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Medicine Matters oncology

Hello, my name is Tejas Patil. I'm a thoracic oncologist at the University of Colorado Cancer Center. And there were a lot of exciting abstracts in oncogene-driven non-small cell lung cancer at the ASCO 2020.



In the HER2 space, a very exciting abstract was abstract 9504. This is looking at DSA 201, which is an antibody-drug conjugate targeting HER2 activating mutations. And these have been historically a very challenging group to treat. And there are a lot of new exciting targeted therapies in this space.



In this circumstance, we're looking at an antibody-drug conjugate where the target is linked to a chemotherapy payload. What was interesting in this abstract was that they had a very high incidence of brain metastases-- almost 45% at baseline. And they still had an objective response rate of 61.9%, which is very encouraging. There was a duration of response of 14 months.



One thing I noticed when reading this abstract was that while these objective response rates and duration responses were encouraging, there was a very high incidence of adverse events-- about 64.3% total. And of that, there was 26% of grade 3 neutropenia. There was also 16% anemia in cases of ILD reported.



So my thoughts on this is that this is a very encouraging abstract-- certainly reporting the high incidence of baseline brain metastases. I would like to see intracranial objective response rate moving forward. I think for duration of response of 14 months is very encouraging, especially in this subgroup. But we'll need to be mindful of the cytopenias of this therapy moving forward.



The next set of abstracts that I found particularly interesting in ASCO 2020 all related around EGFR. In particular, EGFR exon 20 insertions, which have historically been a very challenging subgroup with very limited response to currently available targeted therapies. What was interesting in these three abstracts was the different types of strategies used to manage these EGFR exon 20s. And the abstracts that I will plan on covering are Abstract 9512, 9513, and 9514.



So the first abstract I'm covering is looking at an EGFR MET bispecific antibody. This is JNJ. And its patient population includes a patient with EGFR exon 20 insertion mutations. And this was a study that was looking at treatment-related adverse events as its primary endpoint.



And, interestingly, in this group, a rash was seen in about 72% of patients. There was infusional-related toxicities seen in about 60% of patients. And what's important to know is that it's about 36% grade-3 toxicities.



The median duration of response was 10 months in a group of 14 patients in this trial. And the median PFS was 8.3 months. So what are my takeaways from this study?



I think it's an encouraging response rate and certainly an encouraging duration of response. When we look at the post-hoc analysis of afatinib. So this is the LUX-2, LUX-3, and LUX-lung studies.



There was an objective response rate of 8.7% and immediate PFS of 2.7 months. I think that treatment-related events are going to be an important aspect of this product when it moves forward in the clinical practice and space.



The next abstract that I wanted to cover was Abstract 9513. This is looking at osimertinib for EGFR exon 20 insertions. And this was a smaller study that had 20 patients enrolled. And here they were looking at the response rate to first osimertinib in this subgroup.



And what you will see is that there was an objective response rate of 25% and a disease control rate of 85%. The median duration of response was 5.7 months. And the median PFS was 9.7 months.



And both of these are, as expected, considerably worse than drug-sensitive EGFR mutations such as exon 19 deletion or L858R. My thoughts here is that the PFS is actually interestingly comparable to the JNJ bispecific antibody. But there is certainly a worse objective response rate.



Ultimately, the side effect profile is what you would expect with patients receiving osimertinib. And given that what we're seeing here is essentially a very robust disease control rate but not a lot of objective responses, my sense is that this will unlikely be the best long-term option for this group moving forward. But we will wait to accumulate more data and see how this matures.



The next abstract I wanted to cover was 9514 on poziotinib. So this was this study looking at same subgroup, EGFR population with exon 20 insertions. They enrolled 115 patients in this study. There was a response rate of 14.8% with a disease control rate of 68.7%.



I think the major takeaways from this study were that it failed to meet its objective response rate, which was a primary endpoint. And then, furthermore, there was a significant percentage of grade 3 rash and was about 28%. And grade 3 diarrhea was about 26%, which are off-target EGFR side effects.



So I think, moving forward, this will be a drug that will be challenging for patients to take. And I think we'll have to see how other treatment options for EGFR exon 20 insertions emerge when we think about where we prioritize poziotinib.



And then the last abstract I wanted to cover in the EGFR space was the 9506. This was the overall survival analysis for the clinical trial NEJ026.



So this looked at a patient population of 226 patients with non-small cell lung cancer with activating EGFR mutations. They were randomized to bevacizumab plus erlotinib versus erlotinib. And the PFS was the primary endpoint. And from a previous phase II trial, it was shown that the erlotinib with bevacizumab group had a PFS of 16 months versus 13.3 months.



And in this trial, they also added overall survival, which showed no difference between the patients treated with erlotinib plus bevacizumab versus the patients treated with erlotinib alone. Additionally, a subgroup analysis showed that there was no difference when you looked at exon 19 versus L858R mutations.



So my thoughts for this is that while there was no overall survival benefit, I think there's still a role for bevacizumab in patients with EGFR mutations, specifically patients with brain metastases where you would like to use a steroid-sparing agent.



I think the combination of erlotinib plus bevacizumab makes a lot of sense there. The clinical relevance of this study is somewhat unclear given that osimertinib now has moved to the first-line setting and is routinely used in most patients with EGFR lung cancer.



We will await an ongoing clinical trial that looks at a combination of osimertinib plus bevacizumab and see if there are similar results from that. I will briefly mention Adora trial, which was one of the talks at this year's plenary session at ASCO 2020. This was a study looking at the use of adjuvant osimertinib in the patient with stage 2A to 3A EGFR-mutant lung cancer.



My take on this study is that it's a bit of a tricky situation. When patients have stage 2 and stage 3 lung cancer, the benchmark really should be, have we cured this patient of their disease? They are at a point that they have non-metastatic disease and have potentially curable disease for which they need no further therapy.



The outcome that they have chosen, which is disease-free survival is a little bit difficult to interpret in this context. For example, one important question moving forward could be whether the overall survival of these patients is different if you did this adjuvant strategy or waited till they relapsed and added osimertinib at that time.



And I think that study and that question will be a very important question moving forward. Additionally, it's very important to understand and figure out which patients are at highest risk of relapse at the time of completing curative-intent therapy.



So studies looking at evaluating micrometastatic disease through circulating tumor DNA are going to be very important when you start to think of how we substratify this group. In any event, this is an important study, and I think will be practice-changing for patients with EGFR lung cancer and certainly brings up a whole host of new questions to ask.