Analysis of time-to-treatment discontinuation of targeted therapy, immunotherapy, and chemotherapy in clinical trials of patients with non-small-cell lung cancer.

BACKGROUND: Pragmatic end points, such as time-to-treatment discontinuation (TTD), defined as the date of starting a medication to the date of treatment discontinuation or death has been proposed as a potential efficacy end point for real-world evidence (RWE) trials, where imaging evaluation is less structured and standardized. PATIENTS AND METHODS: We studied 18 randomized clinical trials of patients with metastatic non-small-cell lung cancer (mNSCLC), initiated after 2007 and submitted to U.S. Food and Drug Administration. TTD was calculated as date of randomization to date of discontinuation or death and compared to progression-free survival (PFS) and overall survival (OS) across all patients, as well as in treatment-defined subgroups [EGFR mutation-positive treated with tyrosine kinase inhibitor (TKI), EGFR wild-type treated with TKI, ALK-positive treated with TKI, immune checkpoint inhibitor (ICI), chemotherapy doublet with maintenance, chemotherapy monotherapy]. RESULTS: Overall across 8947 patients, TTD was more closely associated with PFS (r = 0.87, 95% CI 0.86-0.87) than with OS (0.68, 95% CI 0.67-0.69). Early TTD (PFS-TTD ≥ 3 months) occurred in 7.7% of patients overall, and was more common with chemo monotherapy (15.0%) while late TTD (TTD-PFS ≥ 3 months) occurred in 6.0% of patients overall, and was more common in EGFR-positive and ALK-positive patients (12.4% and 22.9%). In oncogene-targeted subgroups (EGFR positive and ALK positive), median TTDs (13.4 and 14.1 months) exceeded median PFS (11.4 and 11.3 months). CONCLUSIONS: At the patient level, TTD is associated with PFS across therapeutic classes. Median TTD exceeds median PFS for biomarker-selected patients receiving oncogene-targeted therapies. TTD should be prospectively studied further as an end point for pragmatic randomized RWE trials only for continuously administered therapies.

Age-related differences in patient-reported outcomes in patients with advanced lung cancer receiving anti-PD-1/PD-L1 therapy.

BACKGROUND: Older adults with lung cancer often have comorbidities that may increase risk of symptomatic adverse events (AEs) and physical function decline. The objective of this study was to examine age-related differences in patient-reported symptoms and functional domains in patients with advanced lung cancer receiving immunotherapy drugs. METHODS: Three randomized controlled trials of anti-programmed death receptor-1/programmed death-ligand 1 therapy in patients with advanced non-small cell lung cancer that included patient-reported outcomes (PROs) were identified. Baseline PRO data were pooled for treatment arms from 2 trials that included the same PRO tools. Age-related differences in baseline mean scores for each of the health-related quality of life functional and symptom scales were assessed for patients ≥70 years and <70 years. Mean change from Baseline at 3 months was also calculated and plotted for each age group. The adequacy of PRO assessments was assessed by comparing clinician-reported AE data in the 3 trials to the item content of the PRO tools included. RESULTS: Across the 3 trials, 75 of patients were under 70 and 26% patients were 70 and older. Comparing baseline scores in the 2 trials with the same PRO tool, older adults reported small differences including lower physical functioning, less pain, insomnia and financial difficulties, and higher social functioning than younger patients at baseline. No large differences in the distributions of mean change from baseline in function or symptom were identified. Several common clinician-reported symptomatic AEs were not assessed by the PRO strategy employed in the 3 trials. Three clinician-reported symptomatic AEs (rash, fever, and pruritus) that were commonly reported in the safety data (9%-19%) were not assessed using the PRO tools employed. CONCLUSION: While several small differences were seen, there did not appear to be large differences at baseline or in the distributions of change from baseline in PRO functional domains between younger and older patients with lung cancer undergoing anti-programmed death receptor -1/programmed death-ligand 1 therapy. Relevant symptomatic side effects were not assessed by PRO measures in these trials, and this is a limitation of current PRO assessment strategies.

Exploratory analysis of the association of depth of response and survival in patients with metastatic non-small-cell lung cancer treated with a targeted therapy or immunotherapy.

