Overall survival of EGFR-mutated non-small cell lung cancer patients treated with Osimertinib (Tagrisso)

The two main types of lung cancer are small cell (SCLC, 10-15%) and non-small cell lung cancer (NSCLC, 85-90%) with the former almost exclusively due to smoking (less than 5% of SCLC cases occur in those who have never smoked). For NSCLC, approximately 15-20% of cases in the United States are found in individuals who have never smoked. Interestingly, the presence of EGFR mutations, which will be discussed below, is more common in non-smokers compared to smokers.

There is a close relationship between EGFR and HER2, which plays an important role in breast cancer development. HER2 (Human Epidermal Growth Factor Receptor 2) and EGFR (Epidermal Growth Factor Receptor) are both members of the human epidermal growth factor receptor (EGFR) family, which also includes HER3 (ErbB3) and HER4 (ErbB4). These receptors are part of the ErbB family of receptor tyrosine kinases (RTKs), which play crucial roles in cell growth, survival, differentiation, and migration by phosphorylating tyrosine amino acids on target proteins. 

EGFR is often overexpressed in various cancers, including lung, colorectal, and head and neck cancers. This overexpression can lead to increased cell proliferation and survival, contributing to tumor growth. Mutations in EGFR, particularly in its tyrosine kinase domain, can lead to constitutive activation without ligand binding. These mutations are common in non-small cell lung cancer (NSCLC) and can drive oncogenesis. EGFR inhibitors, such as tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, are used in treating cancers with EGFR overexpression or mutations.

Likewise, HER2 is frequently overexpressed or amplified in breast cancer (approximately 20-30% of cases) and is also seen in gastric and ovarian cancers. HER2 overexpression leads to aggressive tumor behavior and poor prognosis. HER2-targeted therapies, including monoclonal antibodies (e.g., trastuzumab, pertuzumab) and TKIs (e.g., lapatinib), have significantly improved outcomes for patients with HER2-positive cancers.

When treating lung cancer, the first order of business is to remove (resect) the tumor. Then, there is follow-up (adjuvant) therapy to make sure the cancer does not return. Historically, for resectable non-small-cell lung cancer (NSCLC), the standard care involved surgical resection followed by adjuvant treatment, which primarily involved chemotherapy. Unfortunately, the benefit of chemotherapy was limited, with a high risk of disease recurrence or death, increasing with disease stage. In addition, patients with EGFR-mutated NSCLC may have higher risk of recurrence after postoperative chemotherapy compared to those with EGFR wild-type disease.

For NSCLC the stages are as follows (based on the size of the tumor and how far it has spread):

• Stage 0 (In situ): Cancer cells are found only in the innermost lining of the lung and have not invaded deeper tissues or spread outside the lung.
• Stage I: The tumor is 3 - 4 cm and has not spread to lymph nodes.
• Stage II: The tumor is larger than 4 - 5 cm and may have spread to nearby lymph nodes.
• Stage III: The tumor is larger than 5 cm and has spread to nearby lymph nodes in the chest, or other structures near the lung.
• Stage IV: The tumor has spread to distant organs.

Each of these stages can be further subdivided into A, B, etc. e.g. Stage IIA or Stage IIB.

Fortunately, there have been numerous advances developing more effective treatments. In particular, the approvals of new targeted treatments and immunotherapies have improved disease-free survival in patients with resectable NSCLC.

In this post, I will focus on one particular targeted treatment the drug Osimertinib (brand name Tagrisso), a selective irreversible inhibitor of both wild-type and mutant EGFR tyrosine kinase receptor. An irreversible drug makes a covalent bond, not just a non-covalent bond, with the target; the covalent bond is far more stable so that the inhibitor is not likely to separate from the target. Osimertinib is considered a third-generation tyrosine kinase inhibitor (TKI) because its irreversible action, and because it can inhibit mutants that arise from resistance to previous generation TKIs. Osimertinib was approved by the FDA in 2015 thanks in large part to its effectiveness against EGFR-mutated NSCLC.

A new study was reported in The New England Journal of Medicine that quantified more precisely the survival benefit. The study design was a phase 3, double-blind, placebo-controlled trial (randomized controlled trial). 682 Patients with resected, EGFR-mutated, stage IB to IIIA non-small-cell lung cancer (NSCLC) were randomized 1:1 to receive either Osimertinib or placebo (339 to Osimertinib, 343 to placebo).

The primary endpoint was investigator-assessed disease-free survival among patients with stage II to IIIA disease. The key secondary endpoints were overall survival (time from randomization to death from any cause or last known date alive) and safety. An earlier analysis in 2020 examined disease-free survival at an earlier time point. This more recent work reported the 5-year overall survival (whether disease-free or not).

For stage II to IIIA disease, the 5-year overall survival was 85% for Osimertinib versus 73% for placebo. The overall hazard ratio for death in the treatment group was 0.49 (P<0.001), i.e. 50% reduced chance of dying. The Kaplan–Meier curves displayed early separation that continued beyond 5 years (see Figure 1). The survival benefit was consistent across various subgroups (stage IB, II, IIIA; with or without adjuvant chemotherapy). CNS metastases are a poor prognostic factor, and Osimertinib reduced CNS recurrence compared to earlier-generation EGFR-TKIs.

The authors conclude that "[a]djuvant osimertinib provided a significant overall survival benefit among patients with completely resected, EGFR-mutated, stage IB to IIIA NSCLC."

Figure 1. Kaplan-Meier plot of 5-year (60 months) overall survival among patients with stage II to IIIA non-small cell lung cancer (NSCLC) treated with Osimertnib or placebo. The overall survival was 85% (15% died) in Osimertnib group compared to 73% (27% died) in placebo group resulting in a hazard ratio of 0.49 (Tsuboi et al. NEJM, 2023).