Osimertinib: A Novel Therapeutic Option for Overcoming T790M Mutations in Non–Small Cell Lung Cancer

Lung cancer is the leading cause of cancer death for men and women in the United States. A total of 224,390 new cases of lung cancer and 158,080 deaths were estimated to have occurred in 2016. Furthermore, one in four deaths due to cancer is expected to be from lung cancer (Siegel, Miller, & Jemal, 2016). Despite this high morbidity and mortality, tremendous advancements have been made in the treatment of lung cancer with the use of novel targeted therapies (Johnson, Schiller, & Bunn, 2014).

Non–small cell lung cancer (NSCLC) accounts for 85% to 90% of all primary lung cancers, and a significant proportion of patients present with metastatic disease at diagnosis (Reck et al., 2014). Several genetic aberrations for the histologic subtype adenocarcinoma have been identified and are known to increase tumorigenesis and early carcinogenesis; therefore, molecular profiling of tumor samples is now considered to be the standard of care (Siegelin & Borczuk, 2014).

The most common driver mutations associated with adenocarcinoma are epidermal growth factor receptor (EGFR) mutations (Midha, Dearden, & McCormack, 2015). Historically, chemotherapy has been the standard in first-line therapy for metastatic NSCLC, but with limited overall effectiveness (Scagliotti et al., 2002). However, the approval of tyrosine kinase inhibitors (TKIs) such as gefitinib (Iressa), erlotinib (Tarceva), and afatinib (Gilotrif) have yielded significant increased response rates, quality of life, and fewer toxicities compared with chemotherapy (Mok et al., 2009; Rosell et al., 2012; Sequist et al., 2013; Burotto, Manasanch, Wilkerson, & Fojo, 2015). Therefore, these treatments are recommended as initial therapy in patients whose tumors harbor sensitizing EGFR mutations (National Comprehensive Cancer Center, 2017).

Patients who initially respond to the TKIs invariably develop biologic resistance after 8 to 16 months of therapy (Gao & Costa, 2016; Yu et al., 2013). The most common mechanism of acquired resistance is through the EGFR T790M mutation, which is seen in up to 50% to 60% of resistant cases (Yu et al., 2013; Peters, Zimmermann, & Adjei, 2014). Once T790M resistance emerges, the median survival is less than 2 years (Yu et al., 2013; Sequist et al., 2011).

Third-generation EGFR inhibitors such as osimertinib (Tagrisso; also known as AZD9291) have demonstrated the ability to block the growth of T790M-positive tumors and display an increased affinity for EGFR mutations compared with wild-type EGFR (Sequist et al., 2011; Tan, Gilligan, & Pacey, 2015; Liao, Lin, & Yang, 2015; Cheng, Nair, & Murray, 2016). Osimertinib was granted accelerated approval by the US Food and Drug Administration (FDA) in 2015 for the treatment of patients with advanced and metastatic EGFR T790M–mutant NSCLC who experienced disease progression on prior TKI therapy.

PHARMACOLOGY AND MECHANISM OF ACTION

Osimertinib is a novel irreversible TKI with a greater affinity for mutant EGFR than wild-type EGFR (Greig, 2016). The discovery process for osimertinib was as novel as the agent itself. A systematic approach of a compound generation was employed using structure-based design for irreversible inhibitors and property-based evolution to determine kinase selectivity (Yver, 2016). When osimertinib was evaluated in preclinical trials, the agent demonstrated potent inhibition of EGFR and T790M signaling pathways in vitro and sustained tumor regression in vivo (Yver, 2016).

Osimertinib belongs to a class of small-molecule TKIs that irreversibly bind to various intracellular tyrosine kinase domains of receptors. Unlike other EGFR TKIs, osimertinib is structurally different and inhibits not only sensitizing EGFR mutations, but also HER2, HER3, HER4, ACK1, and BLK (AstraZeneca, 2016). Intracellular binding of osimertinib prevents tyrosine kinase activation and, therefore, inhibits EGFR downstream signaling pathways, which results in a decrease in angiogenesis and cancer-cell proliferation (Harari, 2004; Salomon, Brandt, Ciardiello, & Normanno, 1995).

