A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer

Background: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. Objective: We aimed to develop alternative dosing regimens to reduce drug expenses. Methods: We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. Results: We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. Conclusions: Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.</p

Global maps of soil temperature

Research in global change ecology relies heavily on global climatic grids derived from estimates of air temperature in open areas at around 2 m above the ground. These climatic grids do not reflect conditions below vegetation canopies and near the ground surface, where critical ecosystem functions occur and most terrestrial species reside. Here, we provide global maps of soil temperature and bioclimatic variables at a 1-km² resolution for 0–5 and 5–15 cm soil depth. These maps were created by calculating the difference (i.e., offset) between in-situ soil temperature measurements, based on time series from over 1200 1-km² pixels (summarized from 8500 unique temperature sensors) across all the world’s major terrestrial biomes, and coarse-grained air temperature estimates from ERA5-Land (an atmospheric reanalysis by the European Centre for Medium-Range Weather Forecasts). We show that mean annual soil temperature differs markedly from the corresponding gridded air temperature, by up to 10°C (mean = 3.0 ± 2.1°C), with substantial variation across biomes and seasons. Over the year, soils in cold and/or dry biomes are substantially warmer (+3.6 ± 2.3°C) than gridded air temperature, whereas soils in warm and humid environments are on average slightly cooler (-0.7 ± 2.3°C). The observed substantial and biome-specific offsets emphasize that the projected impacts of climate and climate change on near-surface biodiversity and ecosystem functioning are inaccurately assessed when air rather than soil temperature is used, especially in cold environments. The global soil-related bioclimatic variables provided here are an important step forward for any application in ecology and related disciplines. Nevertheless, we highlight the need to fill remaining geographic gaps by collecting more in-situ measurements of microclimate conditions to further enhance the spatiotemporal resolution of global soil temperature products for ecological applications

Global maps of soil temperature

Research in global change ecology relies heavily on global climatic grids derived from estimates of air temperature in open areas at around 2 m above the ground. These climatic grids do not reflect conditions below vegetation canopies and near the ground surface, where critical ecosystem functions occur and most terrestrial species reside. Here, we provide global maps of soil temperature and bioclimatic variables at a 1-km2 resolution for 0–5 and 5–15 cm soil depth. These maps were created by calculating the difference (i.e. offset) between in situ soil temperature measurements, based on time series from over 1200 1-km2 pixels (summarized from 8519 unique temperature sensors) across all the world\u27s major terrestrial biomes, and coarse-grained air temperature estimates from ERA5-Land (an atmospheric reanalysis by the European Centre for Medium-Range Weather Forecasts). We show that mean annual soil temperature differs markedly from the corresponding gridded air temperature, by up to 10°C (mean = 3.0 ± 2.1°C), with substantial variation across biomes and seasons. Over the year, soils in cold and/or dry biomes are substantially warmer (+3.6 ± 2.3°C) than gridded air temperature, whereas soils in warm and humid environments are on average slightly cooler (−0.7 ± 2.3°C). The observed substantial and biome-specific offsets emphasize that the projected impacts of climate and climate change on near-surface biodiversity and ecosystem functioning are inaccurately assessed when air rather than soil temperature is used, especially in cold environments. The global soil-related bioclimatic variables provided here are an important step forward for any application in ecology and related disciplines. Nevertheless, we highlight the need to fill remaining geographic gaps by collecting more in situ measurements of microclimate conditions to further enhance the spatiotemporal resolution of global soil temperature products for ecological applications

Global maps of soil temperature.

Research in global change ecology relies heavily on global climatic grids derived from estimates of air temperature in open areas at around 2 m above the ground. These climatic grids do not reflect conditions below vegetation canopies and near the ground surface, where critical ecosystem functions occur and most terrestrial species reside. Here, we provide global maps of soil temperature and bioclimatic variables at a 1-km2 resolution for 0-5 and 5-15 cm soil depth. These maps were created by calculating the difference (i.e. offset) between in situ soil temperature measurements, based on time series from over 1200 1-km2 pixels (summarized from 8519 unique temperature sensors) across all the world's major terrestrial biomes, and coarse-grained air temperature estimates from ERA5-Land (an atmospheric reanalysis by the European Centre for Medium-Range Weather Forecasts). We show that mean annual soil temperature differs markedly from the corresponding gridded air temperature, by up to 10°C (mean = 3.0 ± 2.1°C), with substantial variation across biomes and seasons. Over the year, soils in cold and/or dry biomes are substantially warmer (+3.6 ± 2.3°C) than gridded air temperature, whereas soils in warm and humid environments are on average slightly cooler (-0.7 ± 2.3°C). The observed substantial and biome-specific offsets emphasize that the projected impacts of climate and climate change on near-surface biodiversity and ecosystem functioning are inaccurately assessed when air rather than soil temperature is used, especially in cold environments. The global soil-related bioclimatic variables provided here are an important step forward for any application in ecology and related disciplines. Nevertheless, we highlight the need to fill remaining geographic gaps by collecting more in situ measurements of microclimate conditions to further enhance the spatiotemporal resolution of global soil temperature products for ecological applications

