On March 30, 2017, osimertinib (Tagrisso) was granted regular approval for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M–mutant non–small cell lung cancer (NSCLC), as detected by a U.S. Food and Drug Administration (FDA)-approved test, who have progressed on or after EGFR tyrosine kinase inhibitor therapy.1,2 Osimertinib was granted accelerated approval in this setting in November 2015 on the basis of response rate.
Supporting Efficacy Data
The current approval is based on findings in an open--label phase III trial (AURA3) in patients with metastatic EGFR T790M–mutation-positive NSCLC who had progressive disease following first-line EGFR tyrosine kinase inhibitor therapy.2,3 All patients were required to have EGFR T790M mutation–positive NSCLC identified by the cobas EGFR mutation test performed in a central laboratory. In the trial, 419 patients were randomized 2:1 to receive oral osimertinib at 80 mg once daily (n = 279) or platinum-based doublet chemotherapy (n = 140); chemotherapy consisted of pemetrexed (Alimta) at 500 mg/m2 plus either carboplatin AUC = 5 or cisplatin at 75 mg/m2 on day 1 of every 21-day cycle for up to 6 cycles followed by pemetrexed maintenance therapy. Patients in the chemotherapy group with radiologic disease progression according to both investigator and blinded independent central reviews could receive osimertinib at disease progression.
Patients had a median age of 62 years (15% ≥ 75 years), 64% were female, 65% were Asian and 32% white, 68% were never smokers, all had a World Health Organization (WHO) performance status of 0 or 1, and 54% had extrathoracic visceral metastases, including 34% with central nervous system (CNS) metastases (11% with measurable metastases), and 42% had bone metastases.
Osimertinib is an EGFR tyrosine kinase inhibitor that binds irreversibly to some mutant forms of EGFR (T790M, L858R, and exon 19 deletion) at approximately ninefold lower concentrations than to wild-type EGFR.
Median investigator-assessed progression-free survival was 10.1 months in the osimertinib group vs 4.4 months in the chemotherapy group (hazard ratio [HR] = 0.30, P < .001). A sensitivity analysis using blinded independent central review showed median progression-free survival of 11 months vs 4.2 months (HR = 0.28, 95% confidence interval = 0.20–0.38). Confirmed objective response rate on investigator assessment was 65% vs 29% (P < .0001), with median response durations of 11 months vs 4.2 months. In patients with measurable CNS disease, response rates on independent central review were 57% vs 25%, with median response durations of not reached (range = 1.4–12.5 months) vs 5.7 months (range = 1.4–5.7 months). Overall survival data are not yet mature.
How It Works
Osimertinib is an EGFR tyrosine kinase inhibitor that binds irreversibly to some 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 vitro and in animal 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 AUC 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.
How It Is Used
The recommended dose of osimertinib is 80 mg once daily until disease progression or unacceptable toxicity. The presence of an EGFR T790M mutation in a tumor or plasma specimen (if tumor tissue is unavailable) should be confirmed by an FDA-approved test prior to initiation of treatment.
Recommended osimertinib dose modifications follow. For cardiac adverse reactions, patients with QTc interval > 500 ms on ≥ 2 separate electrocardiograms should have treatment withheld until QTc interval is < 481 ms or there is recovery to baseline if baseline was ≥ 481 ms, with treatment resumed at 40 mg/d. Treatment should be permanently discontinued in patients with QTc interval prolongation and signs/symptoms of life-threatening arrhythmia; and patients with symptomatic congestive heart failure or asymptomatic left-ventricular dysfunction that persists ≥ 4 weeks. For pulmonary adverse reactions, treatment should be permanently discontinued in patients with interstitial lung disease or pneumonitis. For other adverse reactions, treatment should be withheld for up to 3 weeks for grade 3 or 4 events, resumed at 80 or 40 mg/d for improvement to grade 0 to 2 within 3 weeks, and permanently discontinued in those with no improvement within 3 weeks.
Concomitant administration of osimertinib with strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort) should be avoided. If concurrent use is unavoidable, the osimertinib dose should be increased to 160 mg/d and then reduced back to 80 mg/d 3 weeks after discontinuation of the strong CYP3A inducer.
In AURA3, left-ventricular ejection fraction was evaluated at screening and every 12 weeks. The most common adverse events of any grade in the osimertinib group were diarrhea (41% vs 11% in the chemotherapy group), rash (34% vs 6%), dry skin (23% vs 4%), nail toxicity (22% vs 2%), and fatigue (22% vs 40%). The most common grade 3 or 4 adverse events were fatigue (1.8% vs 5.1%), diarrhea (1.1% vs 1.5%), and decreased appetite (1.1% vs 2.9%). The most common grade 3 or 4 laboratory abnormalities were lymphopenia (8.2% vs 9.9%) and neutropenia (2.2% vs 12%).
Serious adverse events were reported in 18% vs 26% of patients, with no single adverse event occurring in ≥ 2% of the osimertinib group. Adverse events led to dose reduction in 2.9% of osimertinib patients, with the most common causes of reduction or interruption being QTc prolongation (1.8%), neutropenia (1.1%), and diarrhea (1.1%). Adverse events led to discontinuation of osimertinib in 7%, with the most common reason being interstitial lung disease/pneumonitis (3%). One osimertinib patient (0.4%) died of interstitial lung disease/pneumonitis.
Evaluation in 833 patients receiving osimertinib in AURA3 and 2 single-arm trials showed that the most serious adverse reactions were interstitial lung disease (3.5%), QTc interval prolongation (0.7%), cardiomyopathy (1.9%), and keratitis (0.7%).
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
Osimertinib carries warnings/precautions for interstitial lung disease/pneumonitis, QTc interval prolongation, cardiomyopathy, keratitis, and embryofetal toxicity. Electrocardiograms and electrolytes should be monitored in patients with a history of or predisposition to QTc prolongation or who are taking medications known to prolong QTc interval. Cardiac monitoring including left-ventricular ejection fraction assessment should be conducted in patients with cardiac risk factors. Patients with signs/symptoms of keratitis should promptly be referred for ophthalmologic evaluation. Women should be advised of the potential risk to the fetus and to use effective contraception during treatment and for 6 weeks after the final dose; men should be advised to use effective contraception for 4 months after the last dose. ■
1. U.S. Food and Drug Administration: Osimertinib (Tagrisso). Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm549683.htm. Accessed April 25, 2017.
2. Tagrisso (osimertinib) tablets prescribing information, AstraZeneca Pharmaceuticals LP, March 2017. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm549683.htm. Accessed April 25, 2017.