Levy Discusses Treatment Considerations for a Patient With EGFR-Mutant NSCLC

Ben Levy, MD

Ben Levy, MD

Ben Levy, MD, recently shared the treatment considerations and decisions he makes when treating patients with metastatic non—small cell lung cancer (NSCLC). Levy, clinical director of Medical Oncology, John Hopkins Sydney Kimmel Center, Washington, DC, explained his treatment decisions based on a case scenario during aTargeted Oncologylive case-based peer perspectives presentation.

Case

A 66-year-old Asian woman presented to her primary care physician complaining of visual disturbances, nausea, fatigue, and sporadic headaches. She had a history of hypertension, which was managed on candesartan (Atacand), and hyperlipidemia, which was managed on simvastatin (Zocor). She had no prior smoking history. A physical exam showed that her blood pressure was 148/70 and a left lower lobe auscultation revealed breath sounds. She had an ECOG performance status of 1.

An MRI of the head revealed a right parietal mass at the gray-white junction with vasogenic edema. A CT-guided transthoracic needle biopsy of the lung lesion showed grade 2 adenocarcinoma, acinar. Molecular testing noted anEGFRexon 19 deletion. She was staged with T2 N0 M1c.

Targeted Oncology: What are your general impressions of this patient?

Levy:This is a 66-year-old female, which is not an uncommon clinical phenotype, who develops NSCLC and presents to her primary care physician with visual disturbances and sporadic headaches. Her physician exam reveals decreased breast sounds in the left lower lobe and her complete blood count is within normal limits.

She had an MRI of her brain due to her symptomatology and it reveals a right parietal mass at the gray-white junction with vasogenic edema. The CT of the chest reveals a 3.4 cm mass in the left lower lobe with small liver nodules. Due to the CT findings, a CT-guided needle biopsy of the lung lesion shows an adenocarcinoma with acinar features. Her molecular interrogation reveals anEGFRexon 19 mutation. She is a stage T2 N0 M1c and her performance status is 1.

Do you wait for results from a full panel of tests for oncogenic drivers before starting therapy in patients with metastatic NSCLC?

I would say that it depends on the patient's symptomatology. If the patient needs urgent treatment and we don't have the molecular test back, we will go ahead and start them on cytotoxic chemotherapy in the hopes that we can gain the information soon and deliver genotype-directed therapy then.

However, not all patients want systemic chemotherapy. Oftentimes, if we can wait and the patient is not symptomatic, we will until the mutation profiling comes back and then we can deliver potential targeted therapy.

What are the therapeutic options for this patient?

The therapeutic options for this patient are competing strategies. There are now first-, second-, and third-generation tyrosine kinase inhibitors (TKIs). Currently, gefitinib (Iressa), erlotinib (Tarceva), and afatinib (Gilotrif) are the FDA-approved EGFR TKIs. However, a recent phase III study called FLAURA compared the next-generation TKI of osimertinib (Tagrisso) to first-generation TKIs.¹Because of the benefit we saw with osimertinib, this is probably the preferred frontline treatment for this patient.

Would you initiate multidisciplinary assessment for treatment of her central nervous system involvement?

We need to be mindful of whether this patient, who has symptomatic brain metastasis, needs radiation or whether we can get away with just giving this patient osimertinib. Radiation would probably be the preferred option in this case, given that she is symptomatic, but if there was less vasogenic edema with less symptoms, I would certainly consider giving osimertinib.

Do you prefer to use osimertinib upfront or hold its use if anEGFRT790M mutation develops?

I think we now have good data that osimertinib not only hits T790M, but it hits exon 19 and 21 as well. There is superiority in terms of progression-free survival (PFS) and a trend towards overall survival (OS) with the use of osimertinib, compared with first-generation TKIs. I think that we have to apply the action to use our best drug first and, based on the FLAURA data, osimertinib is that drug.

The patient received osimertinib at a dose of 80 mg once daily. She experienced a good partial response, but 10 months after initiation she complained of headaches and worsening fatigue. A CT showed 3 new liver lesions and a brain MRI showed 1 new lesion. She had an ECOG performance status of 1.

