Lung cancer is one of the most frequently diagnosed cancers, and is the leading cause of cancer-related mortality worldwide and in the United States among men and women. Non–small-cell lung cancer (NSCLC) is the most common form of the disease, accounting for approximately 85% of all lung cancer cases.1 NSCLC comprises several histologies, including adenocarcinoma, squamous-cell carcinoma, nonsquamous carcinoma, large-cell anaplastic carcinoma, and adenosquamous carcinoma.1
Traditionally, metastatic NSCLC has been treated with systemic (cytotoxic) chemotherapies. Although the use of platinum-based 2-drug regimens has improved the median overall survival in patients with newly diagnosed advanced NSCLC, these combination chemotherapies are limited by significant toxicities, including myelosuppression, nausea and vomiting, kidney damage, and alopecia.1 Single-agent chemotherapy has been the standard of care for patients with relapsed metastatic NSCLC.1
With enhanced understanding of lung cancer cell biology and gene expression, the development of novel agents has altered the treatment paradigm for NSCLC.2,3 Overall, 9 targeted agents are currently available for the treatment of patients with advanced NSCLC, including afatinib, alectinib, bevacizumab, ceritinib, crizotinib, erlotinib, gefitinib, necitumumab, and ramucirumab.4
Mutations in the epidermal growth factor receptor (EGFR) are found in approximately 10% of patients with NSCLC in North America, and in approximately 33% of patients with NSCLC in East Asia.2 The majority of EGFR mutations occur in females who have adenocarcinoma but who have never smoked.2
For patients with metastatic NSCLC and sensitizing EGFR mutations (eg, exon 19 deletion, L858R), the National Comprehensive Cancer Network clinical guidelines recommend the use of tyrosine kinase inhibitors (TKIs) as initial and subsequent therapy.4 A total of 3 oral TKIs—gefitinib, afatinib, and erlotinib—target EGFR, and have demonstrated activity in patients with metastatic NSCLC with specific EGFR mutations.4
However, the use of oral TKIs to treat metastatic NSCLC with EGFR mutations is not curative. The majority of this patient population show signs of disease progression within 8 to 16 months after starting therapy with a TKI.4 One of the mechanisms by which subclones of NSCLC cells acquire resistance to EGFR-targeted TKI therapy is the development of the EGFR T790M mutation.4,5 This mutation reflects substitution of a single amino acid from threonine to methionine at position 790 in the EGFR wild-type kinase domain.5 Until recently, none of the oral TKIs approved for advanced NSCLC specifically targeted the EGFR T790M mutation, rendering the treatment for this subgroup of patients suboptimal.4
First Agent Targeting NSCLC with the EGFR T790M Mutation
On November 13, 2015, the US Food and Drug Administration (FDA) approved osimertinib (Tagrisso; AstraZeneca), a TKI, for the treatment of patients with metastatic NSCLC with the EGFR T790M mutation, as detected by an FDA-approved test, whose disease progressed during or after therapy with an EGFR TKI.6-8
Also on November 13, 2015, the FDA approved cobas EGFR Mutation Test v2 (Roche Molecular Systems), the first companion diagnostic test that detects the specific EGFR resistance mutation that osimertinib targets. This newly approved version of the test adds the T790M mutation to the clinically relevant mutations detected by the original cobas EGFR Mutation Test (v1).6
Osimertinib was approved under the FDA’s accelerated approval program, which provides patients early access to a new therapy while its developer conducts clinical trials to confirm the clinical benefits that have been determined using surrogate end points.6 Overall, 2 multicenter, phase 2 clinical trials, AURA extension and AURA2, demonstrated that patients with NSCLC whose disease progressed during or after therapy with an EGFR TKI had complete or partial objective tumor responses after treatment with osimertinib.6-8
According to Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products, “Our understanding of the molecular basis of lung cancer and reasons these cancers become resistant to prior treatments is rapidly evolving. This approval provides a new treatment for patients who test positive for the EGFR T790M resistance mutation, and is based on substantial evidence from clinical trials that shows Tagrisso had a significant effect on reducing tumor size in more than half of patients who were treated.”6
Mechanism of Action
Osimertinib is an oral inhibitor of EGFR. Osimertinib binds irreversibly to specific mutated forms of EGFR, including T790M, L858R, and exon 19 deletion.8
Overall, 2 pharmacologically active metabolites, AZ7550 and AZ5104, circulate at approximately 10% of the parent drug and have similar inhibitory profiles to osimertinib. AZ7550 has demonstrated potency similar to osimertinib, whereas AZ5104 showed greater potency against exon 19 deletion, T790M, and EGFR wild-type.8
Osimertinib blocks the activity of HER2, HER3, HER4, ACK1, and BLK at clinically relevant concentrations based on in vitro studies.8
Dosing and Administration
The presence of the EGFR T790M mutation should be confirmed before starting therapy with osimertinib. The recommended dose is 80 mg orally once daily, taken with or without food. Missed doses of osimertinib should not be made up.8
Osimertinib is provided in 2 dosage strengths, including 40-mg and 80-mg tablets.8
Clinical Trials: AURA Extension and AURA2
