Projected environmental and public health benefits of extended-interval dosing: an analysis of pembrolizumab use in a US national health system.

BACKGROUND: Health care is a major source of greenhouse gas emissions, leading to climate change and public health harms. Changes are needed to improve the environmental sustainability of health-care practices, but such changes should not sacrifice patient outcomes or financial sustainability. Alternative dosing strategies that reduce the frequency with which specialty drugs are administered, without sacrificing patient outcomes, are an attractive possibility for improving environmental sustainability. We sought to inform environmentally sustainable cancer care by estimating and comparing the environmental and financial effects of alternative, clinically equivalent strategies for pembrolizumab administration. METHODS: We conducted a retrospective analysis using a cohort of patients from the Veterans Health Administration (VHA) in the USA who received one or more pembrolizumab doses between May 1, 2020, and Sept 30, 2022. Using baseline, real-world administration of pembrolizumab, we generated simulated pembrolizumab use data under three near-equivalent counterfactual pembrolizumab administration strategies defined by combinations of weight-based dosing, pharmacy-level vial sharing and dose rounding, and extended-interval dosing (ie, every 6 weeks). For each counterfactual dosing strategy, we estimated greenhouse gas emissions related to pembrolizumab use across the VHA cohort using a deterministic environmental impact model that estimated greenhouse gas emissions due to patient travel, drug manufacture, and medical waste as the primary outcome measure. FINDINGS: We identified 7813 veterans who received at least one dose of pembrolizumab-containing therapy in the VHA during the study period. 59 140 pembrolizumab administrations occurred in the study period, of which 46 255 (78·2%) were dosed at 200 mg every 3 weeks, 12 885 (21·8%) at 400 mg every 6 weeks, and 14 955 (25·3%) were coadministered with infusional chemotherapies. Adoption of weight-based, extended-interval pembrolizumab dosing (4 mg/kg every 6 weeks) and pharmacy-level stewardship strategies (ie, dose rounding and vial sharing) for all pembrolizumab infusions would have resulted in 24·7% fewer administration events than baseline dosing (44 533 events vs 59 140 events) and an estimated 200 metric tons less CO2 emitted per year as a result of pembrolizumab use within the VHA (650 tons vs 850 tons of CO2, a relative reduction of 24%), largely due to reductions in distance travelled by patients to receive treatment. Similar results were observed when weight-based and extended-interval dosing were applied only to pembrolizumab monotherapy and pembrolizumab in combination with oral therapies. INTERPRETATION: Alternative pembrolizumab administration strategies might have environmental advantages over the current dosing and compounding paradigms. Specialty medication dosing can be optimised for health-care spending and environmental sustainability without sacrificing clinical outcomes. FUNDING: None.

Pneumonitis After Chemoradiotherapy and Adjuvant Durvalumab in Stage III Non-Small Cell Lung Cancer.

PURPOSE: Adjuvant durvalumab after definitive chemoradiotherapy (CRT) for unresectable stage III non-small cell lung cancer (NSCLC) is well-tolerated in clinical trials. However, pneumonitis rates outside of clinical trials remain poorly defined with CRT followed by durvalumab. We aimed to describe the influence of durvalumab on pneumonitis rates among a large cohort of patients with stage III NSCLC. METHODS AND MATERIALS: We studied patients with stage III NSCLC in the national Veterans Health Administration from 2015 to 2021 who received concurrent CRT alone or with adjuvant durvalumab. We defined pneumonitis as worsening respiratory symptoms with radiographic changes within 2 years of CRT and graded events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. We used Cox regression to analyze risk factors for pneumonitis and the effect of postbaseline pneumonitis on overall survival. RESULTS: Among 1994 patients (989 CRT alone, 1005 CRT followed by adjuvant durvalumab), the 2-year incidence of grade 2 or higher pneumonitis was 13.9% for CRT alone versus 22.1% for CRT plus durvalumab (unadjusted P < .001). On multivariable analysis, durvalumab was associated with higher risk of grade 2 pneumonitis (hazard ratio, 1.45; 95% CI, 1.09-1.93; P = .012) but not grade 3 to 5 pneumonitis (P = .2). Grade 3 pneumonitis conferred worse overall survival (hazard ratio, 2.51; 95% CI, 2.06-3.05; P < .001) but grade 2 pneumonitis did not (P = .4). CONCLUSIONS: Adjuvant durvalumab use was associated with increased risk of low-grade but not higher-grade pneumonitis. Reassuringly, low-grade pneumonitis did not increase mortality risk. We observed increased rates of high-grade pneumonitis relative to clinical trials; the reasons for this require further study.

Optimizing the doses of cancer drugs after usual dose finding.

