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Osimertinib is prescribed to patients with metastatic non‐small cell lung cancer (NSCLC) and a sensitizing EGFR mutation. Limited data exists on the impact of patient characteristics or osimertinib exposure on effectiveness outcomes. This was a Dutch, multicenter cohort study. Eligible patients were ≥18 years, with metastatic EGFRm+ NSCLC, receiving osimertinib. Primary endpoint was progression‐free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Kaplan‐Meier analyses and multivariate Cox proportional hazard models were performed. In total, 294 patients were included. Primary EGFR‐mutations were mainly exon 19 deletions (54%) and p.L858R point mutations (30%). Osimertinib was given in first‐line (40%), second‐line (46%) or beyond (14%), with median PFS 14.4 (95% CI: 9.4‐19.3), 13.9 (95% CI: 11.3‐16.1) and 8.7 months (95% CI: 4.6‐12.7), respectively. Patients with low BMI (<20.0 kg/m2) had significantly shorter PFS/OS compared to all other subgroups. Patients with a high plasma trough concentration in steady state (Cmin,SS; >271 ng/mL) had shorter PFS compared to a low Cmin,SS (<163 ng/mL; aHR 2.29; 95% CI: 1.13‐4.63). A significant longer PFS was seen in females (aHR = 0.61, 95% CI: 0.45‐0.82) and patients with the exon 19 deletion (aHR = 0.58, 95% CI: 0.36‐0.92). A trend towards longer PFS was seen for TP53 wild‐type patients, while age did not impact PFS. Patients with a primary EGFR exon 19 deletion had longer PFS, while a low BMI, male sex and a high Cmin,SS were indicative for shorter PFS and/or OS. Age was not associated with effectiveness outcomes of osimertinib. [ABSTRACT FROM AUTHOR]

Background The risk for thromboembolisms in nonsmall cell lung cancer (NSCLC) patients is increased and often requires treatment or prophylaxis with direct oral anticoagulants (DOACs). Small-molecule inhibitors (SMIs) to treat NSCLC may cause relevant drug-drug interactions (DDIs) with DOACs. Guidance on how to combine these drugs is lacking, leaving patients at risk of clotting or bleeding. Here, we give practical recommendations to manage these DDIs. Methods For all DOACs and SMIs approved in Europe and the USA up to December 2021, a literature review was executed and reviews by the US Food and Drug Administration and European Medicines Agency were analysed for information on DDIs. A DDI potency classification for DOACs was composed and brought together with DDI characteristics of each SMI, resulting in recommendations for each combination. Results Half of the combinations result in relevant DDIs, requiring an intervention to prevent ineffective or toxic treatment with DOACs. These actions include dose adjustments, separation of administration or switching between anticoagulant therapies. Combinations of SMIs with edoxaban never cause relevant DDIs, compared to more than half of combinations with other DOACs and even increasing to almost all combinations with rivaroxaban. Conclusions Combinations of SMIs and DOACs often result in relevant DDIs that can be prevented by adjusting the DOAC dosage, separation of administration or switching between anticoagulants. [ABSTRACT FROM AUTHOR]

Pazopanib and axitinib are both U.S. Food and Drug Administration approved ATP-competitive inhibitors of the vascular endothelial growth factor receptor. Pazopanib and axitinib have been shown to be effective and tolerable treatment options for patients with metastatic renal cell cancer and therefore have enlarged the armamentarium for this disease. This concise drug review discusses the clinical benefits, clinical use, mechanism of action, bioanalysis, pharmacokinetics, pharmacogenetics, pharmacodynamics, drug resistance, toxicity, and patient instructions and recommendations for supportive care for these two drugs. [ABSTRACT FROM AUTHOR]

