Afatinib Tolerability-Guided Dosing Supported For EGFR-Mutated NSCLC

Afatinib dose adjustment can reduce side effects without reducing the survival benefit for patients with non-small-cell lung cancer

medwireNews: Tolerability-guided dosing is feasible for patients receiving afatinib for advanced epidermal growth factor receptor (EGFR) mutation-positive, non-small-cell lung cancer (NSCLC), analysis of data from the LUX-Lung 3 and 6 clinical trials suggests.

Reducing the afatinib dose by 10 mg decrements, from 40 mg/day to a minimum of 20 mg/day, “reduced the incidence and severity of treatment-related AEs [adverse effects] without affecting efficacy, allowing patients to continue effective therapy while obtaining clinical benefit”, say Yi-Long Wu, from Guangdong General Hospital in Guangzhou, China, and co-workers. 

Grade 3 or more severe drug-related AEs, grade 2 nausea or vomiting for at least 7 days or grade 2 and worsening renal function led to afatinib dose reduction in 53.3% of the 229 patients in the LUX-Lung 3 trial and 28.0% of the 239 participants in the LUX-Lung 6 study. The majority of reductions in both trials occurred within 6 months of beginning treatment, at 86.1% and 82.1%, respectively.

By contrast, dose escalation to 50 mg/day, in the absence of any drug-related AEs above grade 1 after the first cycle, was reported for 7.0% and 15.9% of the LUX-Lung 3 and 6 participants, respectively, the researchers note in the Annals of Oncology.

Dose reduction resulted in a significant decrease in treatment-related AEs, from 100.0 % to 86.1% of patients in LUX-Lung 3 and 74.6% of those in LUX-Lung 6, and the rate of grade 3 or more severe side effects fell from 73.0% to 20.5% and from 80.6% to 11.9%, respectively.

Pharmacokinetic analysis of patients from both trials showed that the average trough plasma concentration of afatinib on day 22 was higher among patients who subsequently reduced their dose to 30 mg/day than those who continued with the 40 mg/day regimen, with a geometric mean of 45.6 versus 24.3 ng/mL. And these values were comparable between these groups on day 43, at 23.3 versus 22.8 ng/mL.

Patients who escalated their afatinib dose may have had below-average exposure to the drug at 40 mg/day dosage, the researchers add. Their geometric mean was 20.3 ng/mL at day 22, increasing only slightly to 24.2 ng/mL by day 43, so that this figure remained within the range of patients who continued at 40 mg/day, the team notes.

Finally, median progression-free survival was comparable between the patients in both the LUX-Lung 3 and 6 trials who reduced their dose within 6 months of beginning treatment and those who did not, at 11.3 versus 11.0 months and 12.3 versus 11.0 months, respectively.

The researchers note that women, patients aged at least 65 years and those with lower body weights were more likely to reduce their afatinib dose than male patients, younger individuals and those with a higher body weight. Japanese patients enrolled in the LUX-Lung 3 trial also had a higher rate of dose reduction than those from other parts of the world.

However, the authors emphasize: “It is important to note that adaptation of the approved afatinib starting dose based on clinical characteristics is not recommended as there are no data to support this.”

Reference

Yang JC-H, Sequist LV, Zhou C, et al. Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials. Ann Oncol 2016; Advance online publication 6 September. doi: 10.1093/annonc/mdw322

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