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Osimertinib in NSCLC
Osimertinib: A New EGFR Inhibitor to Overcome Acquired Resistance in Advanced NSCLC

Released: April 29, 2016

Expiration: April 28, 2017

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Case Report
A 64-year-old woman presented with weight loss, a persistent cough, and a reported episode of hemoptysis. Workup revealed a right-lower lobe lung mass, mediastinal adenopathy, bilateral pulmonary nodules, and a liver lesion. She was diagnosed with lung adenocarcinoma, based on a core-needle biopsy of the right lower lobe lung mass. The tumor had an activating EGFR mutation in exon 19. She was started on erlotinib 150 mg/day. She achieved a PR, experienced meaningful improvement in her symptoms, and was able to return to her regular life.

However, approximately 1 year later, CT scan revealed new pulmonary nodules, but she was not symptomatic. Five months later, the nodules had increased in size and she developed a cough. The progression was deemed sufficient to discontinue further therapy with erlotinib. Biopsy of a lung lesion revealed the EGFR T790M mutation in addition to the exon 19 mutation. She was started on osimertinib, a third-generation EGFR inhibitor, at 80 mg/day. She tolerated it well and had a PR within 2 months, which has now been sustained for 5 months. She is being followed every 2 months in the clinic.

Acquired Resistance to EGFR Inhibition
This case illustrates acquired resistance to EGFR inhibition in lung cancer and a new approach to treating these patients. EGFR TKIs are the standard of care for first-line therapy of patients with NSCLC and EGFR‑activating mutations in exons 19 and 21. These mutations are associated with exquisite sensitivity to EGFR TKIs. Testing for EGFR mutations, along with ALK and ROS1 testing, is part of the routine workup for advanced nonsquamous NSCLC.

Response rates to first‑line EGFR TKI therapy are approximately 50% to 65%, and the median PFS is 9--13 months. Three EGFR TKIs are approved for NSCLC treatment in the United States: erlotinib, gefitinib, and afatinib. Erlotinib and gefitinib are first‑generation EGFR inhibitors, and afatinib is a second‑generation inhibitor that works by causing irreversible blockade of the EGFR. The recent randomized LUX-Lung 7 trial suggested a favorable outcome with afatinib over gefitinib (higher response rate, modest PFS improvement) though afatinib is associated with greater toxicity relative to gefitinib.

Regardless of initial response to EGFR TKI therapy, resistance invariably develops, which in 50% to 60% of patients is due to an EGFR T790M mutation. This mutation alters the structure of the EGFR tyrosine kinase–binding pocket such that first‑generation and second‑generation TKIs are no longer able to inhibit EGFR activity. Other mechanisms of resistance include conversion to small-cell histology in approximately 5% of patients and activation of the MET pathway in another 10% to 15%. Because treatment options vary depending on the mechanism of resistance, it is important to obtain a biopsy upon progression.

Liquid Biopsies
Liquid biopsies represent a promising new technology that can test cell‑free DNA in peripheral blood for EGFR resistance mutations. The sensitivity for detection of the T790M mutation is approximately 65% to 80% and the specificity is 95% to 100%. A positive result indicates the T790M mutation is present, but a negative result still has an approximately 20% to 30% chance that the mutation is present; therefore, a biopsy is still needed. Of note, cell‑free DNA testing does not detect conversion to small-cell lung cancer, which is why I think tissue testing is preferable whenever possible.

Osimertinib
Until recently, patients with the T790M mutation had no effective treatment options other than chemotherapy. But in November 2015, the FDA approved osimertinib, a mutant‑specific EGFR TKI. Osimertinib inhibits EGFR with either exon 19 and 21 mutations or T790M and is highly selective for these mutated versions of this receptor vs wild‑type EGFR, which is consistent with the better reported toxicity profile as noted below.

At the recent European Lung Cancer Conference, Yang and colleagues presented updated results from 2 cohorts of patients with T790M that progressed on a previous EGFR TKI and were treated with osimertinib (N = 400). In these phase II studies, the response rate was 66%, the median PFS was 11 months, and the median duration of response was 12.5 months.

Osimertinib also demonstrated very good tolerability, with grade 1 skin rash and diarrhea as the most common toxicities (grade 3 was very rare). Pulmonary toxicity (interstitial lung disease–like event) was noted in approximately 2% of patients. Low-grade hyperglycemia was seen in just 1 patient, and low-grade QT prolongation was seen in 3%. These data demonstrate that osimertinib is effective and safe for T790M‑positive patients.

Mechanisms of resistance to osimertinib are mediated by mutations at the C797 codon of EGFR; it is not yet known what percentage of patients harbors this or other mechanisms of resistance. Today, for patients who develop resistance to osimertinib, chemotherapy is the standard option—a platinum‑based doublet regimen or single‑agent chemotherapy for those with previous platinum treatment. Of note, anecdotal evidence indicates that osimertinib has activity in the brain, and some studies have already treated patients with brain metastases.

Conclusion
Treatment of EGFR mutation–positive patients with NSCLC has undergone major change with the approval of osimertinib as second‑line therapy for patients with T790M resistance to first-line treatment with first‑generation or second‑generation EGFR TKIs. Osimertinib is also now being tested in earlier stages of NSCLC and in combinations. Similar promising third-generation EGFR TKIs are also in development (eg, rociletinib, HM61713 BI 1482694) for patients with acquired resistance to first-generation and second-generation EGFR TKIs.

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In how many of your patients with lung cancer who progress on an EGFR TKI are you obtaining new biopsy tissue to evaluate the cause of resistance?
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