Since the middle of the 20th century, oncology's dose-finding paradigm has been oriented toward identifying a drug's maximum tolerated dose, which is then carried forward into phase 2 and 3 trials and clinical practice. For most modern precision medicines, however, maximum tolerated dose is far greater than the minimum dose needed to achieve maximal benefit, leading to unnecessary side effects. Regulatory change may decrease maximum tolerated dose's predominance by enforcing dose optimization of new drugs. Dozens of already approved cancer drugs require re-evaluation, however, introducing a new methodologic and ethical challenge in cancer clinical trials. In this article, we assess the history and current landscape of cancer drug dose finding. We provide a set of strategic priorities for postapproval dose optimization trials of the future. We discuss ethical considerations for postapproval dose optimization trial design and review three major design strategies for these unique trials that would both adhere to ethical standards and benefit patients and funders. We close with a discussion of financial and reporting considerations in the realm of dose optimization. Taken together, we provide a comprehensive, bird's eye view of the postapproval dose optimization trial landscape and offer our thoughts on the next steps required of methodologies and regulatory and funding regimes.

Targeted randomization dose optimization trials enable fractional dosing of scarce drugs.

Administering drug at a dose lower than that used in pivotal clinical trials, known as fractional dosing, can stretch scarce resources. Implementing fractional dosing with confidence requires understanding a drug's dose-response relationship. Clinical trials aimed at describing dose-response in scarce, efficacious drugs risk underdosing, leading dose-finding trials to not be pursued despite their obvious potential benefit. We developed a new set of response-adaptive randomized dose-finding trials and demonstrate, in a series of simulated trials across diverse dose-response curves, these designs' efficiency in identifying the minimum dose that achieves satisfactory efficacy. Compared to conventional designs, these trials have higher probabilities of identifying lower doses while reducing the risks of both population- and subject-level underdosing. We strongly recommend that, upon demonstration of a drug's efficacy, pandemic drug development swiftly proceeds with response-adaptive dose-finding trials. This unified strategy ensures that scarce effective drugs produce maximum social benefits.

Combining atezolizumab 1200 mg with bevacizumab 15 mg/kg: based on science or just revenues?

Dose optimisation is increasingly important in oncology, as exemplified by the US Food and Drug Administration's Project Optimus initiative, which is aligned with similar initiatives in other countries. In parallel, multiple stakeholders have raised concerns about anticancer drug prices, affordability, and access. This is of particular concern to government payers as well as patients and physicians in low- and middle-income countries. As anticancer drugs have historically been approved at the maximally tolerated dose, it is now highly relevant to question whether lower doses are equally effective and can be delivered at lower doses, resulting in less toxicity for patients, and lower costs for patients and payers. We illustrate this opportunity by discussing the combination of atezolizumab and bevacizumab, approved in multiple countries for both non-small cell lung cancer and hepatocellular cancer. Our conclusion is that the cost of this regimen can be reduced by more than 80%, an opportunity that should be considered by patients, prescribers, payers, and policymakers.

Alternative Trastuzumab Dosing Schedules Are Associated With Reductions in Health Care Greenhouse Gas Emissions.

PURPOSE: Cancer care-related greenhouse gas (GHG) emissions harm human health. Many cancer drugs are administered at greater-than-necessary doses, frequencies, and durations. Alternative dosing strategies may enable reductions in cancer care GHG emissions without compromising patient outcomes. MATERIALS AND METHODS: We used streamlined life-cycle analysis in a case-control simulation to estimate the relative reductions in GHG emissions that would be expected to result from using each of three alternative dosing strategies of trastuzumab (6-month adjuvant treatment duration, once every 4-week dosing, and both) in human epidermal growth factor receptor 2 (HER2)+ breast cancer. Using primary data and conversion factors from the environmental science literature, we estimated per-patient relative reduction in GHG emissions and, using SEER data, health impacts (in terms of disability-adjusted life-years [DALYs] and excess mortality per kg CO2) on bystanders for each alternative dosing strategy. RESULTS: Compared with the trastuzumab dosing strategy commonly used at baseline (12-month duration of adjuvant therapy and once every 3-week dosing in all settings), adoption of both 6-month adjuvant trastuzumab and once every 4-week trastuzumab dosing would reduce GHG emissions by 4.5%, 18.7%, and 14.6% in the neoadjuvant, adjuvant, and metastatic settings, respectively. We estimate that US-based adoption of alternative trastuzumab dosing would reduce annual DALYs and excess lives lost due to environmental impact of US-based trastuzumab therapy for HER2+ breast cancer by 1.5 and 0.9, respectively. CONCLUSION: Alternative dosing strategies may materially reduce the population health impacts of cancer care by reducing environmental impact. Regulatory decision making and health technology assessments should consider a treatment's environmental and population health impacts. Clinical trials of alternative dosing strategies are justified on the basis of environmental and population health impacts.

Adopting Weight-Based Dosing With Pharmacy-Level Stewardship Strategies Could Reduce Cancer Drug Spending By Millions.

