Levy Discusses Remaining Questions in NSCLC as Field Awaits Frontline Osimertinib Approval

Benjamin P. Levy, MD

Benjamin P. Levy, MD

While the FDA approval of osimertinib (Tagrisso) for patients withEGFR T790M—positive non–small cell lung cancer (NSCLC) who progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy has made a significant impact in the field of lung cancer, questions still remain. Investigators are still trying to determine the optimal treatment for patients whose tumors do not have a T790M mutation. Additionally, if osimertinib is granted approval for the frontline treatment of allEGFR-mutant patients, an unmet need will rise in determining what treatment patients should receive following the third-generation EGFR inhibitor, explains Benjamin P. Levy, MD.

Osimertinib was granted a priority review by the FDA in December based on data from the phase III FLAURA study, in which frontline osimertinib reduced the risk of progression or death by 54% versus standard TKI therapy—erlotinib (Tarceva) or gefitinib (Iressa). In the double-blind study, the median progression-free survival (PFS) was 10.2 months (95% CI, 9.6-11.1) for standard therapy and 18.9 months (95% CI, 12.5-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57;P<.0001).

Under the priority review, the FDA is expected to make its decision on the approval within 6 months of receiving the supplemental application.

Currently, there are multiple clinical trials ongoing to address the outstanding questions that still exist in the field, Levy explains. In an interview withTargeted Oncology, Levy, clinical director of medical oncology, Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital, discussed some of the ongoing trials exploring osimertinib and how the FLAURA data have impacted treatment decisions.

TARGETED ONCOLOGY:What are the challenges involved in managing acquired resistance to EGFR TKIs? How has this changed?

Levy:This is a field that is moving and evolving quite rapidly. What we now know is patients whose tumors progress on a first- or second-generation TKI should be tested for T790M. T790M can be tested in blood or tissue, and there is data suggesting you should start with blood. If positive, you can now give osimertinib, which is approved in this space. If the blood is negative, then patients should get a tissue biopsy. I don't think we have any controversies currently about what to do when patients truly progress and you're ready to make a therapeutic switch. You should test for T790M and, if positive, patients should get osimertinib.

I think the real questions are two-fold, one is what to do for patients that are T790M-negative. There are multiple clinical trials going on right now looking at novel combination strategies. I think we are still trying to find the optimal therapy. Chemotherapy certainly works in that setting. Afatinib (Gilotrif) and cetuximab (Erbitux) may be an option for these patients. I think what we know does not generally work is immunotherapy. Immunotherapy is probably not the best drug for these patients withEGFRmutations who progress on a first- or second-generation TKI. I think the second big issue is predicated on a potential new approval, which is that osimertinib may move frontline. If that happens, what to do after osimertinib is an outstanding question and multiple clinical trials are looking at this.

We saw from the phase III FLAURA data that osimertinib outperformed a first-generation TKI with a huge benefit in PFS. Based on that, I think osimertinib will move frontline for allEGFR-mutant patients. I think the question becomes what to do afterwards. We just don't know yet. We're starting to understand mechanisms of resistance to osimertinib, but I think this is where we really have an unmet need, and it's a good unmet need.

TARGETED ONCOLOGY:FLAURA was such a practice-changing trial. Can you comment on the importance of that trial?

Levy:I think that FLAURA mirrored what we saw from the phase I frontline experience with osimertinib. And seeing PFS ranges first line in the 18- to 20-month range, which we have never seen before, somewhat mirrors the alectinib (Alecensa) data in theALK-positive patient population. When you're getting to a PFS of close to 2 years, that's practice-changing. Not to mention the toxicity discrepancies between osimertinib and a first- or second-generation TKIs. I've had the fortunate opportunity to now prescribe osimertinib frontline twice since the data came out. It's a very different discussion with these patients because you don't really need to educate them about the rash or diarrhea because there is a very low incidence of that, from the trials and from my experience. This had been practice-changing, not only because we're seeing these huge PFS benefits, but also because we're seeing lower toxicity, and there is good data to suggest that osimertinib has a very good chance of crossing the blood-brain barrier and eliciting responses in the brain. We saw data at the ASCO Annual Meeting to speak to that. For all of those reasons, I have always been taught to use your best drug first.

Opponents of this say, &ldquo;what are you going to do next after you get osimertinib?&rdquo; This is where we need to move the field. This is why osimertinib is now first, and now we can start to figure out what to do next, the same way we didn't know what to do next after erlotinib. I look forward to the FDA approval of this. In the meantime, I think we all deserve getting the best drug first, and I think based on the FLAURA data, that is osimertinib.

TARGETED ONCOLOGY:The NCCN gave a 2A recommendation to osimertinib in the first-line. Are you surprised by the NCCN decision before the approval?

Levy:No, I think we have to think ahead of the approvals. There are so many drugs coming out so rapidly, it's impossible for the FDA to approve them right away. There is lag time, and the question is what do you do in the lag time? Do you wait for the approval or do you try? Yes, it requires more work sometimes, it requires getting on the phone with the insurance companies, it requires you to send literature to support your decision-making, but I think it's in the best interest of the patient. We all have to be patient-focused when we're talking about decisions we make in the clinic. If I were a patient with anEGFR-mutant lung cancer, I would also want osimertinib based on the data, the discrepancy in toxicities, and its proclivity to cross the blood-brain barrier. I think we should try very hard to get this drug first to patients.

TARGETED ONCOLOGY:Can you discuss some of the ongoing clinical trials for patients who progress on osimertinib?

Levy:We are just starting to learn, and we have very few datasets looking at mechanisms of resistance to osimertinib. Some of these have been looked at in plasma ctDNA, and some have been looked at in rebiopsying. We have learned a few things from the World Conference on Lung Cancer, which was in Japan. One of the trials that is being done is called TATTON. It's looking at osimertinib in combination with a MET inhibitor. MET may be one of those mechanisms that is at play upon resistance. The other therapeutic strategy we've been looking at is going back to the first-generation TKI and combining that with osimertinib.

One of the interesting mechanisms of resistance to osimertinib is C797S. C797S is a resistance mutation, which may predict sensitivity to the first-generation TKIs, erlotinib (Tarceva) or gefitinib (Iressa). We are just beginning to understand how to manage these patients. We first have to understand tumor biology. I don't think we're there yet. Once patients start to progress or their tumors start to grow on ongoing trials with osimertinib, we'll get a bigger body of evidence showing what the true mechanisms of resistance are. I would say, certainly options are MET inhibitors in combination with osimertinib for patients who have MET amplification, which is at play post-osimertinib, or using a first-generation TKI for patients that have C797S.

However, to make matters more complicated, all C797S comes in different shapes and sizes, and it's not all the same. Some is in trans position with T790M. Some is in the cis position with T790M. These are things that we're just starting to look at to better manage these patients.

TARGETED ONCOLOGY:Can you also give some examples of the ongoing trials for patients with T790M-negative disease?

Levy:Similar to the patients that are T790M-positive, these are patients that may harbor C797S. These are patients that also may have MET amplification. I would also say there is a tremendous effort in the immunotherapy space. We generally think of immunotherapy as not being the best drug for patients withEGFR