Case 4: Metastatic EGFR+ NSCLC Progressing on Osimertinib

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARDBenjamin P. Levy, MD:Our last case is going to be on anEGFR-mutant lung cancer patient. This is clearly a space that’s also witnessed incredible advances over the past 6 to 12 months. The advances have been practice-changing.

This is a 71-year old Hispanic female who presented to her primary care physician complaining of visual disturbances and headaches. Her past medical history is consistent with hypertension, managed on a beta-blocker, and hyperlipidemia. She’s a never-smoker. Upon presentation for her physical exam, her blood pressure was 150/90. Her right lower lobe auscultation reveals decreased breath sounds. Her complete blood count is within normal limits. Imaging is ordered due to her symptoms and an MRI [magnetic resonance imaging] of the head shows widely scattered lesions and a 1.2-cm occipital mass with no edema. A CT [computed tomography] of the chest, abdomen, and pelvis reveals a 3.7-cm mass in the right lower lobe, several small nodules in the right adrenal gland, and left supraclavicular lymphadenopathy.

She has a CT-guided transthoracic needle biopsy of the lung, which reveals a grade 2 adenocarcinoma. A molecular interrogation is consistent with anEGFRexon 19 deletion. Her staging is T2a N3 M1. She has a preserved performance status of 1. The patient is started on osimertinib.

The patient has follow up scans at 3, 6, 9, and 12 months. The scan at 3 months shows response. That response is maintained at 6, 9, and 12 months. A CAT scan at 18 months after starting osimertinib shows systemic progression in the lung. A repeat MRI of the brain, however, shows disease stability in the brain.

The patient’s physical exam, at that time, is consistent with decreased breath sounds on auscultation, a low-grade temperature, and some tachypnea. She does have a repeat biopsy, in which molecular interrogation is performed. The exon 19 deletion is retained. She’sT790M-negative. PD-L1 is also tested and is 100%.

We have some relevant data, that recently published in the past 6 to 12 months, that certainly relates to this case. The first, of course, is the FLAURA data that recently published in theNew England Journal of Medicine. That was a randomized phase III trial comparing a next-generation TKI [tyrosine kinase inhibitor], osimertinib, with standard of care—a first-generation TKI. I think we were all surprised to see the benefit that we did with osimertinib. Data would suggest that it’s a wonderful T790M-directed therapy, but we need to remember that it’s exquisitely sensitive against the exon 19 and 21 mutations. This data showed a benefit in progression-free survival [PFS]. The PFS in the osimertinib arm was close to 19 months. We’re starting to see trends in overall survival, although that data is still immature. Importantly, roughly 20% of patients on this trial had brain metastases. The PFS was maintained in patients with brain metastases when osimertinib was compared to standard of care. And then, without seeing CNS [central nervous system] metastases, there was a benefit as well.

Importantly, if you look at the intracranial responses in the patients who had brain metastases who received osimertinib, the response rates are north of 70%. We’ll certainly talk about the benefit that we’re seeing with osimertinib in the brain. Is that a reason not to offer stereotactic radiosurgery, or radiation to the brain for this patient? But certainly, we’re seeing high response rates in the brain.

And then, from the phase I experience with this drug, there has been some interrogation via plasma, post-osimertinib, for looking at mechanisms of resistance. This pie graph is not as clean as the pie graph we see from the first- and second-generation TKIs, in regard to mechanisms of resistance.

We’re just starting to learn about mechanisms of resistance with osimertinib as a frontline drug, and even as a second-line drug. Of course, we haveC797Shere, soKRASmay be relevant; orMETamplification; orTP53. So, they’re all over the map here. I think we’ll learn more, in the next 6 to 12 months, about what the mechanisms of resistance are and how to drug those mechanisms of resistance.

There are a lot of questions on the role of immunotherapy inEGFR-mutant lung cancer. We’ve learned that single-agent immunotherapy is probably not the best drug as any line of therapy forEGFR-mutant lung cancer, although that’s debatable. The second piece of data that I want to talk about is the IMpower 150 data. This was data that was presented at the ASCO [American Society of Clinical Oncology] Annual Meeting. It subsequently published in theNew England Journal of Medicine. This was an open-label, phase III study of more than 1200 patients who were randomized across 3 arms. The real analysis that was important compared carboplatin/paclitaxel/bevacizumab/atezolizumab versus carboplatin/paclitaxel/bevacizumab—arm B versus arm C.

Importantly, unlike many trials evaluating immunotherapy, this trial did allow for patients who hadEGFRandALKrearrangements, who had received a prior TKI. Again, recently published in theNew England Journal of Medicine, we saw a benefit in progression-free survival between arm B and arm C. The addition of atezolizumab to that carboplatin/paclitaxel/bevacizumab backbone, that ECOG [Eastern Cooperative Oncology Group] 4599 backbone, did show a benefit in progression-free survival. It did show a benefit in overall survival. Looking at thatEGFR-andALK-rearranged subset was just as important.

Again, this is a group of patients that we don’t normally think derive a meaningful benefit to immunotherapy, but we saw a benefit by adding atezolizumab to carboplatin/paclitaxel/bevacizumab, compared to carboplatin/paclitaxel/bevacizumab, in this patient population. So, I think this is starting to alter our thoughts on the role of immunotherapy. Is this a regimen that’s ready for primetime in a patient who isEGFR-positive and has progressed on a tyrosine kinase inhibitor?

Transcriipt edited for clarity.