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Joel Neal, MD, Ph.D.: Let’s move on to treatment approaches. We’ve talked a bit about how patients have been treated historically, but I think it’s worth getting into our approach to treatment on the first line. Alex, what do you offer patients with newly diagnosed EGFR exon 20 insertion that you found before starting other treatment? This is one of the keys: waiting 2 or 3 weeks for the results of the mutation for patients with a high probability EGFR mutations. What is your favorite therapy? Let’s say there’s a patient with a few tiny metastases to the brain, about 3mm — not a big burden in the middle of the lungs, adenocarcinoma.
Alexander I. Spira, MD, PhD, FACP: I am a person on pemetrexed carboplatin. I’m sure most of us are. I used to avoid I / O [immuno-oncology] agents. There’s not a lot of data in this situation, obviously, but I’m expanding on what is known about exons 19 and exons 21 and that immunotherapy really doesn’t work very well in this population. Usually I just treat with double chemotherapy. I’m sure some deal with triple therapy. Maybe you do, like I said, and you’re not going to go wrong in either situation.
For people with minimal brain metastases or very small metastases – 2-3mm – pemetrexed is penetrating enough that you can at least hold back the radiation. But if someone has a bigger 1, I usually give them stereotaxis, which is the standard of care for most people these days. I can’t tell you the last time I did a complete brain scan on someone except at the end of their life. For me, it’s about the carboplatin-pemetrexed treatment. On the second line — I selfishly suppose — we’ve been very lucky because we have some of these exon 20 drugs on trial, like you’ve been doing for 3-4 years. I didn’t have to give a standard second-line treatment, which for me would be docetaxel, a drug we all hate giving for obvious reasons. And you?
Joel Neal, MD, Ph.D.: My first-line approach: We are moving a bit more towards bevacizumab and antiangiogens when we can to treat these patients. They are often young and relatively fit, so bevacizumab likely increases the response rate slightly. They certainly increase progression-free survival. We have seen a lot of data for EGFR exon 19 and L858R with the combination of TKI [tyrosine kinase inhibitors] as well as antiangiogenic therapies that reinforce this. John Heymach still says that the strongest predictor of response to antiangiogenic therapies – the only true predictor we’ve found despite 15 years of research – is the presence of EGFR mutations. These behave very much the same, biologically, and I try to give bevacizumab when I can.
I don’t do immunotherapy. I am not in favor of a four drug approach using pemetrexed as there is no FDA approval for carboplatin, pemetrexed, bevacizumab, and any associated checkpoint inhibitors. You could potentially consider the IMpower150 trial regimen, which is carboplatin, paclitaxel, bevacizumab, and aezolizumab, but paclitaxel has a lot of negative side effects associated with it and of course less CNS. [central nervous system] penetration than pemetrexed. Carboplatin-pemetrexed is viable for sure, and with bevacizumab, when I can do it, I do it on the front line.
In the second line, it’s a debate between immunotherapy, which is tempting, and may work in some patients – maybe a PD-L1 level would influence me somehow. Or there’s also docetaxel, docetaxel-ramucirumab, gemcitabine and drugs like that. With SRS [stereotactic radiosurgery] question, often I will refer patients just so that other practitioners can keep an eye on the patients with me. Patients will say the radiation oncologist and neurosurgeons will say, “How good is your medicine? They can say, “It might work, maybe not.” The main reason I tended to irradiate patients was to make them eligible for second-line clinical trials, because sometimes patients have “untreated” brain metastases, and we have never irradiated them in the past. . They are gone, but we think they will grow back if we start something without good CNS coverage.
Alexander I. Spira, MD, PhD, FACP: That’s a good point, and I would have done it myself, anticipating the second-line clinical study. Just like you, I’m not a fan of the IMpower150 trial regimen. It significantly affects the quality of life between neuropathies, in all patients. It’s just the general discomfort of therapy. The history of bevacizumab has been a long one, coming from [The University of Texas] MD Anderson [Cancer Center] and John Heymach. We heard, in only 1 of these stories, that you were just waiting for this book to close. Either everyone will read it or not everyone will read it. It’s always one of those things that people are very stubborn about.
Joel Neal, MD, Ph.D.: Fortunately, we don’t just have these therapies. For the CNS metastasis and progression issues we talked about at the start of the program, there are a few new molecules emerging; they are really exciting, in terms of straightforward processing of EGFR exon 20 insertions. First of all, what has been your experience? Have you tried other TKIs – first, second and third generation TKIs – in the treatment of lung cancer with exon 20 insertion and got answers?
Alexander I. Spira, MD, PhD, FACP: I have never tried them myself. Some people have been referred to me for clinical studies. Like the agreement, we participated in the mobocertinib clinical study and the afatinib clinical study. I have had people who have received these off the label. Most do not, especially because the doctor did not realize that it was a EGFR mutation that does not tend to respond to these. They just saw a EGFR mutation and said, ‘Look, that didn’t work. It’s probably more common than you might think, but I’ll tell you from my anecdotal experiences that it’s usually a sweep and then they move on. While I think there is some data, you might want to talk about a higher dose of osimertinib because there is little data out there. There is nothing overwhelming yet.
Joel Neal, MD, Ph.D.: That’s right. If I remember correctly, we were initially excited about afatinib because afatinib followed lorlatinib. Gefitinib was a second generation drug that rebounded irreversibly, which is why it was tested. If I remember correctly, progression free survival was maybe 3 months, with a few patients having a transient response but not much response. Despite the approval of afatinib in atypical mutations, it is not so active in EGFR exon 20-insertion lung cancer. Regarding osimertinib, Zosia Piotrowska [from Massachusetts General Hospital] led an ECOG cooperative group study, and I believe 4 of 17 patients responded to 160 mg per day of osimertinib, a higher dose than would normally have been tested. Off-label, without any other therapeutic approach, apart from a clinical trial, it was not a bad option. But it certainly hasn’t gotten response rates high enough to say it’s something we regularly recommend.
Alexander I. Spira, MD, PhD, FACP: This story happened with the advent of mobocertinib and some other drugs, so if it had come out a year or two ago it might have made a lot of headlines. I think it has been overshadowed by some of the newer drugs.
This transcript has been edited for clarity.
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