More Data Are Needed to Understand the Mechanisms of Resistance in NSCLC, Levy Says

Benjamin P. Levy, MD

Benjamin P. Levy, MD

During aTargeted Oncologycase-based peer perspectives meeting, Benjamin P. Levy, MD, discussed his clinical considerations for the management of non—small cell lung cancer (NSCLC). Levy, clinical director of medical oncology, John Hopkins Sidney Kimmel Cancer Center, Sibley Memorial Hospital, explained his treatment decisions using 2 case scenarios during the live event.

Case 1

A 75-year-old woman presented with persistent cough and congestion lasting more than 6 months, along with recent onset of dizziness and headaches. She was a non-smoker and drank alcohol 1-2 times per week.

Her past medical history showed Crohn’s disease, which was managed on infliximab (Remicade); hypothyroidism, which was moderately well-managed on levothyroxine (Synthroid); and osteoarthritis that was managed as needed on naproxen (Aleve). Her physical exam and cardiac workup were normal, and her complete blood count was within normal limits. She had an ECOG performance status of 2.

A chest x-ray showed mass in the upper right lung. A CT of the chest, abdomen, and pelvis showed a solid 6 x 8 cm right-sided pleural mass abutting the apical aspect of the chest wall, and 2 small hepatic nodules measuring 1.5 cm and 2 cm. She later underwent a bronchoscopy and biopsy of the lung mass, which showed a pathology was consistent with large cell carcinoma. She was shown to have anEGFRL858R mutation. PD-L1 testing by immunohistochemistry showed 0% expression in tumor cells. A brain MRI showed multiple brain metastases.

The patient was later diagnosed with stage IV NSCLC.

What are your initial impressions of this patient?

This is a patient who presented with advanced stage lung cancer, but who also has a pre-existing autoimmune disease managed on infliximab. She has hypothyroidism managed on levothyroxine. The biopsy is performed on this patient because she presents with cough and congestion. A CT scan shows a right-sided lung mass. The biopsy is done and is consistent with anEGFRmutation. In this patient, the brain MRI shows multiple brain metastases as well. She is also noted to have some liver metastases as well.

It doesn't say in the case what happened to the brain nodules, but this patient was started on a first-generation tyrosine kinase inhibitor (TKI), which was gefitinib (Iressa). I can only assume that this case happened prior to the first-line approval of osimertinib (Tagrisso). Importantly, she has an initial response but then, at 6 months, there was progression in the lung and liver, as well as in the brain. The patient's performance status then declined, and a circulating tumor DNA assay was done, which identified the T790M resistance mutation.

What are the options for treatment of the brain nodules?

There are a lot of nuances to this case. One is, how do you manage a patient who presents with asymptomatic brain metastases who isEGFRpositive? I think a lot of us, if they are asymptomatic and the brain metastases are small, would offer the patient a TKI first without giving whole brain radiation therapy. I believe that was what was done in this case. This patient was offered gefitinib and had some control but progressed at 6 months.

Would you preform tissue testing for T790M resistance mutation?

The second nuance of this case is, what do you do when the first-generation TKI no longer works? Of course, you order a plasma test on these patients. If the plasma test is positive for T790M, you don't need to do a tissue biopsy. If it is negative, you do need to do the tissue biopsy.

The patient was started on gefitinib. Imaging was performed at 6 months, which revealed an increase in the size of the lung lesion as well as a new lung, liver, and brain lesions. Her ECOG performance status remained at 2. A circulating tumor deoxyribonucleic acid (DNA) assay was performed and was negative for T790M resistance mutation.

What are the options for second-line therapy for this patient?

In this case, the plasma test was positive and, appropriately, the patient went on osimertinib. We do have to remember that osimertinib is now approved frontline. This case presentation happened, I can only assume, before the frontline indication occurred. For those patients who remain on a first- or second-generation TKI, when they do progress we still want to do the plasma test and the tissue biopsy if the plasma is negative. But this is certainly a case where the patient should be on osimertinib. In this case, for a patient who has unfortunately progressed on a first-generation TKI with gefitinib and whose plasma test is T790M positive, I would certainly offer this patient osimertinib.

The nice thing about this drug is that it does not only achieve disease control below the neck, by controlling the cancer in the liver and lungs, but the drug has wonderful penetrance in the brain. This patient could then be adverted from whole brain radiation.

I think that this case highlights a couple of things: the management of asymptomatic brain metastases in a patient who isEGFRpositive and what to test for and how to test when a patient progresses on a first-generation TKI. I think we can start with plasma. If the plasma is negative, then we should proceed with a tissue biopsy. But if the plasma is positive, certainly for T790M, this is a case that certainly could be made for giving osimertinib next.