Clinical Pharmacology of Genotype-Directed Anticancer Therapy : Towards Rational Combination Strategies

In the past two decades, a major paradigm shift has taken place in the field of cancer therapy. From non-specific cytotoxic chemotherapy that damages both tumor and normal cells, to more specific targeted agents directed against specific genetically mutated proteins that tumor cells rely on for their uncontrollable expansion. However, although successes have been achieved with this strategy, its major limitation lays in the extensive heterogeneity within tumors. Most tumors harbor multiple oncogenic mutations, making them less dependent on a single driver, acquired resistance may emerge through new mutations, and as many molecular signaling pathways are interconnected, inhibiting one may activate the other. The research described in this thesis mainly focused on novel anticancer agents and combination strategies to improve the anticancer efficacy of the genotype-directed treatment strategy. In this regard, we made great progress for patients with BRAF mutated (BRAFm) colorectal cancer (CRC), a patient group with a very poor prognosis and for whom no effective treatment options are available. Whereas in patients with BRAFm melanoma, pharmacological inhibition of BRAF resulted in dramatic responses and a significant survival benefit compared to standard chemotherapy, the antitumor activity of BRAF inhibitors in patients with BRAFm CRC was disappointing. Preclinical work demonstrated the presence of a negative feedback activation loop that activates the epidermal growth factor receptor (EGFR) and thereby reactivates the MAPK- and phosphoinositide 3-kinase (PI3K) signaling pathways upon BRAF inhibition in BRAF mutated CRC cells, explaining their resistance against single-agent BRAF inhibitor. Following these findings, we investigated the concept of combined BRAF plus EGFR inhibition in human patients for the first time, in multiple clinical phase I/II studies. In these studies, we demonstrated that combinations of BRAF inhibitors plus anti-EGFR antibodies are safe and tolerable, we established the recommended phase II doses, and we obtained early evidence of clinical antitumor activity, showing a promising progression-free survival benefit compared to historical data on the current standard treatment options. A second research focus of this thesis comprised rational combinations of targeted therapy and chemotherapy. Given the critical role of the Wee1 tyrosine kinase in maintaining genomic stability upon DNA damage, inhibition of Wee1 combined with DNA-damaging chemotherapy has become a promising strategy for the treatment of cancer. Because cells that lack a functional p53 protein rely on Wee1 function for DNA repair, p53-deficient tumors are particularly sensitive to Wee1 inhibition combined with chemotherapy. Following our large phase I study in which we investigated the safety of Wee1 inhibitor AZD1775 combined with different chemotherapeutic agents and established the recommended phase II doses, we conducted a proof of concept phase II study with AZD1775 plus carboplatin in patients with p53-deficient platinum-resistant ovarian cancer. The data collected in this study demonstrated encouraging efficacy as AZD1775 plus carboplatin compared favorable to first-line and second-line treatment options in this patient population. Therefore AZD1775 combined with carboplatin could improve clinical outcome in a patient population that has shown poor prognosis and very limited response to currently available treatment options

Clinical Pharmacology of Genotype-Directed Anticancer Therapy: Towards Rational Combination Strategies