CLINICAL TRIALS

The promising evidence from preclinical research on osimertinib paved the way for further clinical trials. The phase I/II dose-escalation AURA trial evaluated the safety, efficacy, and tolerability of osimertinib in patients with advanced EGFR-mutated, T790M-positive NSCLC who received prior EGFR TKI therapy. The phase I portion of the trial enrolled 31 patients to receive osimertinib ranging from 20 to 240 mg/day. A total of 51% of patients experienced a partial or complete response (n = 1), 33% had stable disease, and 14% had progressive disease; the objective response rate (ORR) was 67% (95% confidence interval [CI]: 52%–70%). The maximum tolerated dose was not reached, but higher doses were associated with more side effects. Therefore, 80 mg daily was recommended for future trials (Jänne et al., 2015).

In April 2014, the FDA granted osimertinib breakthrough therapy designation following evidence from the phase I AURA trial. Subsequently, two phase II trials were developed. The AURA extension trial evaluated an additional 222 patients (n = 253) to determine ORR. The ORR was 61% (78 of 127; 95% CI: 52%–70) for those with EGFR T790M–mutant NSCLC, and the median duration of progression-free survival (PFS) was 9.6 months (95% CI: 8.3 to not reached; Jänne et al., 2015).

The phase II AURA2 was a multicentered, open-label, single-arm trial of 210 patients with T790M mutations who received osimertinib at 80 mg daily. After a median follow-up of 13 months, the ORR was 70%. Six patients experienced a complete response, and 67% of patients achieved a partial response. The rate of stable disease at 6 weeks of treatment was 21%, and the disease control rate for these patients was 92%. The median PFS was 9.9 months (Goss et al., 2016). These data contributed to the FDA approval of osimertinib for the treatment of patients with metastatic NSCLC who have EGFR T790M–mutant disease and whose disease progressed following EGFR inhibitor therapy.

A recent phase III randomized trial compared osimertinib with platinum-pemetrexed (Alimta) chemotherapy in 419 patients with EGFR T790M–positive metastatic NSCLC. The trial demonstrated that osimertinib improved PFS compared with chemotherapy (10.1 vs. 4.4 months; hazard ratio, 0.3; 95% CI: 0.23–0.41; p < .001). The ORR was also significantly improved with osimertinib (71%; 95% CI: 65%–76%) than with cytotoxic chemotherapy (31%; 95% CI: 24%–40%; Mok et al., 2017).

ADVERSE EVENTS

The most common adverse events among patients receiving osimertinib were diarrhea, rash, dry skin, and nail toxicity. Grade 3 adverse effects were rather minimal (AstraZeneca, 2016; Table 1). Osimeritinib is associated with several serious side effects that require vigilant monitoring. They include cardiotoxicities, such as QTc prolongation and cardiomyopathy, and pulmonary toxicities, such as interstitial lung disease (ILD) and pneumonitis (AstraZeneca, 2016). Additionally, unlike the first- and second-generation EGFR TKIs, osimertinib was associated with neutropenia, which was reported in approximately 5% of patients in the AURA3 trial (Mok et al., 2017). It is imperative that advanced practitioners (APs) monitor patients for these unique and rare toxicities.

Table 1.

Common Adverse Events (> 20%) Associated With Osimertinib (N = 411)

DOSING AND ADMINISTRATION

Osimertinib is commercially available in 40-mg and 80-mg tablets, and the recommended starting dose is 80 mg once daily until disease progression or unacceptable toxicity. Doses may be reduced to 40 mg for certain toxicities. Osimertinib can be administered with or without food, and absorption is not affected by agents that alter gastric acid.

