Benjamin P. Levy, MD

During aTargeted Oncologycase-based peer perspectives program, 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, reviewed his treatment options and the other factors that go into his treatment decision making based on a case scenario of a patient withEGFR-positive NSCLC.

Case

A 66-year-old Caucasian woman presented to her primary care physician complaining of visual disturbances, nausea, fatigue, and sporadic headaches. Her history revealed hypertension, managed on candesartan (Atacand) and hyperlipidemia managed on simvastatin (Zocor). She did not have a smoking history. On physical exam, her blood pressure was 148/70 and a left lower lobe auscultation revealed decreased breath sounds. Her complete blood count was within normal limits.

An MRI of the head demonstrated a right parietal mass at the gray-white junction with vasogenic edema. Additionally, a CT of the chest, abdomen, and pelvis revealed a 3.4-cm mass in the left lower lobe, and several small liver nodules. The patient’s CT-guided transthoracic needle biopsy of the lung lesion showed grade 2 adenocarcinoma, acinar.

Molecular testing revealed that the patient had anEGFRexon 19 deletion. She was staged at T2aN0M1c and her ECOG performance status was 1.

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

Levy:The first case is a woman who presents to her primary care physician with visual disturbances, nausea, fatigue, and headaches. She has the typical comorbidities. Her blood pressure is slightly elevated, and she has decreased breath sounds. The MRI of the head demonstrates right parietal mass at the gray-white junction with vasogenic edema. It doesn't say the size of the mass. The CT scan reveals a 3.4-cm mass in the left lower lobe and there is a biopsy done of the lung lesion that showed adenocarcinoma.

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

Levy:At my practice, it takes an eternity to get the results sometimes. If we didn't know theEGFRstatus at this point and if you are waiting and the patient is symptomatic and has a brain met, most people would deal with the brain met while they are waiting.

If you were starting [treatment in this] patient, who is a never-smoker, and you are still waiting on testing and you've already addressed the brain, the systemic regimen I would choose would be carboplatin plus pemetrexed (Alimta).

Targeted Oncology: Which new genes should routinely be tested for alterations in NSCLC?

Levy:There are new guidelines. It is now mandatory to test for:EGFR, ALK, ROS1,andBRAF. How they are done, whether they are done sequentially or at the same time, is up for debate. The question then becomes: Should we be testing for others, includingMET, RET, HER2,andKRAS? I can't tell you how many additional mutations I have picked that aren'tEGFRorALKin a never-smoker by doing next-generation sequencing (NGS). So, I'm a big proponent of NGS, although it does take longer.

We have some data withMETexon 14 skipping mutations, but we don't know how to manageMETamplifications. We have Loxo-292 which was the highlight at the ASCO Annual Meeting this year forRET-rearranged lung cancer with a response rate north of 75%.1We also have some drugs in the pipeline forHER2. ForKRAS, we have no idea how to treat it other than cytotoxic chemotherapy.

All institutions should offer 1 of these options: a comprehensive cancer panel withEGFR, ALK, ROS1, BRAF, MET, HER2, RET,and KRAS;or targeted agents including EGFR, ALK, ROS1, and then offer a second test with an expanded panel includingBRAF, MET, HER2,andRET. There was poster at ASCO regarding the cost effectiveness of this process and whether or not a comprehensive cancer panel saves money because it is very expensive.2It turned out that it did actually save money, at least in this hypothetical model, compared to sequential testing. It is something to consider.

Targeted Oncology: What is the rationale for treating your patient with osimertinib (Tagrisso) in the frontline setting?

Levy:There are evolving standards in NSCLC and they happen quickly. The FLAURA study investigated frontline osimertinib, and it had some interesting nuances.3It was a clean trial for patients withEGFRexon 19 or exon 21 mutations. Stable central nervous system (CNS) metastases were permitted. They were randomized to either erlotinib (Tarceva) or gefitinib (Iressa), first-generation tyrosine kinase inhibitors (TKIs), versus the third-generation TKI osimertinib. Remember, osimertinib was initially developed as a T790M-indirected therapy. People forgot that it also hit exon 19 and exon 21 quite nicely and exquisitely, so it made sense to do a frontline trial.

The primary endpoint was progression-free survival (PFS). More than half of the patients were Asian, of note. We saw a PFS advantage of close to 9 months with osimertinib. There is no doubt that this drug outperformed the first-generation agents. The question then becomes: Is osimertinib frontline better than gefitinib followed by osimertinib? That is really where there is a lot of discussion. There is a trend toward overall survival (OS) as well, however, there is more follow up that is needed. There were recent data that showed osimertinib is the superior drug to penetrate the brain, though.

The trial looked at patients with CNS metastases and without, and there was benefit with osimertinib for both cohorts. If we look at the CNS response rate in those patients who had measurable CNS at baseline, you can see there is a lot of response in the brain. It is an easy decision for the brain. There is no other way to say itosimertinib was superior to the standard of care and penetrated the brain. Additionally, the adverse events (AEs) were much better with osimertinib.

