Pennell Provides Perspective on EGFR-Targeted Agents in NSCLC

Nathan Pennell, MD, PhD

As more patients with non—small cell lung cancer (NSCLC) are being tested for EGFR mutations and more therapies are being approved by the FDA, a new challenge is rising in the field, explains Nathan Pennell, MD, PhD.

“The question is, ‘What is the best one to use?’” says Pennell, who gave a lecture on EGFR-positive NSCLC during the 2016 OncLive State of the Science Summit on Metastatic Non—Small Cell Lung Cancer. “We actually have 3 approved first-line EGFR TKIs in the United States. We have erlotinib (Tarceva), gefitinib (Iressa), and afatinib (Gilotrif), which is a second-generation irreversible pan-HER inhibitor.”

Pennell cautions, however, that these agents should not be administered to patients unless they carry the EGFR mutation.

OncLive: What is the latest news in the realm of EGFR-positive NSCLC?

In an interview with OncLive during the meeting, Pennell, associate professor of Medicine at Cleveland Clinic, discussed these 3 available—and competing—agents in this space, as well as ongoing clinical trials at Cleveland Clinic exploring other regimens for the EGFR-mutant patient population.Pennell: EGFR-mutant non—small cell lung cancer is the most common genetically driven type of lung cancer. It was first identified in 2004 from subgroups of the large unselected trials of the EGFR inhibitors erlotinib and gefitinib, when they discovered that about 10% of patients on those trials had these really dramatic responses. Interestingly, they happened to be women who had never smoked and had adenocarcinoma. Researchers took those tumors, sequenced their EGFR gene, and found that they had recurring mutations in the EGFR tyrosine kinase domain.

Since then, we know that these are present in 10% to 15% of everyone with adenocarcinoma. In people who have never smoked, it is actually probably closer to 40%. For a number of years now, it has been very standard for patients in the United States to have their EGFR gene mutation status tested at diagnosis if they have any nonsquamous tumor. The reason for that is we now have several very good randomized trials of EGFR inhibitors versus chemotherapy in the first-line setting.

The first one was called the Iressa Pan-Asia (IPASS) Trial, which was done in Asia. It compared gefitinib with carboplatin and paclitaxel and showed that people with an EGFR mutation had a much better progression-free survival (PFS), a much higher response rate, and less toxicity with gefitinib. Those who didn’t have an EGFR mutation—even if they were never-smokers with an adenocarcinoma—actually did much worse with the EGFR inhibitor.

Can you shed more light on afatinib?

That really was the first time we saw that. It’s the genotype that matters, and not the phenotype. That has been reproduced in western Caucasian populations and has been reproduced in half a dozen different trials. We now know that EGFR inhibitors are clearly superior to chemotherapy with a longer PFS, higher response rate, less toxicity, and longer duration of control, so that is standard everywhere.There were a couple of phase III trials that led to the approval of afatinib. Afatinib versus chemotherapy in EGFR-mutant lung cancer had a very similar improvement in PFS and response rate compared with chemotherapy that we saw in the first-generation inhibitors.

What is a little unique about afatinib is that, in subgroup analyses of the exon 19 deletion, there was a very significant improvement in overall survival for afatinib compared with chemotherapy. That was not seen in the second most common group, which were the patients with an exon 21-point mutation. Those did not have a survival benefit, but still had the same PFS benefit. This suggests that perhaps afatinib is a better choice than the other EGFR inhibitors, specifically for the exon 19 deletion patients.

What should community oncologists be most aware of with EGFR-targeted agents?

The flip side, of course, is that afatinib is somewhat more toxic than the first-generation inhibitors. It’s a more potent inhibitor of EGFR. You get more wild-type toxicities—more rash and diarrhea. They have some unique toxicities that you don’t see with the first-generation inhibitors, such as stomatitis and paronychia, which you see fairly often with afatinib. More than half of people with afatinib will need a dose reduction to manage these toxicities, but they can get along with it with proper management. For healthy young people with exon 19 deletions, afatinib is my TKI of choice in the first-line setting. For older patients who are worried about toxicity, erlotinib is still the one that I use most often.The take-home points should be to make sure that you are testing every patient first-line for EGFR mutations and work with your pathologists. Work with your hospital to make sure that they are doing this quickly. You need to make sure that when you see the patient in a truly meaningful amount of time, you can have that information so that you don’t have to wait and risk people getting too sick to get treated before you start.

