Bright Future for Osimertinib in EGFR T790M–Positive Lung Cancer

A Backbone for Combination Therapies to Further Prolong Benefit From Targeted Therapy




The AURA3 study confirms the fundamental role of EGFR T790M testing in patients with acquired EGFR tyrosine kinase inhibitor resistance in order to plan subsequent treatment.
— Geoffrey R. Oxnard, MD

The AURA3 study—reported by Mok and colleagues and reviewed in this issue of The ASCO Post—confirms the dramatic activity of osimertinib (Tagrisso) in patients with advanced epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) and acquired resistance to prior EGFR tyrosine kinase inhibitor therapy mediated by the EGFR T790M mutation.1 The high response rate (71%) and long median progression-free survival (10 months) seen in AURA3 confirm the findings of prior phase II studies with this agent.2

The primary endpoint of the AURA3 study was to demonstrate a significant improvement in progression-free survival compared with platinum/pemetrexed (Alimta) chemotherapy, and this aim was clearly met (hazard ratio = 0.30, P < .001). As a result, it is expected that osimertinib (also known as AZD9291), which currently has accelerated U.S. Food and Drug Administration (FDA) approval based on phase II data, will receive full FDA approval and even greater clinical uptake internationally.

AURA3 vs IMPRESS

It is important to note that this is only the second phase III trial completed for patients with EGFR-mutant NSCLC and acquired resistance to tyrosine kinase inhibitor therapy. The prior IMPRESS study evaluated platinum/pemetrexed chemotherapy with or without continued gefitinib (Iressa) and was negative, with both arms demonstrating a response rate of ~30% and a median progression-free survival of ~5 months.3 The control arm of AURA3 confirms the real but modest activity of combination chemotherapy in this population, with a response rate of 31% and a median progression-free survival of 4.4 months.

One key difference between these trials is that the IMPRESS study enrolled an unselected population with acquired resistance to EGFR tyrosine kinase inhibitor therapy, whereas the AURA3 study was limited to patients undergoing a biopsy at the time of resistance with genotyping positive for the EGFR T790M mutation. In patients with resistance mediated by a mechanism other than T790M, chemotherapy remains the standard therapy. Given the nominal activity of immune checkpoint inhibitors in patients with EGFR-mutant NSCLC,4 there remains a clear need for targeted therapy options targeting other resistance mechanisms.

Fundamental Role of EGFR T790M Testing

The AURA3 study confirms the fundamental role of EGFR T790M testing in patients with acquired EGFR tyrosine kinase inhibitor resistance in order to plan subsequent treatment. EGFR T790M testing represents perhaps the first companion diagnostic in oncology that requires a new biopsy at resistance to determine a patient’s appropriateness for targeted therapy. However, such molecularly guided resistance therapy is now being investigated across a range of solid tumors.

For EGFR tyrosine kinase inhibitor resistance, T790M testing is made easier by the wide availability of assays that test the plasma cell-free DNA (cfDNA) present in a patient’s blood. A post hoc analysis of the AURA trial revealed that EGFR T790M detected in plasma cfDNA is associated with a high response rate and prolonged progression-free survival on osimertinib, similar to EGFR T790M detected with a tumor rebiopsy.5

In the AURA3 trial, of 359 patients who tested positive for T790M on tumor biopsy and with plasma available for analysis, only 184 patients had the T790M detected in cfDNA using the companion diagnostic cobas EGFR Mutation Test—representing a sensitivity of 51%. This is lower than the sensitivity of 61% reported in the earlier analysis of the AURA2 study,6 likely because patients enrolling onto AURA3 were “second-line” (chemotherapy-naive), whereas patients in AURA2 could have had more heavily pretreated disease. This finding highlights how plasma genotyping is likely to have reduced sensitivity when used earlier in a patient’s treatment course, when the cancer may shed less tumor DNA into the blood.

