Osimertinib: A New Standard of Care for Stage III EGFR-Mutated Non-Small Cell Lung Cancer

The recent approval of osimertinib (brand name Tagrisso) by the U.S. Food and Drug Administration (FDA) marks a significant advancement in the treatment of locally advanced, unresectable stage III non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations.

“The current standard for patients with unresectable stage III NSCLC is chemotherapy and radiation followed by durvalumab (Imfinzi) … However, it is thought that immunotherapy works poorly in patients with EGFR mutations. This [approval] opens up a new, practice-changing option for patients with EGFR mutations who are treated with chemotherapy and radiation,” Dr. Brendon Stiles, Chief of the Divisions of Thoracic Surgery & Surgical Oncology at Montefiore and Albert Einstein College of Medicine, tells SurvivorNet Connect.

Because NSCLC accounts for approximately 85% of all lung cancers and EGFR mutations are present in about 10-15% of these cases in Western populations and up to 40% in Asian populations, this approval can provide hope for a lot of patients.

The LAURA Trial: A Landmark Study

The FDA’s approval of osimertinib in this setting is based on the results of the phase III LAURA trial (NCT03521154), a double-blind, randomized, placebo-controlled study published in the NEJM.

The trial enrolled 216 adult patients with locally advanced, unresectable stage III NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations. All participants had not experienced disease progression during or after definitive platinum-based chemoradiation therapy.

Patients were randomized in a 2:1 ratio to receive either osimertinib 80 mg orally once daily or placebo, continuing until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), and safety profiles.

What Did the Results Show?

The results of the LAURA trial were compelling:

• Progression-Free Survival (PFS): Osimertinib demonstrated a statistically significant improvement in PFS compared to placebo. The median PFS was 39.1 months (95% CI: 31.5 months, not estimable) in the osimertinib arm versus 5.6 months (95% CI: 3.7 months, 7.4 months) in the placebo arm. This represents a seven-fold increase in median PFS (HR 0.16; 95% CI: 0.10-0.24; p < 0.001).

• One- and Two-Year PFS Rates: The PFS rates at 1 and 2 years were 74% and 65%, respectively, for patients receiving osimertinib, compared to 22% and 13% for those receiving placebo.
• Objective Response Rate (ORR): The ORR was 57% (95% CI: 49%-66%) in the osimertinib group versus 33% (95% CI: 22%-45%) in the placebo group.
• Duration of Response (DoR): The median DoR was substantially longer for osimertinib at 36.9 months (95% CI: 30.1 months, not calculable) compared to 6.5 months (95% CI: 3.6 months, 8.3 months) for placebo.
• Overall Survival (OS): While OS data were immature at the time of analysis, with only 36% of the prespecified deaths reported, there was no observed trend toward a survival detriment. The median OS was 54.0 months (95% CI: 46.5 months, not calculable) for the osimertinib arm and was not reached (95% CI: 42.1 months, not calculable) for the placebo arm (HR 0.81; 95% CI: 0.42-1.56; p = 0.530).

“I expect that almost all patients with stage III lung cancer and typical EGFR mutations will benefit [from the new approval],” Dr. Stiles says.

“The control arm in the trial did quite poorly suggesting that these patients almost have the equivalent of metastatic cancer. They’ve benefited strongly from the addition Tagrisso to their treatment regimen.  In the trial patients treated with Tagrisso has a remarkable 84% reduction in recurrence or death.  Nearly three fourths of Tagrisso recipients were alive and progression free at 12 months, compared to only about one fourth of placebo patients,” he adds.

Safety Profile

Osimertinib was generally well-tolerated, with a safety profile consistent with previous studies. The most common adverse reactions (occurring in ≥20% of patients) included:

• Hematologic Abnormalities: Lymphopenia, leukopenia, thrombocytopenia, neutropenia
• Pulmonary Events: Interstitial lung disease/pneumonitis
• Dermatologic Reactions: Rash, nail toxicity
• Gastrointestinal Symptoms: Diarrhea
• Musculoskeletal Pain
• Respiratory Symptoms: Cough
• Infections: COVID-19 infection was reported among adverse events, likely reflecting the timing of the trial during the pandemic

No new safety signals were identified, and adverse events were manageable with dose modifications and supportive care.

Clinical Implications

The approval of osimertinib in this setting is poised to change clinical practice significantly. Osimertinib is a third-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations, with activity in the central nervous system (CNS).

Advantages Over Previous Therapies

• Targeted Therapy Post-Chemoradiation: This is the first time a targeted therapy has been approved for use after chemoradiation in patients with EGFR-mutated stage III NSCLC, addressing a critical unmet need.
• Improved CNS Penetration: Osimertinib has demonstrated efficacy in preventing CNS progression, a common site of metastasis in EGFR-mutated NSCLC.
• Extended PFS: The significant extension in PFS allows patients to maintain quality of life longer without disease progression.

Practical Considerations

• Patient Selection: It’s crucial to identify patients with EGFR exon 19 deletions or exon 21 L858R mutations using FDA-approved tests to determine eligibility for osimertinib therapy.
• Timing of Initiation: Osimertinib should be started within 42 days after completing chemoradiation, provided there is no evidence of disease progression.
• Dosage: The recommended dose is 80 mg orally once daily, with or without food, until disease progression or unacceptable toxicity occurs.