Introduction: Brain metastases (BM) are common in patients with advanced EGFR -mutated ( EGFR m+) NSCLC. Despite good BM-related outcomes of osimertinib, several patients still experience intracranial progression. A possible explanation is pharmacologic failure due to low plasma trough levels (C min,SS ) and consequently limited intracranial osimertinib exposure. We investigated the relation between osimertinib C min,SS and BM development or progression., Methods: A prospective multicenter cohort study, including patients receiving osimertinib for advanced EGFR m + NSCLC. At osimertinib start, patients were allocated to the BM or no or unknown BM cohort and were further divided into subgroups based on osimertinib C min,SS (low, middle, and high exposure). Cumulative incidence of BM progression or development and overall survival were determined for each group., Results: A total of 173 patients were included, with 49 (28.3%) had baseline BM. Of these patients, 36.7% experienced BM progression, of which 16.7% in the low (<159.3 ng/mL), 40.0% in the middle, and 47.1% in the high (>270.7 ng/mL) C min,SS subgroups. After 12 months, the cumulative incidence of BM progression for the BM cohort was 20% (95% confidence interval [CI] 2.6-49.0), 31% (95% CI:10.6-53.9), and 31% (95% CI:10.8-54.5) per C min,SS subgroup, respectively. After 20 months, this was 20% (95% CI:2.6-49.0), 52% (95% CI:23.8-74.2), and 57% (95% CI:24.9-79.7), respectively. For the no or unknown BM cohort, 4.0% developed BM without differences within C min,SS subgroups., Conclusions: No relation was found between osimertinib C min,SS and BM development or progression in patients with advanced EGFR m + NSCLC. This suggests that systemic osimertinib exposure is not a surrogate marker for BM development or progression., Competing Interests: Dr. Veerman reports receiving payment or honoraria for lectures from Eli Lilly (payed to the institute). Dr. Steendam reports receiving an unrestricted research grant from AstraZeneca (payed to the institute), payment or honoraria for lectures from Academic Pharmaceutical, supporting for attending meetings from Eli Lilly and Rochte and fullfilling unpaid roles at NVALT and CieBOD. Prof. dr. Mathijssen reports receiving grants of contracts for investigator initiated research from Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi and Sevier (all payed to the institute). Prof. dr. Tjan-Heijnen reports receiving grants or contracts from Pfizer, Novartis, Eli Lilly, Gilead, Roche, AstraZeneca and Daiichi Sankyo (all payed to the institute), and receiving consulting fees from Eli Lilly, Novartis and AstraZeneca. Drs. Dursun reports receiving payment or honoraria a presentation at Novartis. Prof. dr. Smit reports receiving grants or contracts from AstraZeneca and Daiichi Sankyo (payed to the institute), receiving consulting fees from AstraZeneca, BMS, Boehringer-Ingelheim, Daiichi Sankyo, Sanofi, Eli Lilly, Roche Genentech, Merck, Novartis, Pfizer, Takeda and Taiho (all payed to the institute), participation on a data safety monitoring board or advisory board from DSI and Taiho and receiving payment of honoraria for lectures from Boehringer-Ingelheim. Prof. dr. Dingemans reports receiving grants or contracts from Amgen, Dutch Cancer Society and HANART (all payed to the institute), receiving consulting fees from AMGEN, Bayer, Boehringer-Ingelheim, Sanofy, Roche, Janssen and AstraZeneca (all payed to the institute), and receiving payment or honoraria for lectures from Janssen, Pfizer, AstraZeneca, Eli Lilly and Takeda (all payed to the institute), participation on a data and safety monitoring board or advisory board from Takeda and Roche and is unpaid char at EORTC LCG. Dr. van Geel reports receiving grants or contracts from Academic Alliance Fund (payed to the institute). Dr. Hendriks reports receiving grants or contracts from Roche Genentech, AstraZeneca, Boehringer-Ingelheim, Takeda, Merck, Pfizer and Novartis (all payed to the institute), receiving payment or honoraria for lectures from MSD, Eli Lilly, Sanofi, GSK and High5oncology (all payed to the institute), and personal payments from Benecke, Medtalks, Medimix, VJOncology, participation on a data safety monitoring board or advisory board from BMS, Eli Lilly, Roche Genetech, Pfizer, Takeda, MSD, Merck, Novartis, Boehringer-Ingelheim, Amgen, Janssen and Anhearts (all payed to the institute), and interview sessions funded by Roche Genentech, Bayer and Eli Lilly (all payed to the institute). All other authors declare no conflict of interest., (© 2024 The Authors.)

