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Lung Cancer Case Studies

EGFR+ NSCLC: Treatment Through Multiple Lines of Therapy

Mark Socinski, MD
Published Online:Apr 13, 2018
Mark Socinski, MD, outlines the diagnosis and treatment of a 66-year-old Asian woman who presents with EGFR+ non–small cell lung cancer.

EGFR+ NSCLC


Mark Socinski, MD: Based on the FLAURA data, I have been using osimertinib as first-line therapy in patients who are diagnosed with either an EGFR exon 19 or exon 21 mutation. Now, what happens after osimertinib? Do we understand the mechanisms of resistance? Remember, T790M was the primary required resistance mechanism from first- and second-generation drugs. Osimertinib is a very good T790M drug. What are we seeing?

We don’t have a lot of data, but there are a couple of series that suggest that there may be other mechanisms. There is another mutation, C797S, which affects the binding pocket for osimertinib, and that is an acquired resistance mechanism.

The other thing emerging in these small studies, I still think it’s early, is that the rate of MET amplification, another pathway, is much higher in this population. So, I think physicians need to think about MET amplification, and we do have MET inhibitors. There have been some case reports that suggest that if you combine EGFR and MET inhibition that in patients whose mechanism of acquired resistance are amplification of MET, that may be an effective strategy.

I think when using first- or second-generation EGFR TKIs, it became the standard of care to either rebiopsy or plasma test patients, looking for T790M. Now that we have osimertinib in the first-line setting, T790M is really not an issue at that point. You need to think about other mechanisms of resistance. I would continue to rebiopsy patients. I would look for MET amplification. I would resequence EGFR to see if you have a C797S mutation. I would look for a clinical trial in that setting. There are some preclinical data—this is interesting—that the first-generation agents, gefitinib and erlotinib, may be active in the C797S-mutant subset. We need some clinical data in that realm, but there’s a possibility that even going back to a first-generation agent after a third-generation agent may be the appropriate approach in selected patients.

Based on FLAURA data, osimertinib is the new standard. We talked a little bit about the acquired resistance issues. Chemotherapy is still a good option for these patients. These patients tend to have perhaps a better sensitivity to standard chemotherapy, so I wouldn’t dismiss this. We had some recent exciting data from the IMpower-150 trial that looked at the role of anti-VEGF therapy with atezolizumab, a PD-L1 agent. There was a subset of EGFR mutation–positive patients in which there seemed to be a clear benefit of adding atezolizumab to the combination of carboplatin, paclitaxel, and bevacizumab. That, to me, is an attractive regimen in the EGFR mutation–positive population. I think we need more information about the EGFR mutation subset from IMpower-150. I wouldn’t give up on these patients. I think chemotherapy is an option, and maybe some of these innovative strategies, incorporating anti-VEGF therapy as well as immunotherapy, may be important in this subset of EGFR mutation–positive patients.

Transcript edited for clarity.

December 2017

  • A 66-year-old Asian woman presents to her PCP complaining of visual disturbances, nausea, fatigue, and sporadic headaches
  • History: HTN, managed on candesartan; hyperlipidemia managed on simvastatin; no smoking history
  • PE: BP, 148/70; LLL auscultation reveals decreased breath sounds
  • CBC: WNL
  • Imaging studies:
    • MRI of the head demonstrated a right parietal mass at the gray–white junction with vasogenic edema
    • CT of chest, abdomen, and pelvis revealed a 3.4-cm mass in the left lower lobe, and several small liver nodules
  • CT-guided transthoracic needle biopsy of the lung lesion showed grade 2 adenocarcinoma, acinar
  • Molecular testing: EGFR exon 19 deletion
  • Staging: T2aN0M1c
  • ECOG 1
  • The patient was started on osimertinib 80 mg once daily
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