BACKGROUND: Response Evaluation Criteria in Solid Tumors (RECIST) permits rapid evaluation of new therapeutic strategies in cancer. However, RECIST does not capture the heterogeneity of response in highly active therapies. Depth of tumor response may provide a more granular view of response. We explored the association between, depth of response (DepOR), with overall survival (OS) and progression-free survival (PFS) for patients with NSCLC being treated with an ALK inhibitor (ALKi) or an anti-PD-1 antibody (Ab). METHODS: Experimental arms from two randomized controlled trials (RCTs) of an ALKi and two RCTs of an anti-PD-1 Ab were separately pooled. Patient responses were grouped into DepOR 'quartiles' by percentage of maximal tumor shrinkage (Q1 = 1%-25%, Q2 = 26%-50%, Q3 = 51%-75%, and Q4 = 76%-100%), Q0 had no shrinkage. We carried out a retrospective exploratory responder analysis to evaluate the association between DepOR and OS or PFS using hazard ratios (HR) generated by the Cox proportional hazards model. RESULTS: In the pooled ALK analysis there were 12, 39, 70, 144, and 40 patients in quartiles 0-4, respectively. The DepOR versus PFS/OS analyses HR were: 0.19/0.94 for Q1 0.11/0.56 for Q2, 0.05/0.28 for Q3, and 0.03/0.05 for Q4. In the PD-1 trials within quartiles 0-4 there were 168, 70, 44, 45, and 28 patients, respectively. The DepOR versus PFS/OS analyses HR were 0.3/0.52 for Q1, 0.22/0.47 for Q2, 0.09/0.07 for Q3, and 0.07/0.14 for Q4. CONCLUSIONS: Our analysis suggests a greater DepOR is associated with longer PFS and OS for patients receiving ALKi or anti-PD1 Ab. Overall, this suggests that DepOR may provide an additional outcome measure for clinical trials, and may allow better comparisons of treatment activity.

Collaborating to Compete: Blood Profiling Atlas in Cancer (BloodPAC) Consortium.

The cancer community understands the value of blood profiling measurements in assessing and monitoring cancer. We describe an effort among academic, government, biotechnology, diagnostic, and pharmaceutical companies called the Blood Profiling Atlas in Cancer (BloodPAC) Project. BloodPAC will aggregate, make freely available, and harmonize for further analyses, raw datasets, relevant associated clinical data (e.g., clinical diagnosis, treatment history, and outcomes), and sample preparation and handling protocols to accelerate the development of blood profiling assays.

Drug Development, Trial Design, and Endpoints in Oncology: Adapting to Rapidly Changing Science.

As a result of enhanced understanding of genetic and immunologic underpinnings of cancer, there has been progress in development of targeted and immunotherapies in oncology. The traditional linear sequential model of drug development has evolved. Early clinical trials of breakthrough therapies often include expansion cohorts, termed "seamless drug development." The US Food and Drug Administration (FDA) uses expedited programs, such as breakthrough designation and accelerated approval ensuring that transformative therapies are available to patients earlier in the cycle of evidence generation.

The role of nonrandomized trials in the evaluation of oncology drugs.

Although randomized trials provide the most reliable evidence of a drug's safety and efficacy, there are situations where randomized trials are not possible or ethical. In this article we discuss when and how single-arm trials can be used to support full approval of oncology drugs. These include situations in which an unprecedented effect on tumor response is observed in a setting of high unmet medical need, clinical trial patients have been well characterized, enabling a target population to be clearly defined, experience exists in a sufficient number of patients to allow adequate assessment of the risk:benefit relationship, and a proper historical context can be provided for analysis. We also discuss how response rates might be considered predictive of long-term outcomes or clinically meaningful in and of themselves in certain contexts.

Development of a physiologically based pharmacokinetic model of 2-methoxyethanol and 2-methoxyacetic acid disposition in pregnant rats.

An accurate description of developing embryos' exposure to a xenobiotic is a desirable component of mechanism-based risk assessments for humans exposed to potential developmental toxicants during pregnancy. 2-Methoxyethanol (2-ME), a solvent used in the manufacture of semiconductors, is embryotoxic and teratogenic in all species tested including nonhuman primates. 2-Methoxyacetic acid (2-MAA) is the primary metabolite of 2-ME and the proximate embryotoxic agent. The objective of the work described here was to adapt an existing physiologically based pharmacokinetic (PBPK) model for 2-ME and 2-MAA kinetics during midorganogenesis in mice to rats on gestation days (GD) 13 and 15. Blood and tissue data were analyzed using the extrapolated PBPK model that was modified to simulate 2-ME and 2-MAA kinetics in maternal plasma and total embryo tissues in pregnant rats. The original mouse model was simplified by combining the embryos and placenta with the richly perfused tissue compartment. The model includes a description of the growth of the developing embryo and changes in the physiology of the dam during pregnancy. Biotransformation pathways of 2-ME to either ethylene glycol (EG) or to 2-MAA were described as first-order processes based on the data collected from rats by Green et al., (Occup. Hyg. 2, 67-75, 1996). Tissue partition coefficients (PCs) for 2-ME and 2-MAA were determined for a variety of maternal tissues and the embryos. Model simulations closely reflected the biological measurement of 2-ME and 2-MAA concentrations in blood and embryo tissue following gavage or iv administration of 2-ME or 2-MAA. The PBPK model for rats as described here is well suited for extrapolation to pregnant women and for assessment of 2-MAA dosimetry under various conditions of possible human exposure to 2-ME.