Recently, two small molecular inhibitors (SMIs) -adagrasib and sotorasib- have been introduced for targeting Kirsten rat sarcoma (KRAS) p.G12C mutations in patients with non-small cell lung cancer (NSCLC). In order to support pharmacokinetic research as well as clinical decision making, we developed and validated a simple and accurate liquid chromatography-tandem mass spectrometry method for the multiplexed quantification of adagrasib and sotorasib. This assay was co-validated with the quantification for brigatinib, lorlatinib, pralsetinib and selpercatinib. Methanol was used for single-step protein precipitation. Chromatographic separation was performed using an Acquity® HSS C18 UPLC column, with an elution gradient of ammonium formate 0.1 % v / v in water and acetonitrile. In K2-EDTA plasma, adagrasib was found to be stable for at least seven days at room temperature and 4 °C, and at least 3 months at -80 °C. Sotorasib was found to be stable for at least three days at room temperature, seven days at 4 °C and at least 3 months at -80 °C. The method was validated over a linear range of 80-4000 ng/mL for adagrasib and 25-2500 ng/mL for sotorasib. The assay is therefore well-equipped for determining plasma concentrations in clinical practice., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [P.D. Kruithof – No relationship to disclose. J.L. Gulikers – No relationship to disclose. Y.M. de Beer – No relationship to disclose. L.M.L. Stolk – No relationship to disclose. L.E.L. Hendriks – No relationship to disclose in relation to this paper. Outside of this paper: research funding Roche Genentech, Boehringer Ingelheim, AstraZeneca, Takeda, Merck, Pfizer, Novartis, Gilead under negotiation (all institution); advisory board: Amgen, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Takeda, Merck, Janssen, MSD, Anheart (all institution); speaker educationals/webinars: AstraZeneca, Bayer, Lilly, MSD, high5oncology, Takeda, Janssen, GSK, Sanofi, Pfizer (Inst), Medtalks, Benecke, VJOncology, Medimix (self); Member guideline committees: Dutch guidelines on NSCLC, brain metastases and leptomeningeal metastases (self), ESMO guidelines on metastatic NSCLC and SCLC (non-financial); other (non-financial): secretary NVALT studies foundation, subchair EORTC metastatic NSCLC systemic therapy, vice-chair scientific committee Dutch Thoracic Group; local PI of clinical trials: AstraZeneca, GSK, Novartis, Merck, Roche, Takeda, Blueprint, Mirati, Abbvie, Gilead, MSD, Merck (all institution). S. Croes – No relationship to disclose. R.M.J.M. van Geel – No relationship to disclose.]., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAF V600E colorectal cancer models. Patients with refractory BRAF V600 -mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with ( n = 28) or without ( n = 26) a PI3Kα inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose. Dose-limiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment. The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with BRAF -mutant mCRC; confirmed overall response rates of 19% and 18% were observed and median progression-free survival was 3.7 and 4.2 months for the dual- and triple-therapy groups, respectively. Significance: Herein, we demonstrate that dual- (encorafenib plus cetuximab) and triple- (encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with BRAF -mutant mCRC. Cancer Discov; 7(6); 610-9. ©2017 AACR. See related commentary by Sundar et al., p. 558 This article is highlighted in the In This Issue feature, p. 539 ., (©2017 American Association for Cancer Research.)

Purpose AZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. In a phase I study, the maximum tolerated dose of AZD1775 in combination with carboplatin demonstrated target engagement. We conducted a proof-of-principle phase II study in patients with p53 tumor suppressor gene ( TP53)-mutated ovarian cancer refractory or resistant (< 3 months) to first-line platinum-based therapy to determine overall response rate, progression-free and overall survival, pharmacokinetics, and modulation of phosphorylated cyclin-dependent kinase (CDK1) in skin biopsies. Patients and Methods Patients were treated with carboplatin (area under the curve, 5 mg/mL⋅min) combined with AZD1775 225 mg orally twice daily over 2.5 days every 21-day cycle until disease progression. Results AZD1775 plus carboplatin demonstrated manageable toxicity; fatigue (87%), nausea (78%), thrombocytopenia (70%), diarrhea (70%), and vomiting (48%) were the most common adverse events. The most frequent grade 3 or 4 adverse events were thrombocytopenia (48%) and neutropenia (37%). Of 24 patients enrolled, 21 patients were evaluable for efficacy end points. The overall response rate was 43% (95% CI, 22% to 66%), including one patient (5%) with a prolonged complete response. Median progression-free and overall survival times were 5.3 months (95% CI, 2.3 to 9.0 months) and 12.6 months (95% CI, 4.9 to 19.7), respectively, with two patients with ongoing response for more than 31 and 42 months at data cutoff. Conclusion To our knowledge, this is the first report providing clinical proof that AZD1775 enhances carboplatin efficacy in TP53-mutated tumors. The encouraging antitumor activity observed in patients with TP53-mutated ovarian cancer who were refractory or resistant (< 3 months) to first-line therapy warrants further development.

