PracticeUpdate: One of the interesting studies at ASCO looks at novel treatment combinations for patients with EGFR-mutated lung cancer that has progressed on osimertinib. What are common mechanisms of resistance for patients progressing on osimertinib?
Dr. Goldberg: In recent years, we've been starting to understand the landscape of resistance mechanisms when patients are progressing on first-line osimertinib. Initially, we were looking at second-line osimertinib and what happens at progression, and now that more patients are being treated with first-line osimertinib, we're understanding that landscape as well.
I think you can think about the different mechanisms really in two different categories. One is the EGFR-specific and -dependent mechanisms of resistance. Those are the secondary EGFR mutations, the most common being C797S mutation. That's another mutation that develops in some patients' tumors at progression on osimertinib.
The other class of alterations are the non-EGFR dependent alterations. One of the examples of that is MET amplification, which we see in some patients. There's many others as well. It's not as straightforward as when we saw patients first progressing on the first and second generation EGFR inhibitors, where the EGFR T790M mutation was found in 50% to 60% of patients.
It doesn't seem like there's any one mechanism of resistance that's emerging, that we've seen so far, that makes up the majority, or even half of the cases. It really is a mix of different mechanisms. We've seen some really interesting things, at progression on osimertinib, that potentially could be targeted, but each of them are quite rare on their own.
We've seen ALK fusions and RET fusions and BRAF mutations and many different alterations that are developing at the time of resistance on osimertinib. Now the next step in our clinical trials is trying to figure out how to best overcome those various mechanisms of resistance, so that once progression occurs on osimertinib, we have, ideally, another targeted therapy option to offer to our patients.
PracticeUpdate: What are the current treatment options for these patients?
Dr. Goldberg: The standard treatment for patients progressing on first-line osimertinib is really chemotherapy, potentially in combination with other agents. We really don't know the best strategy for treating patients after progression on osimertinib. Most of these patients will have received osimertinib first line, so that's why platinum-based chemotherapy, usually carboplatin and pemetrexed is really the standard.
There is some rationale to combining that with immune therapy. There's a trial with chemotherapy plus bevacizumab and atezolizumab that looked at EGFR patients as a subset of the patients on the trial, including EGFR, and there seemed to be benefit with that combination. Whether that's better than chemotherapy alone is not entirely clear in that small study. Whether we should be using immune therapy at all in EGFR patients is a bit questionable because, on their own, immune therapies have very low response rates in EGFR-mutant lung cancer.
I think clearly platinum-based chemotherapy, whether or not we add immune therapy and a VEGF inhibitor, is something that is still being worked out in clinical trials, but could be considered. I think that's really the standard approach. Maybe one other thing I'll mention is that, at times, we do think about continuing osimertinib along with chemotherapy, that would be if immune therapy is not being used. The rationale there is that osimertinib might still be contributing to tumor stability at some sites, and then the chemotherapy can overcome the progression at the other sites that are growing. That is sometimes the strategy I think many of us will use, especially in patients who have brain metastases, to maintain the control that osimertinib can typically provide.
That's not something that's been studied prospectively and, I think, hopefully, we'll see more data on that in the future to know if that's a better strategy than either chemo alone or chemo with immune therapy. Again, that really is kind of within our standard realm of drugs that we could consider using. I think in patients that I see who have disease progression on osimertinib, I'm always trying to think about clinical trials, because there's so many different really promising agents that we could think about offering to patients on trials right now.
PracticeUpdate: How were the agents in this trial designed to work?
Dr. Goldberg: This trial is using a combination of two different drugs. One is amivantamab, which is a bispecific antibody against EGFR and MET. The other drug is lazertinib, which is another third generation EGFR tyrosine kinase inhibitor, just as osimertinib is. The idea here is to try to target both the EGFR mutation, as well as MET signaling with that bispecific antibody that also hits MET.
PracticeUpdate: What was the trial design?
Dr. Goldberg: This is a phase 1 trial. Initially they had a dose escalation portion, and then once they understood the toxicity and the recommended phase 2 dose, they moved into dose expansion and looked at various cohorts of patients, some who had been previously treated with EGFR inhibitors and some who had been treated with third generation EGFR inhibitors of various prior treatments. In the dose expansion cohorts, they were looking at other endpoints, including response rates.
PracticeUpdate: What were the key findings?
Dr. Goldberg: This study found that the combination of amivantamab with lazertinib resulted in a response rate of 36% in patients who were previously treated and were progressing on a prior EGFR inhibitor. They also found a median progression-free survival of almost five months and good tolerability of the combination.
In patients that are progressing on a prior EGFR inhibitor, and our treatment is typically chemotherapy of some combination, this represents another really interesting and promising combination of drugs that might be able to overcome resistance in a proportion of patients progressing on TKIs.
PracticeUpdate: Do you anticipate this treatment combination may have a role in future clinical practice?
Dr. Goldberg: I think this combination might, one day, become part of our standard treatment of EGFR-mutant lung cancer. I think it's still has a ways to go in terms of drug development and understanding it better. I think some of the questions that are still outstanding which, at ASCO, we started to see some data on this but I think there's still more to go, is really trying to understand which patients are most likely to benefit from this combination of drugs.
Many people, myself included, thought that it might be the patients who had EGFR-specific mechanisms of resistance, or maybe MET resistance, MET amplification, but it didn't really seem to pan out that way when they looked at the data, at least so far, it's fairly small numbers still. When they looked at patients who had EGFR- or MET-based resistance, the response rate was about 47%. Even patients without MET- or EGFR-based resistance, the response rate was almost 30%.
Maybe there's something there, where there's a bit of an enrichment for benefit, but patients, even without clear mechanisms of resistance within EGFR or MET, still seem to benefit to some degree. I think we are still looking for a biomarker, and that's always what we like to see, especially in this patient population that initially benefits so much from that targeted therapy. We would love to see a biomarker that could guide us as to whether this is an appropriate option for patients.
Interestingly, in this presentation, they also looked at immunohistochemistry to try to identify patients that might respond. They looked at very small numbers of patients, but in patients who had positive IHC for EGFR or MET, they found that there was a higher response rate there.
I think that this might be something that moves forward as a biomarker. I'm sure that there's more investigating that is being done now to really try to understand that better. I think that, yes, I think one day, amivantamab, either alone or in combination, might be a drug that we are using on EGFR-mutant lung cancer.