A mathematical model of production, distribution, and metabolism of melatonin in mammalian systems.

Melatonin is a neuroendocrine hormone which is currently receiving considerable attention as a treatment for jet lag, a treatment for insomnia and, by some, a possible "magic bullet" for delaying the effects of aging and preventing cancer. Production of melatonin is focused primarily in the pineal gland with very wide daily shifts in production controlled by the day/night cycle. The potential for increased disease as a consequence of lower or higher than average production of this hormone has not been well studied, although potential environmental agents may modulate circulating levels (e.g., electric and magnetic fields). In this manuscript, a physiologically realistic mathematical model for the production, distribution, and metabolism of melatonin is developed as a precursor to a future study of the role of chemicals and environmental agents in altering this system. Values for key aspects of the system (e.g., diurnal rates of production of the hormone in the pineal gland) were obtained from the literature and the model was validated against data on circulating levels. The mathematical equations and model parameters are presented.

Development of a physiologically based pharmacokinetic model to describe the disposition of methanol in pregnant rats and mice.

Physiologically based pharmacokinetic (PBPK) models have been developed in recent years to describe the disposition of xenobiotics during gestation. These models can account for the dynamics of physiologic changes associated with pregnancy and represent a significant advantage in quantitatively assessing potential exposure of the conceptus. The PBPK approach was used to develop a model of methanol disposition during gestation in rats and mice. To validate this model, concentrations of methanol in the dam and the conceptus were determined after methanol exposure of rats on Gestational Day (gd) 14 and 20 and of mice on gd 18. At the developmental stages examined, the model provided a good description of methanol disposition in the maternal circulation and the conceptus of both species. Furthermore, the model was capable of providing good fits to methanol concentration-time data from the literature. In pregnant animals, conceptal/maternal AUC and Cmax ratios decreased with increasing dose at both gd 14 and gd 20 in the rat and at gd 18 in the mouse. Additionally, the conceptal/maternal diffusion constant ratio consistently decreased with increasing dose in pregnant rats and mice. These results are consistent with earlier observations that methanol limits its own delivery to the conceptus. Further experimentation is required to continue the process of developing a generalized PBPK model to describe the disposition of xenobiotics in pregnancy, to examine specific mechanisms of nonlinear conceptal methanol disposition, and to expand the model to extrapolate to low-dose human exposures.

Physiologically based pharmacokinetic models applicable to organogenesis: extrapolation between species and potential use in prenatal toxicity risk assessments.

A physiologically based pharmacokinetic (PBPK) model describing the disposition of 2-methoxyacetic acid (2-MAA; the proximate toxicant derived from oxidation of the ethylene glycol ether, 2-methoxyethanol) was developed in pregnant rodents. This model was validated with pharmacokinetic (PK) data from dams and embryos during major organogenesis. A physiological model of human pregnancy was then combined with the PBPK model and linked to an empirical 2-MAA PK model with 2 maternal compartments and a single or multiple conceptus compartment, depending on the developmental stage. This approach is intended to allow more realistic human pregnancy risk assessments by refining the reference dose calculations via uncertainty factors. It will be possible to eliminate an uncertainty factor of 10 for interspecies extrapolations in the 2-methoxyethanol risk assessment if the PBPK model described here is used.

Toxicokinetics of a single 50 mg/kg oral dose of [2,3-14C]acrylamide in White Leghorn hens.

A single oral dose of [2,3-14C]acrylamide (50 mg/kg) was administered in water to adult white leghorn hens. Seven groups of three hens were euthanized between 2 and 120 hr after administration. Within 12 hr, the hens excreted 70% of the administered dose, and more than 99% within 48 hr. Blood, plasma, liver, and muscle contained the greatest percentage of administered dose at 4 hr after dosing. Less than 0.02% of the administered dose appeared in brain at any time. Radiolabel accumulated in the eggs, with 0.52% of the administered dose accumulated within 5 days. Binding of radiolabel to erythrocytes was minimal. Elimination of radiolabel from all tissues was biphasic. Terminal elimination half-lives for 14C were longer than 10 days, at which time less than 0.2% of the administered dose remains in the tissues. Distribution half-lives for 14C were longest for whole blood and shortest for kidney. Radioactivity in the blood and plasma reached a peak at between 4 and 12 hr. Most of this radioactivity was identified as acrylamide, which disappeared biexponentially with terminal elimination half-lives longer than 10 days. Distribution half-lives for acrylamide were longest in brain and shortest in whole blood. These results show that orally administered acrylamide is poorly absorbed and rapidly eliminated from hens and accumulates in their eggs in a nonextractable form.