Tumors, objective response rate (Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints were overall survival, progression‐free survival, duration of response, and safety. Results: Patients (N = 138) were enrolled (137 evaluable for response: cohort 1, n = 31; cohort 2, n = 93; and cohort 3, n = 13). Investigator‐assessed objective response rate was 32%, 21%, and 23% for cohorts 1, 2, and 3, respectively. Treatment‐related adverse events were reported in 81%, 67%, and 69% of patients, respectively, including grade 3–4 treatment‐related adverse events in 16%, 19%, and 15%, respectively. Moreover, 88.6% (86 of 97) paired baseline tumor samples had <5% change in TC/IC PD‐L1 expression over time. Conclusions: Atezolizumab monotherapy showed clinical activity in patients with NSCLC, including those with brain metastases; safety was consistent with previous trials. Atezolizumab has completed phase III monotherapy studies in second‐line. Front‐line trials are ongoing, confirming these favorable results.

Estimation of treatment effects in weighted log-rank tests

Non-proportional hazards have been observed in clinical trials. The log-rank test loses power and the standard Cox model generally produces biased estimates under such conditions. Weighted log-rank tests have been utilized to increase the test power; however, it is not intuitive how to interpret the test result in terms of the clinical effect. We propose a Cox-model based time-varying treatment effect estimate to complement the weighted log-rank test. The score test from the proposed model is equivalent to the weighted log-rank test, and a time-profile of the treatment effect can be obtained by fitting a time-varying covariate Cox model. Simulation results show that the proposed model preserves type-I error and achieve higher power than log-rank tests under non-proportional hazards scenarios. Whereas the standard Cox model produces biased effect estimates, the proposed model produces unbiased estimates if the weight function is correctly specified. It also achieves a better model fit and an enhanced flexibility to accommodate non-proportional hazards compared to the standard Cox model. The proposed approach makes the assumptions of the weighted log-rank test explicit and the validity of assumptions can be assessed based on prior knowledge or model goodness-of-fit. It also helps to translate the weighted log-rank test results into quantitative estimates of the treatment effect with intuitive interpretation. The proposed method can be routinely conducted to complement weighted log-rank tests, especially in the setting where non-proportional hazards are expected.

Effectiveness of bevacizumab exposure beyond disease progression in patients with non-small-cell lung cancer: analyses of the ARIES observational cohort study.

Bevacizumab used in combination with first‐line chemotherapy confers an overall survival (OS) benefit for patients with non‐squamous non–small‐cell lung cancer (NSCLC). This analysis from the ARIES observational cohort study (OCS) was initiated to evaluate the effect of bevacizumab use beyond disease progression (BBP) on clinical outcomes in patients with NSCLC receiving first‐line treatment with bevacizumab and chemotherapy.