Sukhmani Padda, MD, discusses the practice-changing impact of osimertinib and addresses the challenges that still remain in EGFR-positive NSCLC.
Sukhmani K. Padda, MD
Osimertinib (Tagrisso) has effectively overcome the T790M resistance mechanism associated with earlier-generation EGFR TKIs, but patients with EGFR-positive non—small cell lung cancer (NSCLC) are still experiencing disease progression on the third-generation drug, said Sukhmani Padda, MD.
Based on positive data from the phase III FLAURA study, osimertinib has become the frontline standard of care for this patient population. Results showed that osimertinib significantly improved median progression-free survival at 18.9 months versus 10.2 months with the earlier TKIs erlotinib (Gilotrif) and gefitinib (Iressa; HR, 0.46; 95% CI, 0.37-0.57; P <.001). While objective response rates were similar at 80% with osimertinib versus 76% on standard TKIs, the median duration of response was 17.2 months versus 8.5 months in favor of osimertinib (95% CI, 7.3-9.8).1
Padda, an assistant professor of medicine at Stanford Cancer Institute, said that despite the clear survival benefit, patients are now developing resistance mechanisms that are unique to osimertinib.
In a study presented at the 2018 ESMO Congress, researchers suggested that MET amplification and EGFR C797S mutations were key alterations associated with resistance to frontline osimertinib. In this analysis of the FLAURA trial, plasma samples were analyzed through next-generation sequencing at baseline and the time of progression. Findings showed that MET amplification was the most common acquired resistance mechanism in patients who progressed on osimertinib (15%), followed by C797S (7%), and PI3KCA mutations (7%).2
To overcome this challenge, ongoing studies are looking at the use of combination approaches, such as pairing osimertinib with other antibodies.
In an interview with OncLive, Padda discussed the practice-changing impact of osimertinib and addressed the challenges that still remain in EGFR-positive NSCLC.Padda: For third-generation EGFR TKIs, the only one that is FDA-approved right now is osimertinib, which has dramatically changed the landscape. When we are talking about generations of EGFR TKIs, the advantage that third-generation inhibitors have over the older-generation drugs is that they select for activity against T790M, which is one of the most common resistance mechanisms against first- and second-generation EGFR TKIs. In addition, more so than the earlier-generation drugs, third-generation TKIs have less of a EGFR wild-type on-target effect, which means that they have less skin-related toxicities.The safety of this drug is based on its mechanisms. The way osimertinib was designed was to have less EGFR wild-type toxicity. Although it still has some wild-type toxicity—you are not completely absent of having a rash—we are seeing significantly lower rates [versus other TKIs]. There are similar rates of diarrhea that you would see with an earlier-generation TKI. There is also some rare cardiac toxicity that you should be mindful of, in the single-digit [percentage of incidence], such as prolongation of QT interval and decrease in left ventricular ejection fraction.Now that osimertinib has moved to the frontline setting, we have to figure out what to do after resistance to it. There were just data presented at the 2018 ESMO Congress by Suresh S. Ramalingam, MD, of Emory University, that started to examine this specific question.
There are basically 2 dominant [resistance] mechanisms that emerge. One is acquired EGFR mutations, the most common one being C797S, which prevents the binding of osimertinib to its target. Then you have gene amplification, of which MET is the most dominant.
The issue, however, is with the mechanisms of resistance to frontline osimertinib; they are much more heterogeneous than what we saw with progression on first- and second-generation EGFR TKIs. On these earlier drugs, 60% of patients had a T790M mutation develop. We no longer see that kind of dominant resistance mechanism, which complicates things. In addition, these resistance mechanisms that we do see are often happening concurrently. The paradigm then becomes very complex.
Right now, after a patient progresses on frontline osimertinib, we have to rely on platinum doublet chemotherapy thereafter. However, there are many clinical trials looking at combination strategies targeting some of these resistance mechanisms that have been discovered.One of the interesting combinations is EGFR TKI therapy with EGFR monoclonal antibodies. Actually, this was a promising strategy before we had osimertinib in the second-line setting. Therefore, for patients who progressed on erlotinib or gefitinib, with or without evidence of T790M, when they went on to receive this combination, we saw responses in both of those categories.
Similar strategies are being examined following osimertinib resistance. For example, we are seeing osimertinib plus necitumumab (Portrazza) in a National Cancer Institute-sponsored trial. There is also a trial led by Leora Horn, MD, MSc, of Vanderbilt University Medical Center, which is evaluating the use of afatinib (Gilotrif) plus necitumumab.Immunotherapy has not been the biggest hit yet in EGFR-mutant lung cancer, but it plays a role in a very selective patient population. Generally, what we want to do for this group is exploit all of the targeted therapies that we have available, followed by platinum doublet chemotherapy, and then you could consider immunotherapy as a strategy. However, even for patients with high PD-L1 expression, the response rates are not that high. You have to be cautious when you are seeing patients in the clinic and [look for signs for] early progression.Our therapies will have to be increasingly precise. What we know right now, simply from preliminary examination of the FLAURA plasma samples and the heterogeneity of the disease, is that we need to tailor our approach. There is another ongoing phase II study evaluating the molecular characteristics of patients on frontline osimertinib; it is looking at their pretreatment plasma samples, their samples throughout their course of therapy, and also at the time of disease progression.
What we know about the FLAURA study is that [investigators] didn't [perform a tissue biopsy in patients consistently at the time of progression]. This other study will also address that because we have to deal with histologic transformation after frontline osimertinib, including squamous lung cancer and NSCLC.There is a lot of hope right now. As a field, we have increasingly identified that there are many diseases within lung cancer. We know that we have to pick the right therapies for the patients to begin with, [and the right] sequence throughout their disease history. It has become a much more precision-based approach. As we can see from just the frontline osimertinib resistance data, we have a lot more to learn about tailoring our treatments.