EGFR: First Line, Second Line and Beyond in the Age of Osimertinib

At the 2022 Great Debates & Updates in Lung Cancer meeting in New York, Helena Yu, MD, Memorial Sloane Kettering Cancer Center, New York, shared new developments and potential treatments in the first- and second-line settings for patients with EGFR-mutated lung cancer.

In her presentation, Dr Yu covered the various benefits of osimertinib, as well as potential adjuvant therapies and post-EGFR-inhibitor treatments. 

Transcript:

Hi everyone. My name's Helena Yu. I'm a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York. My talk at the Great Debates and Update in Lung Cancer was “EGFR: First Line, Second Line and Beyond in the Age of Osimertinib.” We first went over how osimertinib really is the best-in-class EGFR [tyrosine kinase inhibitor] TKI. It's the only third-generation, mutant-specific, irreversible EGFR inhibitor.

We initially used osimertinib in the later-line setting but, based on the FLAURA study where it was compared to erlotinib or gefitinib and showed improved progression-free survival as well as overall survival, it really became the first-line EGFR-TKI of choice. An important point about osimertinib is that it has excellent [central nervous system] CNS penetration. Some of the data from FLAURA really showed good target shrinkage in CNS metastases, as well as prolonged CNS response and lack of progression in the CNS. So osimertinib is really the EGFR inhibitor monotherapy that's the first-line treatment of choice.

There are also multiple combinations with osimertinib that are being looked at in the first-line setting, such as osimertinib plus VEGF inhibition, so either bevacizumab or ramucirumab. This is really based on earlier studies where these VEGF inhibitors were combined with erlotinib and did show an improvement in progression-free survival, although there was no clear overall survival benefit. There are multiple ongoing studies looking at osimertinib plus these VEGF inhibitors. For example, the ECOG-5182 study is randomizing patients to receive first-line osimertinib, or osimertinib plus bevacizumab. We await data from those studies.

Another important combination that is being looked at is osimertinib plus chemotherapy. I think it's important to remember when you're combining 2 therapies that are active by themselves, that we're not just looking for an improvement in the PFS that is equal to if we sequence these agents, we want to see some amount of synergy, which often translates to an overall survival benefit. The thought is, by giving osimertinib plus chemotherapy upfront, we're better able to eradicate those persister subclones that persist despite EGFR inhibitor. The big upcoming study that's looking at that is the FLAURA 2 study, and that's randomizing patients to receive osimertinib or osimertinib plus platinum pemetrexed chemotherapy. We're interested in that as well.

Targeted therapy combinations are also certainly of interest. The MARIPOSA study, which is looking at amivantamab, a MET/EGFR antibody, with lazertinib, is another investigational third-generation EGFR inhibitor. That's being compared to osimertinib alone, or lazertinib alone, and we also await data from that. I think something to really remember when thinking about sequencing these different therapies for EGFR-mutant lung cancer is that it's important to use your best treatments first. Even in clinical trials of first-line treatments, about a third of patients don't receive second-line treatments. Getting your first shot on goal to be the most effective option becomes critically important.

Something to also bring up is immunotherapy for EGFR-mutant lung cancer. This is a class of drugs that's very active for lung cancer in general but doesn't seem to be as active in EGFR-mutant lung cancer. It's important to remember that the first-line chemotherapy-immunotherapy and immunotherapy studies all excluded patients with EGFR-mutant lung cancer. And there is some data that, 1- immunotherapies are not as effective, and 2- that there are synergistic talks when combining immunotherapy with EGFR-TKIs. And this can also be seen when you're sequencing an EGFR inhibitor after immunotherapy because of the long half-life of immunotherapy. We saw an increase in immune-related toxicities when an EGFR inhibitor was given after a PD-1 inhibitor. So, that’s something to watch out for.

Regarding mechanisms of resistance, all patients ultimately develop progression on EGFR inhibitors. If this is oligoprogression, like progression in 1 or few sites, it always makes sense to do local therapy to the progressing lesions and continue the EGFR inhibitor if possible. Of course, if it's multisite progression or more significant progression, at that point, it's important to do a repeat biopsy, whether that be a tumor biopsy, tumor tissue biopsy, or a liquid biopsy to look to see if there are obvious mechanisms of resistance to osimertinib. In regard to mechanisms of resistance, they're categorized as either on-target, which means EGFR-mediated, which is oftentimes acquired EGFR mutation, or off-target, which is usually an acquired alteration in a different signaling pathway like MET amplification. Or, we can see something called histologic transformation, which is when typically an adenocarcinoma transforms to either a pure small-cell lung cancer or a pure squamous cell lung cancer.

And I think because osimertinib is a better EGFR inhibitor, we're seeing less on-target resistance and more emergence of both off-target resistance as well as histologic transformation. It’s also important to note that about half of resistance to osimertinib is not identified by next generation sequencing. If there is an off-target acquired alteration such as a MET amplification, there are studies looking at combining a MET inhibitor to osimertinib, and those do appear to be effective. If a patient has histologic transformation, then we really need to think about treating those patients with histology-specific chemotherapy. For small-cell transformation, typically we use carboplatin etoposide.

In targeted therapies after osimertinib, there are some promising agents that are currently in clinical development, such as patritumab deruxtecan, which is HER3-directed antibody drug conjugate. And this has been studied post-chemotherapy and post-EGFR inhibitor and showed a response rate of 39%. And this response rate occurred in a broad sort of spectrum of EGFR-mutant lung cancers, some of whom who had both on-target and off-target identified mechanisms of resistance. This treatment does seem to transcend different mechanisms of resistance. Another such treatment post-osimertinib is amivantamab and lazertinib. Again, amivantamab is a MET/EGFR antibody, lazertinib is a third-generation EGFR-TKI. And this was looked at in a similar population. Response rate was 36%. Also, very promising. And this combination, as I mentioned, is being looked at in the first-line setting in the MARIPOSA study, but also in combination with chemotherapy and in the later-line setting. Lots of interesting new data in this space. Thanks for listening.

Source:

Yu, H. EGFR: 1st Line, Second Line and Beyond in the Age of Osimertinib. Presented at: Great Debates & Updates in Lung Cancer; Oct 14-15, 2022.