Diverging paths representing triumph and disaster in lung cancer treatment with osimertinib.

Osimertinib: A Tale of Triumph and Disaster in Lung Cancer Treatment

Rhea Morgan in Health & Wellness August 2025 • 5 min read.

"Navigating CNS Progression in EGFR-Mutated NSCLC with T790M-Unknown Status"

Treatment strategies for EGFR-mutated non-small cell lung cancer (NSCLC) have significantly improved with the introduction of osimertinib. This third-generation EGFR inhibitor has shown remarkable efficacy, especially in cases where the EGFR T790M mutation is present, indicating resistance to earlier-generation treatments. Detecting this mutation in plasma or tumor samples is typically required before prescribing osimertinib.

However, osimertinib's ability to penetrate the central nervous system (CNS) offers a potential advantage, particularly for patients experiencing disease progression in the brain. This article delves into the complexities of using osimertinib when the T790M mutation status is negative or unknown, presenting two contrasting cases that highlight both the promise and the challenges of this approach.

Drawing from a case study, we share the clinical histories of two patients with CNS-prominent progression under first/second-generation EGFR inhibitors, where documenting the T790M resistance mutation was not possible. These cases illustrate the critical importance of considering osimertinib for CNS involvement, irrespective of T790M status, and underscore the urgent need for its broader availability.

The Two Sides of Osimertinib: Hope and Frustration

Diverging paths representing triumph and disaster in lung cancer treatment with osimertinib.

In this report, we delve into two distinct cases of young EGFR-mutated patients facing central nervous system (CNS) progression while on first-generation EGFR tyrosine kinase inhibitors (TKIs). In both instances, attempts to document the presence of the T790M EGFR mutation—typically a prerequisite for osimertinib prescription—proved unsuccessful.

The differing outcomes in these cases underscore a crucial point: the availability and timely administration of osimertinib can drastically alter the course of treatment. One patient experienced a remarkable "triumph" due to off-label access to osimertinib, while the other faced a devastating "disaster" when rapid clinical deterioration prevented its use.

Case 1: The Triumph. A 49-year-old man with EGFR-mutated lung adenocarcinoma developed brain metastases after initial treatment with gefitinib. When liquid biopsy failed to detect the T790M mutation, his neurological symptoms worsened rapidly. Despite the absence of T790M proof, off-label osimertinib was administered, leading to significant improvement and the ability to walk again.
Case 2: The Disaster. A 50-year-old woman with EGFR-mutated lung adenocarcinoma experienced miliary brain dissemination. After initial treatment with afatinib and gefitinib, her condition worsened, and brain MRI revealed diffuse metastases. Although approval for off-label osimertinib was obtained, the patient's rapid decline into a coma prevented drug administration, resulting in a fatal outcome.

These cases highlight the complexities of treatment decisions in the absence of clear molecular markers. While T790M mutation status is a key factor, the potential benefits of osimertinib in CNS disease, coupled with the urgency of the situation, warrant careful consideration even when the mutation is undetectable or unknown.

The Urgency of Access and Future Directions

The contrasting outcomes of these two cases highlight a critical need: prompt availability of osimertinib for patients with EGFR-mutated NSCLC experiencing CNS progression, regardless of their T790M mutation status. The CNS penetration of osimertinib offers a unique therapeutic advantage that should not be overlooked.

As we await the approval and licensing of osimertinib as a first-line treatment option, these experiences serve as a reminder of its potential to offer hope and improve outcomes in challenging cases. The decision to administer osimertinib in T790M-unknown CNS progression requires careful consideration of individual patient factors and the potential risks and benefits.

Ultimately, further research is needed to better understand the mechanisms of resistance and response to osimertinib in T790M-negative or unknown cases. By sharing these experiences, we hope to stimulate discussion and promote a more nuanced approach to treatment decisions in this complex patient population.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1177/0300891618809826, Alternate LINK

Title: Meeting With Triumph And Disaster: Osimertinib In T790M-Unknown Cns Progression In Egfr-Mutated Non-Small Cell Lung Cancer

Subject: Cancer Research

Journal: Tumori Journal

Publisher: SAGE Publications

Authors: Francesco Facchinetti, Francesca Bozzetti, Roberta Minari, Giovanni Ceccon, Teresa Zielli, Irene Florindo, Girolamo Crisi, Marcello Tiseo

Published: 2018-11-05

Everything You Need To Know

How does osimertinib work in treating EGFR-mutated non-small cell lung cancer?

Osimertinib is a third-generation EGFR inhibitor that has demonstrated remarkable efficacy, particularly when the EGFR T790M mutation is present, indicating resistance to earlier-generation treatments for non-small cell lung cancer (NSCLC). While detecting the T790M mutation in plasma or tumor samples is typically required before prescribing osimertinib, its ability to penetrate the central nervous system (CNS) offers a potential advantage, especially for patients experiencing disease progression in the brain. However, access to Osimertinib is not always possible and could lead to deteriation in health.

Why is osimertinib considered even when the T790M mutation status is unknown in EGFR-mutated NSCLC patients?

In some instances, documenting the T790M EGFR mutation is not possible, highlighting the critical importance of considering osimertinib for CNS involvement, irrespective of T790M status. This is because the CNS penetration of osimertinib offers a unique therapeutic advantage, especially when first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) are no longer effective. Access to this drug can alter the course of treatment. These cases highlight the complexities of treatment decisions in the absence of clear molecular markers.

Can you describe the contrasting patient outcomes observed with osimertinib treatment?

The case of the 49-year-old man demonstrates a 'triumph' of off-label access to osimertinib, leading to significant improvement in his condition after initial treatment with gefitinib failed to detect the T790M mutation. In contrast, the case of the 50-year-old woman represents a 'disaster,' where despite obtaining approval for off-label osimertinib after initial treatment with afatinib and gefitinib, her rapid decline into a coma prevented drug administration, resulting in a fatal outcome. These cases underscore how crucial the availability and timely administration of osimertinib can be.

Why is osimertinib considered for central nervous system progression in EGFR-mutated non-small cell lung cancer, especially with unknown T790M status?

When EGFR-mutated non-small cell lung cancer progresses to the central nervous system (CNS), osimertinib is considered due to its ability to cross the blood-brain barrier, potentially targeting cancer cells in the brain. This is particularly relevant even when the T790M mutation status is unknown because waiting for definitive mutation results can delay treatment, which can be detrimental given the aggressive nature of CNS progression. The urgent need for treatment often outweighs the typical prerequisite of confirming the T790M mutation.

What are some future directions in research and treatment strategies related to osimertinib and EGFR-mutated non-small cell lung cancer?

Future research directions include developing more sensitive and rapid diagnostic tests for the T790M mutation, as well as exploring other potential resistance mechanisms to osimertinib. Studies aimed at identifying biomarkers that predict osimertinib response in T790M-negative patients are also warranted. Additionally, clinical trials evaluating combination therapies that include osimertinib for CNS metastases could lead to improved outcomes. Moreover, efforts to improve access to osimertinib through streamlined approval processes and expanded insurance coverage are essential to ensure that all eligible patients can benefit from this treatment.