Immune checkpoint inhibitors, a class of drugs used in approximately forty unique cancer indications, are a sizable component of the economic burden of cancer care in the US. Instead of personalized weight-based dosing, immune checkpoint inhibitors are most commonly administered at "one-size-fits-all" flat doses that are higher than necessary for the vast majority of patients. We hypothesized that personalized weight-based dosing along with common stewardship efforts at the pharmacy level, such as dose rounding and vial sharing, would lead to reductions in immune checkpoint inhibitor use and lower spending. Using data from the Veterans Health Administration (VHA) and Medicare drug prices, we estimated reductions in immune checkpoint inhibitor use and spending that would be associated with pharmacy-level stewardship strategies, in a case-control simulation study of individual patient-level immune checkpoint inhibitor administration events. We identified baseline annual VHA spending for these drugs of approximately $537 million. Combining weight-based dosing, dose rounding, and pharmacy-level vial sharing would generate expected annual VHA health system savings of $74 million (13.7 percent). We conclude that adoption of pharmacologically justified immune checkpoint inhibitor stewardship measures would generate sizable reductions in spending for these drugs. Combining these operational innovations with value-based drug price negotiation enabled by recent policy changes may improve the long-term financial viability of cancer care in the US.

Dose optimisation and scarce resource allocation: two sides of the same coin.

OBJECTIVE: A deep understanding of the relationship between a scarce drug's dose and clinical response is necessary to appropriately distribute a supply-constrained drug along these lines. SUMMARY OF KEY DATA: The vast majority of drug development and repurposing during the COVID-19 pandemic - an event that has made clear the ever-present scarcity in healthcare systems -has been ignorant of scarcity and dose optimisation's ability to help address it. CONCLUSIONS: Future pandemic clinical trials systems should obtain dose optimisation data, as these appear necessary to enable appropriate scarce resource allocation according to societal values.

An evaluation of sotorasib for the treatment of patients with non-small cell lung cancer with KRASG12C mutations.

INTRODUCTION: Improving the clinical outcomes of patients with KRASG12C-mutated non-small cell lung cancer (NSCLC), the majority of whom are current or former smokers, has been a barrier to improving population-level outcomes in NSCLC. Novel and effective KRASG12C inhibitors are emerging, and sotorasib is the first member of that class to achieve commercial availability. AREAS COVERED: In this review, we survey the epidemiology of KRASG12C-mutated NSCLC, as well as sotorasib's chemistry, pharmacology, and clinical trial data. EXPERT OPINION: While sotorasib's development has been unique and exciting, questions persist regarding its intracranial penetrance, optimal dose, and efficacy relative to standard-of-care therapy. Improvements in the clinical activity of KRAS inhibition will hinge on better understanding of resistance mechanisms, the development of broad-spectrum inhibitors with activity beyond G12C mutations, and combination therapy targeting multiple mediators of KRAS signaling and alternative pathways. From a regulatory perspective, sotorasib's development may, in time, prove to be an instructive example for early-phase clinical trialists and regulators focused on dose optimization.

Adoption of Extended-Interval Dosing of Single-Agent Pembrolizumab and Comparative Effectiveness vs Standard Dosing in Time-to-Treatment Discontinuation.

Importance: Extended-interval dosing of pembrolizumab (400 mg every 6 weeks) was approved by US Food and Drug Administration (FDA) in April 2020 as an alternative to standard-interval dosing (200 mg every 3 weeks). Extended-interval dosing may enhance access, alleviate patient and health system financial toxicity, and improve patient quality of life, particularly during the COVID-19 pandemic. Neither adoption nor effectiveness of extended interval in the US has been adequately described. Objective: To describe adoption of extended-interval dosing of pembrolizumab since its FDA approval and to measure its preliminary real-world effectiveness compared with standard-interval dosing. Design, Setting, and Participants: This was a retrospective cohort study that used data from the Veterans Health Administration (VHA), a US-based, nationwide single-payer health system. Participants were veterans who were prescribed single-agent pembrolizumab within the VHA between April 1, 2020, and July 1, 2021. Patients receiving combinations of pembrolizumab and cytotoxic chemotherapy or tyrosine kinase inhibitors were excluded. A subcohort of veterans with non-small cell lung cancer (NSCLC) was also identified using claims-based codes. Exposures: Single-agent pembrolizumab at extended or standard intervals. Main Outcomes and Measures: The number and proportion of single-agent pembrolizumab prescriptions that were extended compared with standard interval. Effectiveness was described in terms of time-to-treatment discontinuation (TTD) and extended- to standard-interval pembrolizumab prescriptions were compared using Cox proportional hazards regression. Results: A total of 835 veterans (mean age [SD], 70.9 [8.7] years; 809 [96.9%] men) began single-agent pembrolizumab during the study period (all-diseases cohort), and of these, 234 (mean [SD] age, 71.6 [7.3] years; 225 [96.2%] men) had NSCLC (NSCLC cohort). Extended-interval adoption reached its steady state plateau of approximately 35% by January 2021; 65% of participants who began standard-interval single-agent pembrolizumab received only standard-interval dosing during the treatment course. In analysis consistent with the intention-to-treat principle, no differences in TTD were observed between standard- and extended-interval dosing in either the all-diseases cohort (HR, 1.00; 95% CI, 1.00-1.00) or the NSCLC cohort (HR, 1.00; 95% CI, 1.00-1.00). Conclusions and Relevance: This retrospective cohort study found that extended-interval dosing comprised a minority of single-agent pembrolizumab prescriptions despite the FDA approval and its potential health system and public health benefits. The findings support the TTD equivalence of standard- and extended-interval pembrolizumab across indications, complementing clinical pharmacology and single-arm clinical trial data in melanoma. This study provides further support for extended-interval pembrolizumab dosing.