The efficacy and safety of osimertinib in NSCLC were demonstrated in 2 phase 2 clinical trials, AURA extension and AURA2.7,8 Both trials were single-arm, open-label studies in patients with EGFR T790M mutation metastatic NSCLC that progressed during systemic therapy, including an EGFR TKI.8 All patients had the EGFR T790M mutation as detected by the cobas EGFR Mutation Test v2.8
In the AURA extension study, 201 patients with EGFR T790M mutation metastatic NSCLC received osimertinib 80 mg once daily until disease progression.8 In the AURA2 clinical trial, 210 patients with EGFR T790M mutation metastatic NSCLC received osimertinib 80 mg once daily until disease progression.8 Patients with a medical history of interstitial lung disease or radiation pneumonitis that required steroid treatment, serious arrhythmia, or baseline corrected QT (QTc) interval >470 msec were excluded from these studies.8
The primary efficacy end point in the 2 studies was the objective response rate according to the Response Evaluation Criteria in Solid Tumors v1.1 as evaluated by an Independent Central Review committee. The secondary end point included the duration of response.8
The majority of patients who were enrolled in the AURA extension study were female (66%), Asian (58%), never smokers (67%), and with a World Health Organization (WHO) performance status of 1 (66%). The patients’ median age was 62 years (range, 37-89 years).8
In addition, 97% of patients had adenocarcinoma of the lung, and 70% had received ≥2 previous treatments for EGFR mutation metastatic NSCLC. The sites of extrathoracic metastasis included bone (51%), brain (37%), and liver (32%). Somatic EGFR mutations in addition to T790M included exon 19 deletion (71%), L858R (25%), G719X (2%), and S768I (2%).8
The majority of patients who were enrolled in the AURA2 study were female (70%), Asian (63%), never smokers (76%), and had a WHO performance status of 1 (60%). The patients’ median age was 64 years (range, 35-88 years).8
In addition, 95% of patients had adenocarcinoma of the lung, and 68% had received ≥2 previous treatments for EGFR-positive metastatic NSCLC. The sites of extrathoracic metastasis included bone (43%), brain (41%), and liver (26%). Somatic EGFR mutations in addition to T790M included exon 19 deletion (65%), L858R (32%), G719X (2%), and S768I (1%).8
Overall, 57% of patients taking osimertinib in the AURA extension study and 61% of patients taking osimertinib in the AURA2 study had a partial or complete reduction in the size of their tumor (Table).8
The majority (96%) of patients with confirmed objective responses to osimertinib had ongoing responses ranging from 1.1 months to 5.6 months after a median follow-up of 4.2 months in the AURA extension study and 4 months in the AURA2 study.8
In a separate, dose-finding portion of the AURA extension study, 63 patients with centrally confirmed T790M mutation–positive NSCLC that progressed during previous systemic therapy received osimertinib (80 mg daily). Among this subset of patients, the overall response rate was 51% with a median duration of response of 12.4 months.8
The safety of osimertinib (80 mg daily) is based on data from the 2 clinical trials involving 411 patients with EGFR T790M mutation NSCLC that progressed after previous EGFR TKI therapy. Of these patients, 81% were exposed to osimertinib for at least 6 months and 24% were exposed to osimertinib for at least 9 months. None of the patients received osimertinib for 12 months.8
Overall, 6% of patients discontinued osimertinib because of adverse reactions, the majority of which included interstitial disease or pneumonitis and cerebrovascular accidents or infarctions.8
Overall, 10 (2%) patients who received osimertinib developed fatal adverse reactions, including interstitial lung disease or pneumonitis (4 patients), pneumonia (4 patients), and cerebrovascular accidents or cerebral hemorrhage (2 patients). In addition, 4% of patients required dose reductions because of adverse reactions, including QTc prolongation (2%) and neutropenia (2%).8
Serious adverse reactions that were reported in ≥2% of patients taking osimertinib included pulmonary embolus and pneumonia.8
Adverse reactions (all grades) that occurred at a frequency of ≥25% in patients taking osimertinib included diarrhea (42%), rash (41%), dry skin (31%), and nail toxicity (25%); none of these events was grade 4.8
Grade 3 or 4 laboratory abnormalities that occurred at a frequency of ≥3% among patients who received osimertinib included neutropenia (3.4%), hyponatremia (3.4%), and lymphopenia (3.3%).8
Osimertinib has no contraindications.8
The concomitant administration of osimertinib with strong cytochrome (CY) P3A inhibitors should be avoided, because strong CYP3A inhibitors may increase the plasma concentrations of osimertinib. The concomitant administration of osimertinib with strong CYP3A inducers should also be avoided, because these agents can decrease the plasma concentrations of osimertinib.8
Drug interaction studies with inhibitors, inducers, or substrates of CYP enzymes and transporters have not been conducted.8
Warnings and Precautions
Interstitial lung disease and pneumonitis. Across clinical trials, interstitial lung disease or pneumonitis occurred in 3% of patients who received osimertinib, with 4 fatalities attributed to these conditions. Treatment should be interrupted in patients with worsening respiratory symptoms that may be indicative of interstitial lung disease. Osimertinib should be discontinued if interstitial lung disease is confirmed.8