If you saw this patient now, how would you treat this patient differently?

If this patient were now in my office, I would not have started with gefitinib. I would have started with osimertinib given the frontline approval. I would not have given this patient whole brain radiation therapy or radiation to the brain, I would just have given osimertinib. But this question is probably layered in because we do still have patients who have been on first-generation TKIs because the approval of osimertinib happened roughly 4 or 5 months ago. So, some of these patients still remain on frontline first- or second-generation TKIs. But, if this patient were in my office, I think the standard of care now for treatment-naïve patients with sensitizingEGFRmutations is osimertinib.

How should this patient be treated after progression on osimertinib?

I think after progression on osimertinib, that is an unanswered question. I think that there is a lot of work that needs to be done. We are still trying to understand mechanisms of resistance to osimertinib frontline. We will have those data maybe in the next year or 2. We have got some early data looking at certain mechanisms of resistance. One of those is C797S. If a patient has this mutation, there is a chance they may respond back to a first-generation TKI. But, also, apart from a clinical trial, I would offer them chemotherapy. But, of course, patients should go on clinical trials. We need to understand better what to do after osimertinib.

Case 2

A 73-year-old Caucasian man was seen in the emergency department for severe dyspnea and chest pain. His past medical history showed symptomatic chronic obstructive pulmonary disorder (COPD) managed on fluticasone and vilanterol inhaler. He was also noted to have a 50-pack/year smoking history.

A chest x-ray revealed a large mass in the lung right upper lobe. A CT of chest, abdomen, and pelvis was performed, showing a 6.8-cm mass right-sided mass invading the chest wall, small left pleural effusion, and several small lytic lesions in the T4/5 vertebrae. A CT-guided transthoracic needle biopsy of the lung lesion confirmed grade 2 adenocarcinoma.

A next-generation sequencing (NGS) test revealed anEGFRexon 21 L858R mutation for this patient. He was staged at T3N0M1. The patient had an ECOG performance status of 1.

What are your general impressions of this patient?

This is a patient who is a 73-year-old man who presents with severe dyspnea and chest pain. He has a history of COPD and a 50-pack/year smoking history. He gets a chest x-ray that shows a large right upper lobe mass and then a CT scan of the chest, abdomen, and pelvis revealed a 6.8-cm mass of the right lung invading the chest wall with a small pleural effusion. He also has small bone lesions in the T4 and T5 vertebrae. He gets a CT-guided biopsy of the lung that revealed an exon 21 L858R mutation.

What is your preferred approach for a symptomatic patient for whom you don’t yet have molecular testing results?

I think if this patient were symptomatic and we did not know the molecular testing yet, I would start them on chemotherapy while we wait for the molecular testing to return. Once that molecular testing returns, if it were positive I would switch them to targeted therapy. But I think there are some thoracic medical oncologists who would continue the chemotherapy if they are doing very well.

How does the presence of an L858R mutation influence your treatment selection?

I think that this patient, with an L858R mutation, warrants osimertinib first. Osimertinib is now approved frontline for sensitizing mutations, including exon 19 and exon 21. This patient was started on afatinib (Gilotrif), which is a second-generation TKI, and had disease progression after 1 year.

The patient was started on afatinib and achieved a partial response, but disease progression was detected on imaging after 1 year. A liquid biopsy was performed and revealed a T790M resistance mutation. The patient was later switched to osimertinib 80 mg once daily for 10 months and started to experience worsening dyspnea.His ECOG performance status was now 2.

What factors influence your decision to switch from osimertinib?

If the patient warrants a therapeutic switch, meaning that they are symptomatic, and their scans show real progression, I generally take them off osimertinib. There are cases where I would continue osimertinib beyond progression and that would be in a case where there is only 1 spot growing or they have brain metastases that are under control by the osimertinib, but other spots are growing in their lungs. That may be an opportunity to continue the osimertinib to continue to achieve disease control in the brain and layer in chemotherapy. I have done this with several patients.

What are the treatment options for this patient upon disease progression on osimertinib?

I still think that we’re in a bit of a vacuum here trying to understand what to do. Mechanisms of resistance have to be elucidated. And they are currently trying to be elucidated, both in plasma and in rebiospies. There have been recent data looking at discrepant outcomes for these patients based on if the patient retains the T790M or loses it. I think that we are still trying to understand how to manage these patients and what the true mechanisms of resistance are. In the next 12 to 18 months, we will have better answers. But we just don't know yet. We are starting to see some novel mechanisms, such asKRASandMETamplifications, small-cell transformation, and I think we are just at the ground floor of trying to understand what to do.

For this patient, outside of a clinical trial, I would offer this patient chemotherapy. But these patients really need to be considered strongly for clinical trial opportunities.