De-escalating adjuvant durvalumab treatment duration in stage III non-small cell lung cancer.

BACKGROUND: One year of adjuvant durvalumab following concurrent chemoradiotherapy significantly improves progression-free survival (PFS) and overall survival (OS) for patients with stage III non-small cell lung cancer (NSCLC). However, the optimal length of adjuvant therapy has not been determined. METHODS: We identified patients with stage III NSCLC treated with definitive chemoradiation and adjuvant durvalumab from November 2017 to April 2021 from the United States Veterans Affairs system. Predictors of early durvalumab discontinuation were evaluated with Cox proportional hazards regression. The effect of differing durations of durvalumab treatment (up to 6, 9, and 12 months) on PFS and OS were compared with a marginal structural model and time-dependent Cox modelling. RESULTS: We included 1006 patients with stage III non-small cell lung cancer who received concurrent chemoradiotherapy and at least one dose of adjuvant durvalumab. The median duration of durvalumab treatment was 7 months (interquartile range 2.8-11.5) and 31% completed the intended durvalumab course. The most common reasons for early discontinuation were tumour progression (22%), immune-related adverse events (15%), and non-immune-related toxicity (6.0%), Marginal structural models suggested similar PFS for 9 months versus 12 months of durvalumab treatment and inferior PFS for 6 months versus 12 months. CONCLUSIONS: A substantial proportion of patients undergoing adjuvant durvalumab discontinue therapy early due to toxicity, and shorter durvalumab treatment durations may provide similar disease control to 12 months of therapy. Prospective randomised controlled studies are needed to characterise the optimal durvalumab treatment duration in locally advanced NSCLC patients.

Prognostic and Predictive Role of PD-L1 Expression in Stage III Non-small Cell Lung Cancer Treated With Definitive Chemoradiation and Adjuvant Durvalumab.

PURPOSE: It is unclear whether programmed death ligand 1 (PD-L1) expression is prognostic or predictive of immunotherapy benefit among patients with stage III non-small cell lung cancer (NSCLC) treated with definitive chemoradiation and adjuvant durvalumab. METHODS AND MATERIALS: We determined pretreatment tumor PD-L1 expression for 312 patients with stage III NSCLC treated with definitive chemoradiation and at least 1 dose of adjuvant durvalumab between November 2017 and April 2021 across the national Veterans Health Administration. Progression-free survival (PFS) and overall survival (OS) in PD-L1 expression subgroups (<1%, 1%-49%, and 50%-100%) were compared with 994 patients with stage III NSCLC treated without adjuvant durvalumab from 2015 to 2016. RESULTS: PD-L1 expression was <1%, 1% to 49%, and 50% to 100% in 109 (34.9%), 96 (30.7%), and 107 (34.3%) patients, respectively. Increasing PD-L1 expression was associated with longer PFS (adjusted hazard ratio [aHR], 0.84 per 25% absolute increase in expression; 95% confidence interval [CI], 0.75-0.94; P = .003) and OS (aHR, 0.86 per 25% absolute increase in expression; 95% CI, 0.74-0.99; P = .036). Compared with the no-durvalumab group, PFS was longer for PD-L1 50% to 100% (aHR, 0.44; 95% CI, 0.32-0.60; P < .001) and PD-L1 1% to 49% (aHR, 0.64; 95% CI, 0.47-0.86; P = .003) but not PD-L1 <1% (aHR, 0.84; 95% CI, 0.64-1.10; P = .19). Similar results were found for OS, with no significant difference between the no-durvalumab group and PD-L1 <1% (aHR, 0.81; 95% CI, 0.58-1.13; P = .22). CONCLUSIONS: Increasing tumor PD-L1 expression is prognostic for PFS and OS among patients with stage III NSCLC treated with adjuvant durvalumab, and patients with PD-L1 expression <1% may have limited benefit from adjuvant durvalumab.