QTc interval prolongation. Heart rate QTc interval prolongation has been observed in patients receiving osimertinib. Periodic monitoring of electrocardiogram and electrolytes is recommended for patients with congenital long QTc syndrome, congestive heart failure, and electrolyte abnormalities, and in patients taking medications known to prolong the QTc interval. Osimertinib should be permanently discontinued in patients with QTc interval prolongation and symptoms of life-threatening arrhythmia.8
Cardiomyopathy. Cardiomyopathy was observed in 1.4% of patients who received osimertinib, with 2 fatalities attributed to cardiomyopathy.8
Left-ventricular ejection fraction should be assessed by an echocardiogram or a multigated acquisition scan before starting osimertinib treatment, and at 3-month intervals while taking it. Osimertinib should be withheld if the ejection fraction decreases by 10% from the pretreatment values and is <50%. Osimertinib should be discontinued if symptomatic congestive heart failure or persistent asymptomatic left-ventricular dysfunction does not resolve within 4 weeks.8
Fetal toxicity. Osimertinib can cause fetal harm when administered to a pregnant woman based on data from animal studies and on its mechanism of action.8
Use in Specific Populations
Pregnancy. Women who may become pregnant while taking osimertinib should be advised of the risk for fetal harm.8
Lactation. There are no data on the presence of osimertinib in human milk, its effects on breast-fed infants, or its effects on milk production. Women who are receiving osimertinib should not breast-feed during treatment and for 2 weeks after the final dose.8
Females and males of reproductive potential. Women of reproductive potential should use effective contraception during treatment with osimertinib, and for 6 weeks after the final dose. Male patients with female partners of reproductive potential should use effective contraception during osimertinib treatment and for 4 months after the final dose.8
Pediatric use. The safety and effectiveness of osimertinib in pediatric patients have not been established.8
Geriatric use. Overall, 45% of patients enrolled in clinical trials of osimertinib were aged ≥65 years, and 13% of patients were aged ≥75 years.8 No overall differences in the drug’s effectiveness were observed based on patients’ age. Grade 3 and 4 adverse reactions associated with osimertinib, and the need for dose modifications for adverse reactions were higher in older patients than in younger patients.8
Renal or hepatic impairment. No studies have been conducted to evaluate the effect of renal or hepatic impairment on the pharmacokinetics of osimertinib. No dosage adjustment is recommended in patients with mild or moderate renal or hepatic impairment. There is no recommended dose of osimertinib for patients with severe renal or hepatic impairment.8
Osimertinib, an oral TKI, is an important new treatment option for patients with EGFR T790M–mutated metastatic NSCLC that progressed during or after therapy with an EGFR TKI. Overall, 2 phase 2 clinical trials demonstrated that osimertinib achieved objective tumor responses and acceptable tolerability in this patient population.
A large phase 3 clinical trial, AURA3, is under way to confirm the role of osimertinib in patients with NSCLC and the EGFR T790M mutation. This open-label, randomized study is comparing the benefit of osimertinib versus platinum-based doublet chemotherapy in patients with EGFR T790M–mutated locally advanced or metastatic NSCLC that progressed after previous therapy with an EGFR TKI.7,9
Osimertinib is also being studied in the adjuvant setting and in the metastatic first-line setting, including in patients with brain metastases and in combination with other compounds.7,10
1. Molina JR, Yang P, Cassivi SD, et al. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83:584-594.
2. Uramoto H, Mitsudomi T. Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer? Br J Cancer. 2007;96:857-863.
3. Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non–small-cell lung cancer. N Engl J Med. 2010;363:1693-1703. Erratum in: N Engl J Med. 2011;364:588.
4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): non-small cell lung cancer. Version 4.2016. January 12, 2016. www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed January 26, 2016.
5. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73.
6. US Food and Drug Administration. FDA approves new pill to treat certain patients with non-small cell lung cancer. Press release. November 13, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm472525.htm. Accessed December 28, 2015.
7. AstraZeneca. Tagrisso (AZD9291) approved by the US FDA for patients with EGFR T790M mutation-positive metastatic non-small cell lung cancer. Press release. November 13, 2015. www.astrazeneca.com/our-company/media-centre/press-releases/ 2015/TAGRISSO-AZD9291-approved-by-the-US-FDA-for-patients-with-EGFR-T790M-mutation-positive-metastatic-non-small-cell-lung-cancer-13112015.html. Accessed December 29, 2015.
8. Tagrisso (osimertinib) tablet [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals; November 2015.
9. ClinicalTrials.gov. AZD9291 versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (AURA3). https://clinicaltrials.gov/ct2/show/NCT02151981?term=NCT02151981&rank=1. Accessed December 29, 2015.
10. ClinicalTrials.gov. Osimertinib. Search results. https://clinicaltrials.gov/ct2/re sults?term=Osimertinib&Search=Search. Accessed December 29, 2015.