Osimertinib Remains Safe, Tolerable After 3 Years of Use in NSCLC

“While stomatitis, diarrhoea and rash were relatively common, most were low grade, and the low rate of treatment discontinuation in the osimertinib arm is reassuring that, even despite the longer treatment duration, the therapy remained tolerable,” said the lead study author.

There were no new safety signals and no deterioration in health-related quality of life (HRQOL) following treatment with osimertinib (Tagrisso) among patients with resected, stage IB to IIIA, EGFR-mutant non–small cell lung cancer (NSCLC), according to findings from an updated analysis of the phase 3 ADAURA trial (NCT02511106).¹

Investigators reported adverse effects (AEs) leading to dose reductions in 12% of patients receiving osimertinib in this updated analysis, which was consistent with the rate of 9% that read out in the primary analysis.² Similarly, AEs leading to dose interruption occurred in 27% of patients in the updated analysis and 24% in the primary analysis, and AEs leading to discontinuation occurred in 13% and 11%, respectively.

In this updated analysis, the most common AEs leading to dose reductions were stomatitis (3%), diarrhea (2%), and paronychia (2%). Dose interruptions, meanwhile, were most commonly attributed to diarrhea (4%) and stomatitis (2%), and discontinuation was most commonly due to interstitial lung disease (2%).

Grade 3 or higher AEs and serious AEs affected 23% and 20% of patients treated with osimertinib, respectively, according to the updated analysis. The corresponding figures from the primary analysis were 20% and 16%, respectively. Nearly all AEs (99%) in the osimertinib group were first reported within 12 months of starting treatment, and most of these occurred within the first month (77%).

Investigators assessed HRQOL using Short Form-36 surveys.¹ Physical component summary mean absolute T-scores ranged from 47 to 50 points with osimertinib vs 46 to 50 with placebo, and mental component summary mean absolute T-scores ranged from 43 to 50 points with osimertinib vs 44 to 51 with placebo. The differences in these mean HRQOL scores between the osimertinib and placebo groups never exceeded 1.5 points, including at treatment discontinuation visits.

“One of the major differences in the design of the ADAURA trial compared to other adjuvant targeted trials in EGFR-mutant NSCLC was that the therapy was given for 3 years instead of 2,” lead study author Tom John, MBBS, PhD, FRACP, said in a comment to CancerNetwork^®. “In order to determine the feasibility of such an approach, the efficacy of the agent needed to be balanced against toxicities. While stomatitis, diarrhoea and rash were relatively common, most were low grade, and the low rate of treatment discontinuation in the osimertinib arm is reassuring that, even despite the longer treatment duration, the therapy remained tolerable.”

John is a medical oncologist, associate professor, and deputy director of the medical oncology service at the Peter MacCallum Cancer Centre in Victoria, Australia.

Investigators of this updated analysis assessed toxicities and QOL across all 682 patients enrolled in ADAURA, who were randomly assigned 1:1 from November 2015 to February 2019 to receive either 80 mg of osimertinib (n = 339) or placebo (n = 343) once daily. As of data cutoff (April 2022), all patients in the placebo group had received at least 1 dose of treatment, and the same was true of 337 patients in the osimertinib group.

Overall, 66% of those in the osimertinib group completed the planned 3 years of treatment compared with 41% in the placebo group. The median total duration of treatment exposure was 35.8 months with osimertinib (range, 0-38) vs 25.1 months with placebo (range, 0-39), and the median actual durations of exposure were 35.4 (range 0-38) and 25.1 (0-39) months, respectively.

The primary end point was disease-free survival (DFS) as assessed by investigators, and key secondary end points included safety and HRQOL.

This updated analysis also found that the most common AEs related to osimertinib were diarrhea (40%), paronychia (25%), and dry skin (22%). There was a single death caused by AEs in the osimertinib group resulting from respiratory failure, and 2 such deaths in the placebo group resulting from an instance of pulmonary embolism and another of an unknown fatal event. Investigators found none of these AEs to be related to the study regimens.

“Balanced against the recently reported OS data showing a significant benefit,³ the safety and tolerability of osimertinib provides reassurance to clinicians and establishes this as a new standard of care for resected, EGFR-mutant NSCLC,” John concluded.

References

1. John T, Grohé C, Goldman JW, et al. Three-year safety, tolerability, and health-related quality of life outcomes of adjuvant osimertinib in patients with resected stage IB-IIIA EGFR-mutated non-small cell lung cancer: updated analysis from the phase 3 ADAURA trial. J Thorac Oncol. Published online May 24, 2023. doi:10.1016/j.jtho.2023.05.015
2. Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071
3. Tsuboi M, Herbst RS, John T, et al. Overall survival with osimertinib in resected EGFR-mutated NSCLC. N Engl J Med. Published online June 4, 2023. doi:10.1056/NEJMoa2304594