Treatment After Progression on Osimertinib for EGFR+ NSCLC

Martin Dietrich, MD, PhD:Treatment post-progression on osimertinib is a big question. We don’t have any therapies approved post-osimertinib, and my recommendation is a clinical trial. There are several overriding mechanisms that are potentially actionable:METamplification,BRAFactivation, an overdrive of the EGFR receptor itself. In the end, those are very difficult assays to run. They require tissue. They require gene expression profiles if they’re not identified by simple mutations. But we know that the post-osimertinib resistance pattern is much more heterogeneous compared to the post-first and second-generation TKIs [tyrosine kinase inhibitors] with a predominant T790M development. So my recommendation right now is a clinical trial. In my practice, if a patient does not match clinical trial criteria, the IMpower150 regimen is going to be my preferred therapy of choice.

Re-biopsy is a concept that has been used in breast cancer for 20 years. In lung cancer, this is a concept that has been established. We’ve had an approval for second-line molecular markers for osimertinib for several years now. But it really hasn’t been used as stringently as it should have been. So I do recommend re-biopsy of growing tissue lesions—I think this is critical—including an RNA-based sequencing profile to look for potential gene expression profile changes that may explain progression. I don’t think that it’s reasonable to fly blind. There’s clearly a change in the disease, clearly a change in the biological behavior that probably results in changes in gene expression or potentially in gene mutations. Understanding these changes is critical in guiding the patient's therapy. The idea of targeted therapy and personalized medicine is to go by these molecular changes, not necessarily to rely on plum sequences of individual treatment regimens.

Liquid biopsy is an option in non—small cell lung cancer upon progression. It obviously only captures DNA changes. They would probably miss the majority of overriding mechanisms in the post-osimertinib setting. I think in the absence of an available tissue biopsy, or if the patient is uncomfortable with additional invasive procedures, it is a reasonable option. I think it carries reasonable sensitivity and is certainly a procedure in which the patient is subjected to very few downsides. So I think it is reasonable in the absence of tissue availability. But tissue has the ability to look at RNA, has the ability to look at additional markers in this setting, and can reconfirm the diagnosis. There is some heterogeneity. You can have obviously multiple clones that may be growing, so my recommendation would be to target the growing lesions of concern with directed tissue biopsy.

Transcript edited for clarity.

Case: A 60-Year-Old Male with Untreated Stage IVEGFR+NSCLC

Initial presentation

• A 60-year—old Caucasian man presented with shortness of breath, mild dry cough
• PMH: hyperlipidemia, hypertension, medically controlled
• SH: non-smoker, worked 40 years in ship-building industry
• PE: Lungs clear on auscultation bilaterally; anxious-appearing; acknowledges feeling nervous about his health

Clinical workup

• Imaging:
  • Chest x-ray showed a right bronchial lung mass
  • Chest/abdomen/pelvic CT scan revealed a 4.6-cm mass on the right main bronchus and ipsilateral subcarinal lymphadenopathy; positive for a single suspicious 2-cm hepatic lesion on the right lobe
  • PET scan showed activity in the right main bronchus and subcarinal nodal area, hepatic lesion was shown to be avid
  • Brain MRI negative for metastases
• Patient underwent bronchoscopy with TBNA
• Diagnosis and staging: Biopsy showed high-grade lung adenocarcinoma; T2N2M1b — IVA
• Molecular testing:EGFRexon 21 L858R, PD-L1 TPS 50%
• ECOG PS 0

Treatment

• Patient started on osimertinib 80 mg PO qDay
  • At 3-week follow-up the patient had been tolerating treatment well; continued osimertinib
• Repeated chest/abdomen/pelvic CT with contrast after every 2 cycles,
  • Partial response after 4 cycles, no disease progression at 3, 6 and 12 months
• Imaging at 19-month follow-up revealed a new solitary liver lesion