In the past two decades, a major paradigm shift has taken place in the field of cancer therapy. From non-specific cytotoxic chemotherapy that damages both tumor and normal cells, to more specific targeted agents directed against specific genetically mutated proteins that tumor cells rely on for their uncontrollable expansion. However, although successes have been achieved with this strategy, its major limitation lays in the extensive heterogeneity within tumors. Most tumors harbor multiple oncogenic mutations, making them less dependent on a single driver, acquired resistance may emerge through new mutations, and as many molecular signaling pathways are interconnected, inhibiting one may activate the other. The research described in this thesis mainly focused on novel anticancer agents and combination strategies to improve the anticancer efficacy of the genotype-directed treatment strategy. In this regard, we made great progress for patients with BRAF mutated (BRAFm) colorectal cancer (CRC), a patient group with a very poor prognosis and for whom no effective treatment options are available. Whereas in patients with BRAFm melanoma, pharmacological inhibition of BRAF resulted in dramatic responses and a significant survival benefit compared to standard chemotherapy, the antitumor activity of BRAF inhibitors in patients with BRAFm CRC was disappointing. Preclinical work demonstrated the presence of a negative feedback activation loop that activates the epidermal growth factor receptor (EGFR) and thereby reactivates the MAPK- and phosphoinositide 3-kinase (PI3K) signaling pathways upon BRAF inhibition in BRAF mutated CRC cells, explaining their resistance against single-agent BRAF inhibitor. Following these findings, we investigated the concept of combined BRAF plus EGFR inhibition in human patients for the first time, in multiple clinical phase I/II studies. In these studies, we demonstrated that combinations of BRAF inhibitors plus anti-EGFR antibodies are safe and tolerable, we established the recommended phase II doses, and we obtained early evidence of clinical antitumor activity, showing a promising progression-free survival benefit compared to historical data on the current standard treatment options. A second research focus of this thesis comprised rational combinations of targeted therapy and chemotherapy. Given the critical role of the Wee1 tyrosine kinase in maintaining genomic stability upon DNA damage, inhibition of Wee1 combined with DNA-damaging chemotherapy has become a promising strategy for the treatment of cancer. Because cells that lack a functional p53 protein rely on Wee1 function for DNA repair, p53-deficient tumors are particularly sensitive to Wee1 inhibition combined with chemotherapy. Following our large phase I study in which we investigated the safety of Wee1 inhibitor AZD1775 combined with different chemotherapeutic agents and established the recommended phase II doses, we conducted a proof of concept phase II study with AZD1775 plus carboplatin in patients with p53-deficient platinum-resistant ovarian cancer. The data collected in this study demonstrated encouraging efficacy as AZD1775 plus carboplatin compared favorable to first-line and second-line treatment options in this patient population. Therefore AZD1775 combined with carboplatin could improve clinical outcome in a patient population that has shown poor prognosis and very limited response to currently available treatment options

Treatment Individualization in Colorectal Cancer

Colorectal cancer has been characterized as a genetically heterogeneous disease, with a large diversity in molecular pathogenesis resulting in differential responses to therapy. However, the currently available validated biomarkers KRAS, BRAF, and microsatellite instability do not sufficiently cover this extensive heterogeneity and are therefore not suitable to successfully guide personalized treatment. Recent studies have focused on novel targets and rationally designed combination strategies. Furthermore, a more comprehensive analysis of the underlying biology of the disease revealed distinct phenotypic differences within subgroups of patients harboring the same genetic driver mutation with both prognostic and predictive relevance. Accordingly, patient stratification based on molecular intrinsic subtypes rather than on single gene aberrations holds promise to improve the clinical outcome of patients with colorectal cancer

Treatment Individualization in Colorectal Cancer

Colorectal cancer has been characterized as a genetically heterogeneous disease, with a large diversity in molecular pathogenesis resulting in differential responses to therapy. However, the currently available validated biomarkers KRAS, BRAF, and microsatellite instability do not sufficiently cover this extensive heterogeneity and are therefore not suitable to successfully guide personalized treatment. Recent studies have focused on novel targets and rationally designed combination strategies. Furthermore, a more comprehensive analysis of the underlying biology of the disease revealed distinct phenotypic differences within subgroups of patients harboring the same genetic driver mutation with both prognostic and predictive relevance. Accordingly, patient stratification based on molecular intrinsic subtypes rather than on single gene aberrations holds promise to improve the clinical outcome of patients with colorectal cancer

Nivolumab exposure in a hemodialysis patient with metastatic melanoma

The effect of intermittent hemodialysis (IHD) on nivolumab serum concentrations in patients with severe renal impairment is largely unknown. Here, we present a 79-year-old patient with metastatic melanoma and end-stage renal disease on IHD three times a week, treated with 480 mg nivolumab every 4 weeks. A serum trough concentration of nivolumab was determined before the start of the third cycle, and two samples were taken immediately before and after a hemodialysis session during this cycle. All nivolumab serum concentrations were within a similar range as those previously measured among patients without renal insufficiency, after a comparable duration of nivolumab treatment. Therefore, we conclude that IHD does not influence nivolumab exposure. Furthermore, nivolumab treatment was continued without complications and appears to be well tolerated for patients on IHD