Small-molecule kinase inhibitors (SMKIs) represent the cornerstone in the treatment of non-small cell lung cancer (NSCLC) patients harboring genetic driver mutations. Because of the introduction of SMKIs in the last decades, treatment outcomes have drastically improved. Their treatment efficacy, the development of drug resistance as well as untoward toxicity, all suffer from large patient variability. This variability can be explained, at least in part, by their oral route of administration, which leads to a large inter- and intra-patient variation in bioavailability based on differences in absorption. Additionally, drug-drug and food-drug interactions are frequently reported. These interactions could modulate SMKI efficacy and/or untoward toxicity. Furthermore, the large patient variability could be explained by the presence of germline variations in target receptor domains, metabolizing enzymes, and drug efflux transporters. Knowledge about these predictor variations is crucial for handling SMKIs in clinical practice, and for selecting the most optimal therapy. In the current review, the literature search included all SMKIs registered for locally-advanced and metastatic NSCLC by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) until March 24th, 2022. The BIM deletion showed a significantly decreased PFS and OS for East-Asian patients treated with gefitinib, and has the potential to be clinically relevant for other SMKIs as well. Furthermore, we expect most relevance from the ABCG2 34 G>A and CYP1A1 variations during erlotinib and gefitinib treatment. Pre-emptive CYP2D6 testing before starting gefitinib treatment can also be considered to prevent severe drug-related toxicity. These and other germline variations are summarized and discussed, in order to provide clear recommendations for clinical practice.

PURPOSE: DPYD -guided fluoropyrimidine dosing effectively limits the risk of severe toxicity while maintaining clinical efficacy. However, recent data suggest that c.1236G>A variant carriers, starting with a 25% reduced dose, have shorter progression-free survival than wild-type patients receiving a full dose. Although overall survival was unaffected, further investigation is warranted. To address this, we retrospectively compared 5-fluorouracil (5-FU) exposure between c.1236G>A variant carriers and DPYD wild-type patients. MATERIALS AND METHODS: Pharmacokinetic data from nine clinical trials involving capecitabine-treated patients were pooled. Blood samples were collected before and after administration of capecitabine to assess systemic levels of its metabolites, including 5-FU. Capecitabine dosages were reduced for c.1236G>A variant carriers in accordance with the clinical guidelines at the time of study execution and varied from no reduction (n = 11) to a 25% (n = 16) or 50% (n = 8) reduction. Pharmacokinetic exposure, expressed as area under the plasma concentration-time curve (AUC _0-∞ ), was determined using noncompartmental analysis and dose-normalized to 850 mg/m ² . RESULTS: In total, 35 heterozygous c.1236G>A patients and 66 DPYD wild-type patients were evaluable. Patients carrying c.1236G>A who received a 50% dose reduction had a lower dose-normalized geometric mean 5-FU exposure (234 ng·h/mL coefficient of variation [CV = 43%]) compared with fully dosed c.1236G>A carriers (553 ng·h/mL [CV = 51%]) and fully dosed DPYD wild-type patients (582 ng·h/mL [CV = 48%]; P < .001). All c.1236G>A carriers who received a 50% dose reduction had AUC _0-∞ values below the AUC _0-∞ range observed in the wild-type group. CONCLUSION: Our findings indicate that an upfront 25% dose reduction for capecitabine in c.1236G>A carriers is likely more appropriate than the currently recommended 50% dose reduction. We stress the importance of individual dose titration in c.1236G>A carriers to avoid both over- and undertreatment.

UGT1A1 genotype-guided dosing reduces severe toxicity in UGT1A1 poor metaboliser (PM) patients treated with irinotecan. However, the impact of a dose reduction on survival remains unknown. This study evaluated whether upfront 30% dose reductions of irinotecan in UGT1A1 PMs affect survival by comparing progression-free survival (PFS) and overall survival (OS) between 30% dose-reduced PMs and fully-dosed UGT1A1 intermediate and normal metaboliser (IM/NM) patients. We conducted a retrospective, multicentre cohort study in patients with pancreatic cancer or colorectal cancer treated with UGT1A1 genotype-guided irinotecan dosing at six Dutch hospitals between August 2017 and April 2024. Patients were included in the primary analysis if irinotecan was dosed according to UGT1A1 genotype (i.e. an initial 100% ± 10% dose intensity for IM/NMs and an initial 70% ± 10% dose intensity for PMs) in at least cycle 1. Survival analyses for PFS and OS were performed using Kaplan–Meier estimates and univariable and multivariable Cox regressions, stratified by tumour type. Safety was also assessed. The primary analysis included 779 patients, 76 (9.8%) of whom were PMs. The median follow-up was 27.8 months (95% CI 15.2–31.6). No significant differences in PFS and OS rates were found between 30% dose-reduced PMs and fully-dosed IM/NMs (stratified log-rank test: PFS: P = 0.54; OS: P = 0.42). In stratified Cox regression analyses, the adjusted hazard ratio of PMs vs IM/NMs was 1.02 (95% CI 0.78–1.32; P = 0.90) for PFS and 1.10 (95% CI 0.82–1.48; P = 0.51) for OS, indicating no significant differences exist in PFS or OS between 30% dose-reduced PMs and fully-dosed IM/NMs. Severe toxicity rates were comparable between 30% dose-reduced PMs and fully-dosed IM/NMs (P = 0.59). An upfront 30% dose reduction of irinotecan in UGT1A1 PMs does not lead to statistically significant differences in survival outcomes compared to fully-dosed IM/NMs. Therefore, UGT1A1 genotype-guided dosing of irinotecan can be confidently performed to improve patient safety. No funding.

Article Is uracil enough for effective pre-emptive DPD testing? was published on July 19, 2024 in the journal Clinical Chemistry and Laboratory Medicine (CCLM) (volume 0, issue 0).