CNS Metastases and Overcoming Resistance

Reassuringly, the AURA3 study found that osimertinib maintained dramatic activity in patients with brain metastases, with a median progression-free survival of 10.8 months and a significant improvement vs chemotherapy (hazard ratio = 0.4). This is an important characteristic of many emerging targeted therapies, which can be highly potent with greater central nervous system (CNS) activity. Indeed, in the BLOOM trial, osimertinib has also been reported to have activity controlling leptomeningeal disease.7 Control of CNS disease may be an important way for this new agent to reduce NSCLC morbidity by delaying the development of brain metastases and avoiding the potential toxicities of brain radiation.

The next challenge will be the development of targeted therapy options that overcome acquired resistance to osimertinib in EGFR-mutant NSCLC. To date, only small cohorts have studied acquired resistance to osimertinib, with one of the largest being our early report identifying a new EGFR mutation, C797S, in 6 of 15 patients with acquired resistance.8 No clinical trials targeting EGFR C797S have yet been launched, and this will be an important space for development of new targeted therapies.

Backbone for Combination Therapies

Fortunately, the favorable tolerability of osimertinib means that it has potential as a backbone for combination therapies. Initial data from the ­TATTON trial has found that osimertinib may be safely combined with a MET inhibitor (savolitinib) or a MEK inhibitor (selumetinib), although combination therapy with a programmed cell death ligand 1 (PD-L1) antibody (durvalumab) was thought to be unsafe due to an increased incidence of interstitial lung disease.9

Furthermore, a myriad of other osimertinib combination studies are now ongoing or in development. The hope is that these trials will identify effective combination therapies that can be used to further delay the need for cytotoxic therapies in EGFR-mutant NSCLC and achieve even more prolonged benefit from EGFR-targeted therapies. ■

Disclosure: Dr. Oxnard has received consulting fees/honoraria from AstraZeneca, Ariad, Bio-Rad, Boehringer-Ingelheim, Chugai, Genentech, Inivata, and Novartis.

References

1. Mok TS, Wu YL, Ahn MJ, et al: Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. December 6, 2016 (early release online).

2. Mitsudomi T, Tsai C, Shepherd F, et al: AZD9291 in pre-treated T790M positive advanced NSCLC: AURA2 phase II study. 2015 World Conference on Lung Cancer. Abstract 1406.

3. Soria JC, Wu YL, Nakagawa K, et al: Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): A phase 3 randomised trial. Lancet Oncol 16:990-998, 2015.

4. Lee CK, Man J, Lord S, et al: Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer—A meta-analysis. J Thorac Oncol 12:403-407, 2017.

5. Oxnard GR, Thress KS, Alden RS, et al: Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small- cell lung cancer. J Clin Oncol 34:3375-3382, 2016.

6. Jenkins S, Yang J, Ramalingam S, et al: Plasma ctDNA analysis for detection of EGFR T790M mutation in patients with EGFR mutation-positive advanced non-small cell lung cancer. J Thorac Oncol 11(4 suppl):S153-S154, 2016.

7. Yang JC-H, Kim D-W, Kim S-W, et al: Osimertinib activity in patients with leptomeningeal disease from non-small cell lung cancer: Updated results from BLOOM, a phase I study. 2016 ASCO Annual Meeting. Abstract 9002.

8. Thress KS, Paweletz CP, Felip E, et al: Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med 21:560-562, 2015.

9. Oxnard GR, Ramalingam SS, Ahn MJ, et al: Preliminary results of TATTON, a multi-arm phase Ib trial of AZD9291 combined with MEDI4736, AZD6094 or selumetinib in EGFR-mutant lung cancer. 2015 ASCO Annual Meeting. Abstract 2509.


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Osimertinib Improves Progression-Free Survival vs Platinum/Pemetrexed in EGFR T790M–Positive NSCLC


Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced [NSCLC] in whom disease had progressed during first-line EGFR-[tyrosine kinase inhibitor] therapy.
— Tony S. Mok, MD, and colleagues

In the phase ...


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