In patients with difficulty swallowing tablets, osimertinib can be dispersed in 2 ounces of noncarbonated water and gently stirred. Once the tablet is in smaller pieces, patients should drink the suspension immediately. Patients should know that the tablet will not completely dissolve. Following administration, patients should add additional water into the container and drink the mixture to ensure a full dose of osimertinib was taken (AstraZeneca, 2016).

Dose adjustments are not recommended for patients with mild or moderate renal impairment. No clinically significant difference in metabolism was observed in patients with mild hepatic impairment. Osimertinib does interact with strong CYP3A inducers, and concomitant administration should be avoided. If therapy with strong CYP3A inducers cannot be avoided, the dose of osimertinib should be increased to 160 mg daily. Osimertinib can increase the exposure of medications that utilize the BCRP substrate, which will potentially increase the risk of exposure-related toxicities with these medications. Providers should monitor for adverse reactions with medications that use the BCRP substrate (AstraZeneca, 2016).

IMPLICATIONS FOR THE ADVANCED PRACTITIONER

It is imperative for APs to provide adequate counseling for patients prior to starting osimertinib. Advanced practitioners should obtain a baseline electrocardiogram (ECG) and monitor electrolytes in patients with a history of or predisposition to QTc prolongation or for those who are on concomitant QTc-prolonging medications. Additionally, APs should note that patients with a baseline QTc of 470 msec or longer were excluded from studies with osimertinib. Per manufacturer recommendations, patients also should receive a baseline scan to assess left-ventricular ejection fraction, and subsequent scans should be performed every 3 months (AstraZeneca, 2016). Patients should also be educated about the signs and symptoms of ILD/pneumonitis and promptly evaluated for new or worsening respiratory symptoms.

Advanced practitionerts should be vigilant that patients are not currently taking strong CYP3A inhibitors or inducers while taking osimertinib. If concomitant therapy with CYP3A inhibitors is necessary, patients should be closely monitored for toxicities (AstraZeneca, 2016).

Osimertinib is associated with embryofetal toxicity. Men and women of childbearing potential should use effective contraception during treatment with osimertinib. Women should continue to use contraception for at least 6 weeks after the final dose of osimertinib, and men should use effective contraception for at least 4 months afterward (AstraZeneca, 2016).

Approximately 4.4% of patients who received osimertinib on clinical trials required dose reductions. The most frequent adverse effects that resulted in a dose reduction were QTc prolongation and neutropenia (AstraZeneca, 2016). Therefore, periodic laboratory monitoring as well as ECG in patients at risk for QTc prolongation is recommended. Table 2 illustrates the recommended dose adjustments for cardiotoxicity, pulmonary toxicity, and other grade 3 or higher adverse reactions.

Table 2.

Recommended Dose Adjustments for Serious Adverse Effects to Osimertinib

ONGOING TRIALS

Osimertinib is currently being evaluated in a variety of settings, such as first-line monotherapy for metastatic NSCLC and in combination with immunotherapy and other targeted agents (Greig, 2016). Osimertinib is believed to have a benefit as initial therapy for patients with metastatic EGFR-mutated NSCLC, because it can delay T790M resistance.

A study of 60 patients was conducted. A total of 30 patients received osimertinib at 80 mg, and 30 patients received 160 mg daily. The ORR was 77%, with a median PFS of 19.3 months for the 160 mg dose; the median PFS for the 80-mg dose had not been reached (Ramalingam et al., 2016). Although these findings are preliminary, they remain promising for further evaluation.

CONCLUSION

Historically, patients with metastatic NSCLC have limited treatment options and experience significant morbidity and mortality. The use of TKIs provides an improved quality of life and better clinical outcomes compared with traditional chemotherapy (Scagliotti et al., 2002). However, acquired resistance to the EGFR TKIs eventually leads to disease progression (Yu et al., 2013). The approval of osimertinib provides a new viable therapeutic option for those with EGFR-mutated disease that harbors the T790M mutation.