In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

In April 2018, osimertinib (Tagrisso) was approved for the first-line treatment of metastatic non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by a U.S. Food and Drug Administration–approved test.^1,2

Supporting Efficacy Data

Approval was based on the findings of the double-blind phase III FLAURA trial, in which 556 patients were randomized to receive osimertinib at 80 mg once daily (n = 279) or standard-of-care treatment (n = 277) with gefitinib at 250 mg (n = 183) or erlotinib (Tarceva) at 150 mg (n = 94) once daily.^2,3 The median age of patients was 64 years (range = 26–93 years; 54% < 65 years); 63% were female; 62% were Asian; 64% were never-smokers; all had a World Health Organization performance status of 0 or 1; 5% had nonresectable stage IIIb and 95% had stage IV disease; 7% had received prior systemic cytotoxic

chemotherapy as neoadjuvant or adjuvant therapy; and 63% tested positive for exon 19 deletion and 37%, for exon 21 L858R mutation. Of patients randomized to receive the standard of care, 20% received osimertinib as the next line of antineoplastic therapy.

The median progression-free survival was 18.9 months in the osimertinib group vs 10.2 months in the standard-of-care group (hazard ratio = 0.46, P < .0001, stratified by Asian vs non-Asian ethnicity and mutation status). The confirmed overall response rate was 77% vs 69%, and the median duration of response was 17.6 vs 9.6 months, respectively. Among 22 osimertinib and 19 standard-of-care patients with baseline central nervous system metastases evaluable for response, the response rates were 77% vs 63%, with a response duration ≥ 12 months in 47% vs 33% of responders. Overall survival data were not mature at the time of the analysis.

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 about ninefold lower concentrations than to wild-type EGFR. Two pharmacologically active metabolites (AZ7550 and AZ5104, circulating at about 10% of parent compound levels) with inhibitory profiles similar to that of 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 (about 8-fold) and wild-type EGFR (about 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 about 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.

Treatment should be withheld in patients with a QTc interval > 500 ms on at least 2 separate electrocardiograms until the QTc interval is < 481 ms or there is recovery to baseline if baseline was ≥ 481 ms; treatment should be resumed at 40 mg/d. Treatment should be permanently discontinued in patients with QTc interval prolongation and signs or symptoms of life-threatening arrhythmia and in patients with symptomatic congestive heart failure. Treatment should be permanently discontinued in patients with interstitial lung disease or pneumonitis. For patients with other adverse reactions of grade ≥ 3, treatment should be withheld for up to 3 weeks and can be resumed at 80 or 40 mg/d with improvement to grade 0 to 2 within 3 weeks; treatment should be 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.

Safety Profile

The median duration of exposure to osimertinib in the FLAURA trial was 16.2 months. The most common adverse events of any grade in the osimertinib group (≥ 20% of patients) were diarrhea, rash, dry skin, nail toxicity, stomatitis, and decreased appetite. The most common grade ≥ 3 adverse events included decreased appetite, prolonged QT interval, and diarrhea. The most common grade ≥ 3 laboratory abnormalities were lymphopenia and neutropenia.

Serious adverse events occurred in 4% of the osimertinib group, with the most common being pneumonia, interstitial lung disease/pneumonitis, and pulmonary embolism. The most common adverse events leading to dose reduction or interruption were QT interval prolongation, diarrhea, and lymphopenia. Adverse events led to treatment discontinuation in 13%, with the most common cause being interstitial lung disease/pneumonitis.

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 for QTc prolongation or who are taking medications known to prolong the QTc interval. Cardiac monitoring should be conducted in patients with cardiac risk factors. Patients with signs or symptoms of keratitis should promptly be referred for ophthalmologic evaluation. Women should be advised 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. Women should not breastfeed while receiving osimertinib treatment. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves osimertinib for first-line treatment of metastatic NSCLC with most common EGFR mutations. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm605113.htm. Accessed September 20, 2018.

2. Tagrisso (osimertinib) tablets prescribing information, AstraZeneca Pharmaceuticals LP, April 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/208065s008lbl.pdf. September 20, 2018.

3. Soria JC, Ohe Y, Vansteenkiste J, et al: Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 378:113-125, 2018.