In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On November 13, 2015, osimertinib (Tagrisso) was granted accelerated approval for the treatment of patients with metastatic EGFR T790M–mutant (as detected by a U.S. Food and Drug Administration [FDA]-approved test) non–small cell lung cancer (NSCLC) who have had disease progression on or after EGFR tyrosine kinase inhibitor therapy.
Supporting Efficacy Data
Approval was based on response rates observed in two single-arm open-label trials in patients who had disease progression on prior systemic therapy, including an EGFR tyrosine kinase inhibitor. All patients were required to have EGFR T790M mutation–positive NSCLC as detected by the cobas EGFR mutation test and received oral osimertinib at 80 mg once daily.
Patients with a history of interstitial lung disease or radiation pneumonitis that required steroid treatment, serious arrhythmia, or baseline QTc interval > 470 ms were excluded from the studies. Overall, patients had a median age of 63 years (13% ≥ 75 years), 68% were female, 60% were Asian and 36% white, 39% had brain metastases (39%), World Health Organization (WHO) performance status was 0 in 37% and 1 in 63%, and 69% had received at least two prior lines of therapy.
Objective response rates on independent review were 57% (all partial responses; 95% confidence interval [CI] = 50%–64%) in study 1 (N = 201) and 61% (complete response in 1%; 95% CI = 54%–68%) in study 2 (N = 210).
Overall, 96% of responding patients in both trials had ongoing responses at the time of primary analysis. Median duration of response had not been reached, with duration of ongoing responses ranging from 1.1 to 5.6 months after a median duration of follow-up of 4.2 months (study 1) and 4.0 months (study 2).
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. 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.
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 eightfold) 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.
How It Is Used
The recommended dose of osimertinib is 80 mg once daily until disease progression or unacceptable toxicity. Recommended osimertinib dose modifications include the following: For cardiac adverse reactions, patients with a QTc interval > 500 ms on two or more separate electrocardiograms should have treatment withheld until the 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 those with QTc interval prolongation and signs/symptoms of life-threatening arrhythmia. Treatment should be withheld for up to 4 weeks in patients with an asymptomatic absolute decrease in left ventricular ejection fraction of 10% from baseline and below 50% and resumed if there is improvement to baseline left ventricular ejection fraction or permanently discontinued if there is not improvement to baseline.
Treatment should be permanently discontinued in patients with symptomatic congestive heart failure. 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 inhibitors, including macrolide antibiotics (eg, telithromycin), antifungals (eg, itraconazole), antivirals (eg, ritonavir), and nefazodone should be avoided. In addition, concomitant administration with strong CYP3A inducers (eg, phenytoin, rifampicin, carbamazepine, St. John’s wort) should be avoided.
Among 411 patients in studies 1 and 2, the most common adverse events of any grade were diarrhea (42%), rash (41%), dry skin (31%), nail toxicity (25%), eye disorders (18%), nausea (17%), decreased appetite (16%), and constipation (15%). The most common grade 3 or 4 adverse events were venous thromboembolism (2.4%) and pneumonia (2.2%). Interstitial lung disease/pneumonitis occurred in 3.3% of patients, and cardiomyopathy occurred in 1.4%. The most common grade 3 or 4 laboratory abnormalities were hyponatremia (3.4%), neutropenia (3.4%), and lymphopenia (3.3%).
Adverse events led to dose reductions in 4.4% of patients, with the most common reasons being QTc prolongation (2.2%) and neutropenia (1.9%), and to discontinuation in 5.6%, with the most common reasons being interstitial lung disease/pneumonitis (2%) and cerebrovascular accident (1%). Overall, cerebrovascular accident occurred in 2.7%.
Serious adverse events reported in ≥ 2% of patients were pneumonia and pulmonary embolus. Fatal adverse events occurred in 3.2% of patients, including four patients (1%) with interstitial lung disease/pneumonitis attributed to osimertinib; four patients died from pneumonia and two from cerebrovascular accident/cerebral hemorrhage.
Osimertinib carries warnings/precautions for interstitial lung disease/pneumonitis, QTc interval prolongation, cardiomyopathy, and embryofetal toxicity. ECGs and electrolytes should be monitored in patients with a history of or predisposition for QTc prolongation or who are taking medications known to prolong QTc interval. Left ventricular ejection fraction should be assessed before treatment and then every 3 months.
Women should be advised of 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. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm472565.htm. Accessed November 24, 2015.
2. Tagrisso (osimertinib) tablets prescribing information, AstraZeneca Pharmaceuticals, November 2015. Available at www.azpicentral.com/tagrisso/tagrisso.pdf. Accessed November 24, 2015.