The second thing is, don’t treat people with an EGFR inhibitor unless they have a mutation. We have very good information that, if you start everyone on an EGFR inhibitor and they don’t have a mutation, they actually do worse. Patients don’t live long enough to make it to chemotherapy if you wait to find that it is not working. Therefore, test everyone—but only treat if you find a mutation. When you do have a mutation, there are 3 good choices. All of them—gefitinib, erlotinib, and afatinib—are very reasonable. There may be a little bit of evidence that afatinib is more effective, but it’s probably not a huge difference, and it does have more toxicity. You can use these criteria to pick this.

Finally, we actually now have an approved drug for people who have acquired resistance to the first- and second-generation inhibitors. It is very important that you get a biopsy of patients when they progress on their EGFR TKI. If they have T790M, we have a drug that we can prescribe them that is very well tolerated and effective in this population called osimertinib (Tagrisso).

You also moderated a panel discussion on adenocarcinoma. What treatment questions are being answered here?

It’s a mutation-specific inhibitor. It has very little of the wild-type side effects that we see with the first- and second-generation inhibitors. They do still have the same minimal risk of interstitial lung disease that we see as a class effect among all EGFR inhibitors. However, it is very tolerable with a response rate of over 60% and a clinical benefit rate of about 90%. This is not something that you want patients to miss; you can’t find it if you don’t look for it, so patients need a biopsy to identify that mutation.For example, if you have someone on erlotinib and they begin to progress in only 1 or maybe a couple of sites, we have some pretty good evidence that those may actually be the only sites that are progressing and that have acquired resistance. You could change to a different drug, but sometimes you don’t have to. Sometimes, you can actually go after those with either surgery or stereotactic radiation.

We actually have a clinical trial open at Cleveland Clinic right now looking at stereotactic radiation for fewer than 3 sites of progression in EGFR-mutant patients who are on a first-generation EGFR inhibitor, and we’re trying to see if we can lengthen the amount of time that patients can stay on treatment before they have to make a change. I like to think of this as, “It’s not a sprint.” You don’t want to use all of the treatments that you’ve got right upfront. You want to consider this a marathon. You want this patient to be alive for years. You want to stretch these things out before you have to make a change.

What are some other clinical trials at Cleveland Clinic in this space?

For patients who do then progress though on more generalized progression, you have to look for the T790M. You can look in the plasma; you can look in the tissue. If you find it, then the second- or the third-generation inhibitors like osimertinib are the right choice or a clinical trial with a similar drug. If it’s negative, you have to switch to chemotherapy but chemotherapy is very effective in these patients. It’s actually more effective in EGFR-mutant patients than it is in EGFR wild-type patients; don’t despair if you have to make the change.We have a couple of pretty interesting trials. We have a first-line trial combining crizotinib (Xalkori)—the most common first-generation ALK inhibitor, and, really, the standard of care for everyone with ALK-positive lung cancer—with an immune checkpoint inhibitor, pembrolizumab (Keytruda). [Pembrolizumab] is something that’s commonly used in the second-line right now and perhaps soon in the first-line for non-driver mutation NSCLC. However, for ALK-positive patients, there’s very little evidence of how people do with checkpoint inhibitors. We are hoping that we can safely combine it with targeted therapy.

We also have a very interesting small cell lung cancer (SCLC) trial for patients who received 4 to 6 cycles of platinum therapy and etoposide for treatment of extensive stage SCLC who have had a good response, [and] starting [them] with maintenance therapy with pembrolizumab. There is at least some pretty good evidence from small phase II trials that checkpoint inhibitors do have activity in SCLC. Therefore, by giving this to people in the maintenance setting after chemotherapy, we hope that we will be able to increase the duration of remissions and survival in these patients.

The Lung-MAP trial is known as the Master protocol for patients with previously treated squamous cell cancer. This is a terrible disease with no available targeted therapies. Every major advance that we have had in lung cancer in the last decade has passed by our patients with squamous cell cancer.

However, they do have potentially actionable mutations and in the Lung-MAP trial, they can be randomized to 1 of a number of different arms of targeted therapies. For patients who don’t have an actionable mutation, they go on to a combination of different immunotherapy trials, so there’s something for every patient who enrolls on this trial. It’s something that is a much better choice than just treating someone with standard therapy off protocol.

The other trial that needs support is the ALCHEMIST trial. This is an adjuvant trial for squamous and nonsquamous patients with stage IB to stage IIIA NSCLC. If they are testing positive for EGFR or ALK, they are randomly assigned to either 2 years of erlotinib, 2 years of crizotinib, or placebo to see if we are prolonging survival with targeted therapies—something that we know is better than chemotherapy in the metastatic setting. I bet that it is better than chemotherapy in the adjuvant setting, but we have never actually proven that. We’re also adding an arm where patients who don’t have a mutation are randomized to nivolumab (Opdivo) or observation.