Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib. (Funded by GlaxoSmithKline Pharmaceuticals; COMPARZ ClinicalTrials.gov number, NCT00720941.).

Regulatory approval of new therapies often depends on demonstrating prolonged survival.Particularly when these survival benefits are modest, consideration of therapeutic benefits to patient-reported outcomes (PROs) may add value to the traditional biomedical clinical trial endpoints. We extend a popular class of joint models for longitudinal and survival data to accommodate the excessive zeros common in PROs, building hierarchical Bayesian models that combine information from longitudinal PRO measurements and survival outcomes. Model development is motivated by a clinical trial for malignant pleural mesothelioma, a rapidly fatal form of pulmonary cancer usually associated with asbestos exposure. By separately modeling the presence and severity of PROs, using our zero-augmented beta likelihood, we are able to model PROs on their original scale and learn about individual-level parameters from both presence and severity of symptoms. Correlations among an individual's PROs and survival are modeled using latent random variables, adjusting the fitted trajectories to better accommodate the observed data for each individual. This work contributes to understanding the impact of treatment on two aspects of mesothelioma: patients' subjective experience of the disease process and their progression-free survival times. We uncover important differences between outcome types that are associated with therapy (periodic, worse in both treatment groups after therapy initiation) and those that are responsive to treatment (aperiodic, gradually widening gap between treatment groups). Finally, our work raises questions for future investigation into multivariate modeling, choice of link functions, and the relative contributions of multiple data sources in joint modeling contexts.

Purpose Anti-human epidermal growth factor receptor 2 (HER2) therapies are associated with interstitial lung disease (ILD), also referred to as pneumonitis. In this literature review, we describe the incidence of ILD among patients with HER2-positive metastatic breast cancer (MBC) receiving anti-HER2 therapies, and we describe existing recommendations for monitoring and managing drug-induced ILD among these patients. Methods We searched PubMed and Embase to identify clinical trials and postmarket observational studies that investigated anti-HER2 therapies for HER2-positive MBC, reported on ILD, and were published during January 1, 2009 to July 15, 2019. Articles were screened by two researchers; data were extracted from the full-text articles. Results The 18 articles selected for this review assessed 9,886 patients who received trastuzumab (8 articles), lapatinib (4 articles), trastuzumab emtansine (3 articles), trastuzumab deruxtecan (2 articles), or trastuzumab duocarmazine (1 article). The overall incidence of all-grade ILD was 2.4% (n = 234), with 66.7% (n = 156) occurring as grade 1-2 events, 0.5% grade 3-4 (n = 54; incidence), and 0.2% grade 5 (n = 16; incidence). The highest ILD incidence (21.4%) was among patients receiving trastuzumab combined with everolimus and paclitaxel. Ten studies indicated that ILD events were managed via dose interruption, dose reduction, or treatment discontinuation; two studies included detailed guidelines on managing druginduced ILD. Conclusions ILD is a well-described adverse drug reaction associated with several anti-HER2 drugs. Published ILD management guidelines are available for few anti-HER2 treatment regimens; however, guidance for monitoring for anti-HER2 drug-induced ILD is lacking.

BACKGROUND In a phase 3, randomized, open-label trial (COMPARZ; NCT00720941), pazopanib was found to be non-inferior to sunitinib in terms of progression-free survival in patients with metastatic renal cell carcinoma with no prior therapy. Overall treatment differences were evaluated in a post hoc analysis using a quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TWiST) methodology. METHODS Each patient’s overall survival was partitioned into 3 mutually exclusive health states: grade 3 or 4 toxicity (TOX), time without symptoms of disease or grade 3/4 toxicity (TWiST), and time after progression or relapse (REL). Time spent in each state was weighted by a health-state utility associated with that state and summed to calculate the Q-TWiST. A threshold utility analysis was used, applying utilities across the range of 0 (similar to death) to 1 (perfect health). RESULTS A total of 1,110 patients were enrolled (557 pazopanib, 553 sunitinib). The mean time spent with TOX was 31 days (95% confidence interval, 13–49) higher for sunitinib compared with pazopanib. In the threshold utility analysis, the difference in Q-TWiST ranged from -11 days (utility TOX=1, REL=0) to 43 days (TOX=0, REL=1), in favor of pazopanib across most utility combinations. Differences were significant in less than half of the utility combinations examined, typically when the utility for TOX was lower than the utility for REL. CONCLUSIONS Patients randomized to pazopanib had slightly longer Q-TWiST compared with sunitinib patients, primarily due to a reduced length of time spent with grade 3/4 toxicities.