On December 18, 2020, osimertinib was approved for adjuvant therapy after tumor resection in patients with non–small cell lung cancer (NSCLC) with tumors with EGFR exon 19 deletions or exon 21 L858R mutations, as detected by a U.S. Food and Drug Administration (FDA)-approved test.^1,2

Supporting Efficacy Data

Approval was based on findings in the double-blind, phase III ADAURA trial (ClinicalTrials.gov identifier NCT02511106).^2,3 In the trial, 682 patients with complete tumor resection, with or without prior adjuvant chemotherapy, were randomly assigned to receive oral osimertinib at 80 mg once daily (n = 339) or placebo (n = 343) following recovery from surgery and standard adjuvant chemotherapy, if given. Patients had to have resectable tumors (stage IB to IIIA) and predominantly nonsquamous histology and EGFR exon 19 deletions or exon 21 L858R mutations identified prospectively from tumor tissue in a central laboratory by the cobas EGFR Mutation Test.

Among all patients, the median age was 63 years (range = 30–86 years), 70% were female, 64% were Asian, and 72% were never-smokers. WHO performance status was 0 (64%) or 1 (36%); 31% had stage IB, 35% stage II, and 34% stage IIIA disease; 55% had exon 19 deletions and 45% exon 21 L858R mutations; and 60% received adjuvant chemotherapy prior to randomization, including 27% with stage IB, 70% with stage II, and 79% with stage IIIA disease.

The major efficacy outcome measure was investigator-assessed, disease-free survival among the 233 osimertinib vs 237 placebo patients with stage II to IIIA disease. Median disease-free survival was not reached (95% confidence interval [CI] = 38.8 months to not estimable in the osimertinib group vs 19.6 months (95% CI = 16.6–24.5 months) in the placebo group (hazard ratio [HR] = 0.17, 95% CI = 0.12–0.23, P < .0001). In the total population (secondary endpoint), median disease-free survival was not reached (95% CI = not estimable to not estimable) in the osimertinib group vs 27.5 months (95% CI = 22–36 months) in the placebo group (HR = 0.20, 95% CI = 0.15–0.27, P < .0001). The proportion of patients with central nervous system involvement at the time of disease recurrence was 1.5% (n = 5) in the osimertinib group and 10% (n = 34) in the placebo group.

How It Works

Osimertinib is an EGFR tyrosine kinase inhibitor that binds irreversibly to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) at approximately ninefold lower concentrations than to wild-type EGFR. Two pharmacologically active metabolites (AZ7550 and AZ5104, circulating at approximately 10% of parent compound levels) with inhibitory profiles similar to osimertinib have been identified in plasma after oral administration of osimertinib. AZ7550 showed a similar potency to osimertinib, whereas AZ5104 showed greater potency against exon 19 deletion and T790M mutants (approximately 8-fold) and wild-type EGFR (approximately 15-fold). In vitro, osimertinib also inhibited the activity of HER2, HER3, HER4, ACK1, and BLK at clinically relevant concentrations.

In cultured cells and animal tumor implantation models, osimertinib exhibited antitumor activity against NSCLC lines with EGFR mutations (T790M/L858R, L858R, T790M/exon 19 deletion, and exon 19 deletion) and, to a lesser extent, those with wild-type EGFR amplifications. Osimertinib has been shown to distribute to the brain in multiple animal species, with brain to plasma area under the curve ratios of approximately 2 after oral dosing; these data are consistent with observations of tumor regression and increased survival with osimertinib treatment in a mutant-EGFR intracranial mouse metastasis xenograft model (PC9; exon 19 deletion).

How It Is Used

The recommended osimertinib dose for adjuvant treatment of early-stage NSCLC is 80 mg once daily until disease recurrence, unacceptable toxicity, or for up to 3 years. Patients should be selected for treatment on the basis of EGFR alterations as detected by an FDA-approved test.

Prescribing information provides instructions on dosage modification, including dose reduction to 40 mg daily and withholding and discontinuation of treatment, for adverse reactions including pulmonary, cardiac, and cutaneous reactions and adverse reactions of grade ≥ 3. Osimertinib should be permanently discontinued for interstitial lung disease or pneumonitis, QTc interval prolongation with signs/symptoms of life-threatening arrhythmia;, symptomatic congestive heart failure, confirmed Stevens-Johnson syndrome or erythema multiforme major, and grade ≥ 3 adverse reactions that do not improve after 3 weeks of withholding treatment.

Concomitant treatment with strong CYP3A inducers (eg, ketoconazole, conivaptan, clarithromycin) should be avoided. Prescribing information provides instructions for use if concomitant administration is unavoidable.

Safety Profile

Among all patients receiving osimertinib in the ADAURA trial, median duration of exposure was 22.5 months at the time of disease-free survival analysis. The most common adverse events of any grade (≥ 15%) in the osimertinib group were diarrhea (47% vs 20% in placebo group), rash (40% vs 19%), nail toxicity (37% vs 4%), stomatitis (32% vs 7%), dry skin (29% vs 7%), pruritus (19% vs 9%), cough (19% vs 19%), and musculoskeletal pain (18% vs 25%). The most common grade ≥ 3 adverse events included diarrhea (2.4% vs 0.3%), stomatitis (1.8% vs 0%), and nail toxicity (0.9% vs 0%). The most common grade 3 or 4 laboratory abnormalities were lymphopenia (3.4% vs 0.9%) and hyperglycemia (2.3% vs 0.9%).

Osimertinib has warnings/precautions for interstitial lung disease and pneumonitis (observed in 3.7% of patients receiving osimertinib in clinical trials), QTc interval prolongation, cardiomyopathy (observed in 3.0%), keratitis, Stevens-Johnson syndrome and erythema multiforme major, cutaneous vasculitis, and embryofetal toxicity. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-osimertinib-adjuvant-therapy-non-small-cell-lung-cancer-egfr-mutations. Accessed January 11, 2021.

2. Tagrisso (osimertinib) tablets prescribing information, AstraZeneca, December 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208065s021lbl.pdf. Accessed January 11, 2021.

3. Wu Y-L, Tsuboi M, He J, et al: Osimertinib in resected EGFR-mutated non–small-cell lung cancer. N Engl J Med 383:1711-1723, 2020.