About 50% of patients got any second-line drug, and that is exactly what the real-world data shows. This runs counter to what we think we are good at in clinic. If you were to tell me that if I put a patient on erlotinib, you only have a 50% chance of getting them on a second-line therapy I would say that's crazy. But, that is not what the data shows. All of the frontline trials show the same data. That is 1 of the reasons I think we should be using our best drug first. There is no doubt that sequencing has its pros, but using your best drug first ensures that the patient actually gets the drug. You cannot ensure that a patient who starts on erlotinib or gefitinib, or even afatinib (Gilotrif), is going to make it to a second-line drug. It is the same reason we started erlotinib first when we had erlotinib or chemotherapy as therapeutic options. There is a lot of rationale to giving this drug frontline.

Targeted Oncology: Is there any reason why you would not give osimertinib as a frontline option to your patient?

Levy:In my mind, there is not a sequencing strategy right now for patients who areEGFRpositive. I think that the only time that I don't consider using osimertinib is in rare mutations. For rare mutations, afatinib has an approval. Osimertinib has data that were presented at World Lung in Toronto that is pretty competitive, but I still feel less comfortable giving it for rare mutations.

Targeted Oncology: What are the other treatment options to consider?

Levy:The ARCHER 1050 study investigated dacomitinib (Vizimpro) versus gefitinib in the frontline setting.4There were no brain mets allowed in this trial. This trial showed PFS benefit with dacomitinib, just like osimertinib. Our even longer follow up showed an OS advantage. The question becomes, where does dacomitinib fit in with all of the data? It is a dangerous drug and I don’t think that the toxicity on paper does it justice. I wouldn't wish this on my worst enemy. The diarrhea, nausea, and rash are real and prevalent when giving the drug. There were a lot of dose modifications that were needed. Sixty-six percent of patients in the dacomitinib arm needed some sort of dose modification compared to 18% with gefitinib. Nevertheless, the drug did show a survival advantage and it was approved by the FDA.

Targeted Oncology: Assume mutation testing was performed and revealed a C797S resistance mutation, how would this influence your decision-making?

Levy:This is where things get even more murky. The interesting thing about a C797S mutation is that some of these patients respond back to erlotinib. If you give osimertinib and identify a C797S mutation either in the plasma or tissue, you can give them either erlotinib of gefitinib and they respond. There has not been 1 case report. We have preclinical evidence and I'm sure there is an ongoing body of literature, but we don't know for sure.

This is a mutation that is coming up more and more as a resistance mechanism to osimertinib. There was just a presentation at ESMO looking at plasma after osimertinib from the frontline trial, which showed the mechanism for resistance is really all over the place.5It is not the clean story of T790M. There are not a lot of targeted therapy options post osimertinib. Hopefully, we will have opportunities to learn more with tissue biopsy.

The patient received osimertinib 80 mg once daily. She experienced a good partial response.

Ten months after initiating osimertinib, she complained of headaches and worsening fatigue. CT imaging showed 3 new liver lesions and a brain MRI imaging showed 1 new lesion. Her ECOG performance status was still 1.

Targeted Oncology: Do you repeat biopsy or liquid biopsy for mutation testing?

Levy:We have a lot of liquid biopsies being performed and they have their challenges. You pick up a lot of noise, and it could be a subclonal mutation that makes no impact whatsoever. Or, you could get something called a clonal hematopoiesis of indeterminate potential (CHIP), which are benign mutations in white blood cells. All of us, over time, develop mutations in our white blood cells as we age, and these are picked up in liquid biopsies. So, if you see aKRASmutation in the blood you may think that the patient has a KRASmutation in the tumor. This may not be the case, it could be a CHIP. I usually do a repeat biopsy and then start them on chemotherapy.

Targeted Oncology: Would you use immunotherapy in the second line?

Levy:There was a meta-analysis looking at all of the trials comparing immunotherapy versus docetaxel.6In the intention-to-treat analysis, immunotherapy was better than docetaxel. However, if you look at theEGFRsubset, docetaxel was favored. Additionally, there was another trial that took patients who were EGFRand PD-L1 positive and, instead of treating them with a TKI, they treated them with pembrolizumab (Keytruda).7They robbed the patients of the TKI. There were 14 patients on this trial, and no patient responded. In fact, the only patient who responded did not actually have anEGFRmutation.

It doesn't work in the first or second line. If you think aboutEGFR, never give immunotherapy unless you're in the sixth or seventh line. I'm not necessarily saying that there aren't responses, but the problem is that if you end up having to give them a TKI, there can be overlapping toxicities with pneumonitis. That is why it is so important to prioritize your tissue. If you get the PD-L1 test back quickly and they are a never-smoker, just be mindful that they might have a genetic underpinning that may preclude them from garnering a benefit from immunotherapy.

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