1. Samson, Kurt

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Lowering the dose of afatinib reduced adverse events without compromising the drug's effectiveness in patients with metastatic non-small cell lung cancer (NSCLC), according to a new post hoc analysis of phase III clinical trial data. The findings, published in the Annals of Oncology, came from a review of data from the LUX-Lung 3 and LUX-Lung 6 trials (Ann Oncol 2016;DOI:10.1093/annonc/mdw322).

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Afatinib is an irreversible epidermal growth factor receptor (EGFR) inhibitor. It was approved by the FDA last April as first-line treatment against specific types of EGFR mutation-positive NSCLC in patients whose disease has progressed after treatment with platinum-based chemotherapy.


LUX-Lung 3 (LL3) and LUX-Lung 6 (LL6) are multicenter, randomized, open-label trials of afatinib versus chemotherapy with pemetrexed/cisplatin and gemcitabine/cisplatin in patients with advanced and metastatic EGFR mutation-positive NSCLC, notably exon 19 deletions (J Clin Oncol 2013;doi:10.1200/JCO.2012.46.1764). Other first-line treatments include the reversible EGFR tyrosine kinase inhibitors erlotinib and gefitinib, and all three agents have demonstrated improvement in progression-free survival in NSCLC patients (J Clin Oncol 2016;doi:10.1200/JCO.2015.63.4154).


Results from the two trials, released in 2015, showed that patients with tumors having a deletion in exon 19, the most common EGFR mutation, lived more than 1 year longer when treated with first-line afatinib compared to standard chemotherapy (Lancet Oncol 2015;1,2:141-151).


The analysis compared lower plasma concentrations of 30 mg rather than the 40 mg starting dose. About half of the patients in the LL3 study had dose reductions, as did almost one-third of those in the LL6 trial, most within the first 6 months of treatment.


In the LL3 analysis, 122 out of 229 patients, or 53.3 percent, had their dosage reduced, as did 67 (28%) of 239 subjects in the LL6 trial, most in the first 6 months, at 86.1 percent and 82.1 percent, respectively.


Afatinib improved progression-free survival in both LL3 and LL6, but there were significantly more adverse events (AE) at the 40 mg dosage. The most common was diarrhea, which occurred in 96 percent of afatinib subjects, versus 23 percent in the pemetrexed/cisplatin arm. Rash or acne was observed in 90 percent versus 11 percent, stomatitis in 71 percent versus 15 percent, and paronychia in 58 percent of treated individuals. There were no cases of the latter AE in the other arm.


"Afatinib's efficacy and safety profile in NSCLC patients has been well-established in multiple large trials, but this is the first analysis to show that afatinib doses can be reduced to help manage treatment-related adverse events without any apparent reduction in efficacy," said principal investigator and lead author James Chih-Hsin Yang, MD, PhD, Director, Department of Oncology, National Taiwan University Hospital Cancer Center.


"This may provide physicians and their patients with confidence and allows physicians to help address adverse events."


Patient Differences

Dose reduction was more likely in patients with higher plasma concentrations of afatinib. At day 43, patients who were reduced to 30 mg had mean plasma concentrations of afatinib of 23.3 ng/mL versus 22.8 ng/mL in subjects who remained at the 40 mg dosage. Dose reductions generally occurred more frequently in women and in individuals weighing less than 50 kg. In LL3 subjects, reduction was more frequent in patients over 65 years of age and among Japanese patients, as well as those with lower body surface areas.


Among 122 patients in LL3 with dose reductions from 40 mg, median total treatment time was 371 days, and ranged from 28 to 827 days, compared with 294 days in subjects who remained at that dose. Median total treatment time in LL6 was 428 days for patients with reduced doses compared to 336.5 days for other subjects. All patients experienced adverse events at 40 mg, including 73 percent with AEs of grade 3 or higher.


According to the authors, the difference in dose reduction frequency between the LL3 and LL6 trials might be due to LL6 having involved subjects exclusively from Asian sites, while LL3 was conducted in a global population, although 24 percent were Japanese.


"It is important that adaptation of the approved afatinib starting dose, based on clinical characteristics, is not recommended as there are no data to support this. Even those who are eventually dose reduced may need the higher starting dose as an initial boost," according to the researchers.


Some patients received higher doses as well: 7 percent of the LL3 and 15.9 percent of LL6 subjects, including 21 patients given 50 mg in LL3. Among these, five were erroneously started on 50 mg and 16 escalated to 50 mg. At weeks 24 and 48, six and three patients in LL3 remained at that dose, respectively, as did 19 and 12 patients in LL6.


The authors emphasized the importance of considering the risk-benefit profile of individual agents when choosing a first-line treatment, including the impact of management strategies and options to address interpatient variability. Established protocols exist for dose modification of afatinib and erlotinib, and dose interruption of gefitinib, based on patient tolerability.


For afatinib, the approved starting dose is 40 mg/day. Dose escalation is permitted in the absence of grade >1 treatment-related AEs in the first 21-day cycle. In the case of grade >=3 or selected, prolonged grade 2 treatment-related AEs, the afatinib dose should be interrupted. Upon recovery to grade 1 or baseline, afatinib should be restarted at a reduced dose of 10 mg decrements to a minimum of 20 mg/day.


Upward Titration

Corey J. Langer, MD, in the Division of Hematology and Oncology at the University of Pennsylvania's Perelman Center for Advanced Medicine, Philadelphia, told Oncology Times that, rather than starting NSCLC patients at the higher dose and reducing it if problems occur, he does the opposite.


"I'm not convinced that using higher doses is better in dealing with these mutations. We usually start patients at 20 mg and then escalate to 30 or 40 mg in the absence of toxicity. We have found this to be pretty well-tolerated. There are almost always adverse events and problems with patient compliance starting with 40 mg."


There have been a number of trials using different agents targeting EGFR mutations, but that only one drug has shown any advantage over chemotherapy in terms of overall survival, he noted.


"I put a lot of stock in survival analyses, and out of three such drugs only afatinib has shown an advantage over chemotherapy in terms of overall survival. Afatinib has demonstrated potential superiority over first-time chemotherapy even though there have not been any head-to-head comparisons so far."


Kurt Samson is a contributing writer.