What is the significance of the FLAURA data?

The FLAURA data was a head-to-head comparison between osimertinib and first-generation TKIs. The data demonstrated improved PFS, improved intracranial control of brain metastases, and a trend towards OS, at the cost of less toxicity.

When you have a drug that shows improvement in outcomes, and specifically the benefit and PFS was 9 months, I think that is meaningful. It suggests that this drug is warranted for treatment-naïve patients, in which anEGFRsensitizing mutation is discovered.

What therapeutic options are available for this patient after her disease progresses?

This is a challenging issue. The therapeutic options at this point have to be divided up into intracranial versus systemically below the neck. For patients who are on osimertinib who develop brain metastases, I would certainly think of giving this patient radiation. This could be stereotactic radiation or whole-brain, but I would try very hard to avoid whole-brain radiation and give them stereotactic radiation therapy.

Do you order repeat biopsy or liquid biopsy for mutation testing?

Post-osimertinib frontline is very much in question. How to use that information to drive decision making is an outstanding issue that we are not very sure of. I would say, for the benefits of a clinical trial, I think that either plasma and/or tissue-biopsy for molecular interrogation would be important. But, whether or not that is going to drive every day decision making for community oncologists, I would say probably not.

Assume mutation testing was performed and revealed anEGFRC797S resistance mutation. How would this influence your decision making?

I think that we are still trying to learn how best to treat C797S. Some C797S mutations may predict sensitivity to the first-generation TKI that we have now decided is no longer beneficial first line. It really depends on the configurations of C797S.

I would say off of a clinical trial, I would offer this patient chemotherapy. We know that chemotherapy works in this patient population, and I would probably add bevacizumab (Avastin) with chemotherapy given that there is additional benefit with this drug, especially forEGFR-mutant lung cancer. I think that we are still learning how to treat C797S and there are a lot of outstanding issues there.

Would you consider a checkpoint inhibitor for this patient?

The other consideration for anyone who progresses on osimertinib, either before chemotherapy or after, is the role of immunotherapy. I think we have very good data that immunotherapy is far inferior to chemotherapy for patients who areEGFRmutated. Immunotherapy, while exciting and generating tremendous enthusiasm in the oncology community, and while we have seen benefits we have never seen before, I think that we are learning more and more that [a patient with]EGFR-mutated NSCLC is not the right patient for immunotherapy. I generally steer away from using immunotherapy in any patient withEGFR-mutant lung cancer.

There have been multiple subset analyses from larger studies looking at how immunotherapy is inferior to docetaxel (Taxotere) inEGFR-mutant lung cancer. We have a subset analysis from the CheckMate 057 trial, which compared nivolumab (Opdivo) with docetaxel in an adenocarcinoma population in the chemotherapy-refractory setting.²In a subset of patients that wereEGFRmutated, immunotherapy was inferior when compared with docetaxel.

The same thing is true with the OAK study.³In the OAK trial that [looked at patients with]EGFR-mutant lung cancer, those patients who progressed on chemotherapy, who may have received a TKI, did worse with immunotherapy compared with docetaxel. There was a recent pooled analysis of all the data showing, again, that patients that areEGFRmutated, do better with docetaxel than they do with immunotherapy. Because of this data, I tend to steer away from giving any patients withEGFR-mutant lung cancer immunotherapy or any immunotherapy combination.

Whether or not immunotherapy can be used as fourth, fifth, or sixth line is not clearly understood. If there is any consideration not to use it, I will not use it. I think that we have to default to chemotherapy or clinical trials for these patients who progress on a TKI.

References:

1. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Presented at: 2017 ESMO Congress; September 9-12, 2017; Madrid, Spain. Abstract LBA2_PR.
2. Paz-Ares LG, Horn L, Borghaei H, et al. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC).J Clin Oncol.2015;33(suppl; abstr LBA109).
3. Barlesi F, Park K, Ciardiello F, et al. Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA44.