Long-Term Improvement in PFS Confirmed With Frontline Osimertinib in EGFR+ NSCLC

James Chih-Hsin Yang, MD

James Chih-Hsin Yang, MD

Following the results from the phase III FLAURA trial (NCT02296125), osimertinib (Tagrisso) has become the standard of care for patients withEGFR-mutated non—small cell lung cancer (NSCLC) in the frontline setting. This third-generation tyrosine kinase inhibitor (TKI) demonstrated an improvement in progression-free survival (PFS) for this patient population.¹

In the phase I AURA trial, patients were followed for a longer period of time and analyzed for the long-term durability of responses to osimertinib.²James Chih-Hsin Yang, MD, shared these findings, confirming the long-term improvement in PFS for patients withEGFR-mutant advanced NSCLC when treated with frontline osimertinib.

In this trial, patients were randomized 1:1 to receive either 80 mg or 160 mg of osimertinib. At the time of data cutoff on May 1, 2018, 11 patients were still receiving treatment. In terms of PFS, 20% of patients were still progression-free with 80 mg of osimertinib versus 14% with 160 mg, estimated by Kaplan-Meier curves.

In addition, the overall response rate was 67% for patients in the 80-mg arm and 87% in the 160-mg arm. At the 3-year data cutoff, 25% of patients maintained their response and were still receiving treatment and at 4 years, the rate was 18%.

“This will be the final analysis of the efficacy and safety for osimertinib used in the frontline,” said Yang. “The findings are very comparable with what has been published, that osimertinib as a frontline treatment is very effective and has a durable, long response.” He also noted that the toxicity profile did not change as well.

In an interview withTargeted Oncology, Yang, director, Graduate Institute of Oncology, and director, Department of Oncology, National Taiwan University Hospital, discussed the updated findings from the FLAURA trial, which confirmed durable responses with frontline osimertinib in patients withEGFR-positive NSCLC. He highlighted what areas research will be focusing on in the coming years for patients harboringEGFRmutations.

TARGETED ONCOLOGY: Could you discuss the rationale for following up on the data from the FLAURA trial?

Yang:We know osimertinib is a very important drug for patients with T790M mutation in the second-line. After 4 studies it’s also being used as a first-line therapy, for patients with anEGFRmutation with advanced disease. The FLAURA trial had a very short follow-up time, but we do have a cohort of patients who had received osimertinib as a first-line for a long time in the phase I study. These are the patients from the expansion cohort, 30 patients received 80 mg of osimertinib and 30 patients received 160 mg of osimertinib as a frontline therapy. We followed them for a long time.

The data cutoff for this presentation was May 1, 2018. In the study, it was started in 2013, which means we had a very long follow-up for these patients’ outcome.

TARGETED ONCOLOGY: Were there any clinical implications from these data?

Yang:What we want to see is the durability of the osimertinib response for these patients. This study has been published before, but we wanted to follow-up to see whether some of the key findings may have had some changes.

We confirmed that the response rate has been very high in these patients, both in the 80 mg cohort and the 160 mg cohort at 67% and 87%, [respectively]. The durability of these patient responses has been very long. The median duration of response is approximately 20 months, so this is very similar to what we have found in the FLAURA study. What we really wanted to see was the long-term durability.

Up until now, at the time of data cutoff, 11 patients are still receiving the treatment. At the 3-year cutoff, 25% of patients are still [alive]. At the 4-year cutoff, 18% of the patients still have durable response. In terms of PFS, if we used 3 months as a cutoff, 20% were still progression free, and at 4 years 14% are still progression free. This is estimated by the Kaplan-Meier curves. This gives us some confidence that these drugs may have a very durable response in progression-free time, at least for some of the patients who receive osimertinib as a first-line therapy.

TARGETED ONCOLOGY: What is important to take away from these findings?

Yang:This will be the final analysis of the efficacy and safety for osimertinib used in the frontline. The findings are very comparable with what has been published, that osimertinib as a first-line treatment is very effective and has a durable, long response. The toxicity profile is very similar to what’s been reported, mainly minor skin rash minus diarrhea, and paronychia. There were no long-term adverse effects or no new adverse effects that have been recorded in this study.

TARGETED ONCOLOGY: Although this is the final analysis for this dataset, are there any next steps planned for osimertinib in patients withEGFR-mutant NSCLC?

Yang:Most if not all patients will receive osimertinib, and while they may have a very long PFS, they still progress. The mechanism of resistance for osimertinib will be the most important research issue in the forthcoming years because osimertinib has become the standard first-line treatment. We want to know what happens to these patients once they progress, whether we can treat them beyond progression or whether there is some new target that we can identify. By using targeted therapy combination approaches, we may be able to control some of these patients to provide them with some chemotherapy-free time.

Obviously, chemotherapy will be the standard of care for these patients who progress on osimertinib, but certainly our mission is to add time for these patients so that they can enjoy their lives.

TARGETED ONCOLOGY: What do we know so far aboutresistance mechanisms to osimertinib?

Yang:There are many genomic analyses on both tissue biopsies and plasma genomic analyses that have been published. In roughly 30% of patients, we can find ac-METamplification and in some patients we discover new mutations inEGFR. The most important one is C797S and some other minorEGFRmutations. In some patients, we can findHER2amplifications, but we also find some others that have been mutually exclusive withEGFRmutations such asKRAS,BRAF, and some small cell transformation. These consist of a very heterogenous picture. Some patients do have 2 mechanisms of resistance. These are the important issues that we need to tackle in forthcoming years.

TARGETED ONCOLOGY: What other areas will research be focused on in the coming years?

Yang:I think in this era of immunotherapy, the role of immunotherapy inEGFR-mutant patients certainly is a very important issue. We want to make best of our knowledge and our tools or drugs to improve our patients’ lives. At least in 1 study, the combination of chemotherapy, atezolizumab (Tecentriq), and bevacizumab (Avastin)—a 4-drug combination—was better than chemotherapy in 1 study. That study containedEGFR-positive patients, but this needs to be confirmed because that was a small cohort of patients.

Currently, there are 2 large studies adding chemotherapy to immunotherapy as a salvage treatment compared to chemotherapy alone. Hopefully, in a few years, we will know whether immunotherapy plus chemotherapy can play some role in those who fail EGFR TKIs. And there are other mechanisms being explored in these patients, so hopefully we will be able to figure out whyEGFR-mutant patients have a relatively “cold” tumor, which means it has very low inflammatory properties so that they don’t respond to checkpoint inhibitors as well. Maybe we can produce some novel immunotherapy for these patients in the future. These are all research focuses for the coming years.

Another focus is targeted therapy plus targeted therapy. Since we already know that some patients havec-METamplification, so adding TKIs with a MET inhibitor will be important. There are already studies showing that this approach is feasible, and we may have a durable response up to 6 or 7 months in those patients who had received a TKI, failed, and then had ac-METamplification. Similar scenarios may be applied, then, toHER2amplifications or other novel mutations we can find in TKI-failure patients.

References:

1. Soria JC, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non—small-cell lung cancer.N Engl J Med. 2018;378(2):113-125. doi: 10.1056/NEJMoa1713137.
2. Yang J, Ramalingam S, Lee C, et al. Osimertinib as first-line (1L) treatment for epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer (NSCLC): Final efficacy and safety results from two phase I expansion cohorts. Presented at: 2019 European Lung Cancer Congress; April 11-13, 2019; Geneva, Switzerland. Abstract 122P.