Aims: The enzymatic activity of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are important for the tolerability and efficacy of the fluoropyrimidine drugs. In the present study, we explored between-subject variability (BSV) and circadian rhythmicity in DPD and TS activity in human volunteers., Methods: The BSVs in DPD activity (n = 20) in peripheral blood mononuclear cells (PBMCs) and in plasma, measured by means of the dihydrouracil (DHU) and uracil (U) plasma levels and DHU : U ratio (n = 40), and TS activity in PBMCs (n = 19), were examined. Samples were collected every 4 h throughout 1 day for assessment of circadian rhythmicity in DPD and TS activity in PBMCs (n = 12) and DHU : U plasma ratios (n = 23). In addition, the effects of genetic polymorphisms and gene expression on DPD and TS activity were explored., Results: Population mean (± standard deviation) DPD activity in PBMCs and DHU : U plasma ratio were 9.2 (±2.1) nmol mg(-1) h(-1) and 10.6 (±2.4), respectively. Individual TS activity in PBMCs ranged from 0.024 nmol mg(-1) h(-1) to 0.596 nmol mg(-1) h(-1) . Circadian rhythmicity was demonstrated for all phenotype markers. Between 00:30 h and 02:00 h, DPD activity in PBMCs peaked, while the DHU : U plasma ratio and TS activity in PBMCs showed trough activity. Peak-to-trough ratios for DPD and TS activity in PBMCs were 1.69 and 1.62, respectively. For the DHU : U plasma ratio, the peak-to-trough ratio was 1.43., Conclusions: BSV and circadian variability in DPD and TS activity were demonstrated. Circadian rhythmicity in DPD might be tissue dependent. The results suggested an influence of circadian rhythms on phenotype-guided fluoropyrimidine dosing and supported implications for chronotherapy with high-dose fluoropyrimidine administration during the night., (© 2016 The British Pharmacological Society.)

Although recent clinical trials of BRAF inhibitor combinations have demonstrated improved efficacy in BRAF-mutant colorectal cancer, emergence of acquired resistance limits clinical benefit. Here, we undertook a comprehensive effort to define mechanisms underlying drug resistance with the goal of guiding development of therapeutic strategies to overcome this limitation. We generated a broad panel of BRAF-mutant resistant cell line models across seven different clinically relevant drug combinations. Combinatorial drug treatments were able to abrogate ERK1/2 phosphorylation in parental-sensitive cells, but not in their resistant counterparts, indicating that resistant cells escaped drug treatments through one or more mechanisms leading to biochemical reactivation of the MAPK signaling pathway. Genotyping of resistant cells identified gene amplification of EGFR, KRAS, and mutant BRAF, as well as acquired mutations in KRAS, EGFR, and MAP2K1 These mechanisms were clinically relevant, as we identified emergence of a KRAS G12C mutation and increase of mutant BRAF V600E allele frequency in the circulating tumor DNA of a patient at relapse from combined treatment with BRAF and MEK inhibitors. To identify therapeutic combinations capable of overcoming drug resistance, we performed a systematic assessment of candidate therapies across the panel of resistant cell lines. Independent of the molecular alteration acquired upon drug pressure, most resistant cells retained sensitivity to vertical MAPK pathway suppression when combinations of ERK, BRAF, and EGFR inhibitors were applied. These therapeutic combinations represent promising strategies for future clinical trials in BRAF-mutant colorectal cancer. Cancer Res; 76(15); 4504-15. ©2016 AACR., (©2016 American Association for Cancer Research.)

Herein we describe a case of a 62-year-old female in good clinical condition with non-small-cell lung cancer who was treated with crizotinib. After 24 days of crizotinib therapy she presented with acute liver failure. Serum aspartate aminotransferase and alanine aminotransferase levels had increased from normal prior to crizotinib start to 2053 IU/L and 6194 IU/L, respectively. Total bilirubin and prothrombin time (PT-INR) increased up to 443 IU/L and 5.33, respectively, and symptoms of hepatic encephalopathy and hepatorenal syndrome emerged. Despite crizotinib discontinuation and intensive supportive therapy, the patient died 40 days after treatment with crizotinib was initiated due to acute liver failure with massive liver cell necrosis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Dihydropyrimidine dehydrogenase (DPD) activity determination in peripheral blood mononuclear cells of DPD deficient patients was hitherto inaccurate due to hemoglobin (Hb) contamination. We developed an improved method for accurate measurement of DPD activity in patients., Results: DPD activity was determined by HPLC with online radioisotope detection using liquid scintillation counting. Hb was determined spectrophotometrically. Method accuracy and precision were significantly improved by using cumulative area of all peaks as IS. Peripheral blood mononuclear cell lysates from DPD deficient patients were highly contaminated with on average 23.3% (range 2.7-51%) of Hb resulting in up to twofold underestimated DPD activity. DPD activities were corrected for Hb contamination. The method was validated and showed good long-term sample stability., Conclusion: This method has increased specificity allowing accurate identification of DPD deficient patients.