Dr. Todd Bauer:
Welcome to The ASCO Post Roundtable Series on ALK-Positive Metastatic Non–Small Cell Lung Cancer. I'm Todd Bauer and I live and work in Nashville, Tennessee at Tennessee Oncology and the Greco-Hainsworth Centers for Research. And I'm delighted to be joined by Dr. Narjust Florez and Dr. Ignatius Ou to talk through this third case.
Dr. Narjust Florez:
Hi everybody, I'm Dr. Narjust Florez. I'm a thoracic medical oncologist at Dana-Farber Cancer Institute.
Dr. Ignatius Ou:
And I'm Ignatius Ou. I'm at the University of California Irvine School of Medicine in Orange, California.
Dr. Bauer:
Well, in our third and final case, we're going to focus on treatment of second-line ALK-positive non–small cell lung cancer with CNS progression on first-line crizotinib.
This is a patient of mine, and Mr. BK presented in June of 2013 at 40 years old with a progressive cough and was ultimately diagnosed with metastatic EML4::ALK-positive non–small cell lung cancer. He did not have any CNS lesions present at the time of diagnosis, and he was started on first-line crizotinib, the only option available at that time. Sadly, about 8 or 9 months later, he did develop seizures and was found to have multiple CNS lesions.
He was treated with whole-brain radiation at that time. And then I enrolled him on the phase I lorlatinib study in April of 2014, which I believe was the second, maybe third cohort in that first-in-human study. He did pretty well on this requiring some dose reductions for modest CNS toxicity until November of 2018. He's at the 75-mg daily dosing and he developed grand mal seizures. I and his wife of course, were terrified that he'd had CNS progression, but indeed there was no progression noted on the MRIs. Lorlatinib was held. He returned completely to his baseline after about 11 days. And we had some very heavy discussions about risk-benefit of even trying him on lorlatinib again. And I will admit I was talked into trying it again at the 50-mg dose with much hesitation.
He maintained a near-complete response since that time. He still has a 2 mm-something in his brain that they're calling potential tumor, but it's been 2 mm for a decade. And in April, just a couple months ago, he unfortunately developed seizures again. Again, no CNS progression at the time. We held lorlatinib at that time and after much discussion we have continued to hold lorlatinib. He has had no recurrence of the seizures and he is in the surveillance phase at this time. So a whole lot to talk about over the course of this guy's past decade of life.
Dr. Ou, I might start with you this time. What do you think about the long-term toxicity of these drugs seeing somebody on a targeted therapy for a decade, long-term benefit, what about the maintenance dose, and what do you think we do next for this patient?
Dr. Ou:
So as your case already proven, I mean, there's really not much long-term toxicity with lorlatinib after the patient has been on for 10 years. That's pretty good test. The 50-mg dose, I have one patient that I also reduced to 50-mg dose, very similar, may not be grand mal seizure, but could potentially be some CNS effect. You have taken the patient off lorlatinib. I think that's good. Alternatively, you probably have thought about adding an antiseizure medicine with lorlatinib if it's not been done. So once the patient is off lorlatinib, I'd just observe and then if need be, re-add back the lorlatinib at 50 mg or even a 25 mg, dose up to 50 mg. So that will be my approach for the next step.
Dr. Florez:
I think something important to mention about long-term toxicities that we learned from the CROWN data that was just presented is that between month 18 and 60, there was no new toxicity reported for the agent. So something in the trial, but doesn't mean the patients are not going to get all the known adverse events. It's just no new adverse events for us. But these can appear in any time.
I had a patient that has been in loratinib for second line and she did great and that was one of my first patients. And it's like, "Oh, lorlatinib is great." And then she developed an adverse event after 2 years. And this is a good example to be vigilant because patients also take a seat back, the caregivers take a seat back, "I've been in this drug, the scans look good." So we need to be vigilant during all phases. And patients may be more hesitant to mention adverse events at this time because the drug had worked for a very long time, but between 18 months and 60 months, nothing new. But the old culprits are still around.
I think for this patient, the dose reduction to 50 mg is fair; he had a near complete response. There is nothing else that would give this patient that. Doesn't matter how much chemotherapy you throw at this. And we forget about the side effects of chemotherapy. Yes, it's a capsule, it has adverse events, but chemo is still not a walk in the park.
Dr. Bauer:
Dr. Florez, one question on that because there's so much discussion about that with lorlatinib and the toxicity. "Oh, it's a terrible hard drug." Do you think we've gotten a little bit spoiled maybe to how well some of our targeted therapies are, and we're a little bit out of our comfort zone at figuring out how to manage these toxicities? Like, "Well, I can give them the easier drug and my life's better. Or what if that drug's better and I need to figure out how to manage that for them?"
Dr. Florez:
Well, we all learned how to manage immune-related adverse events. I was in my mentor's, Dr. Alex Adjei's office after nivolumab was approved and we had the first hypothyroidism, we were like, "Oh, hypothyroidism, what is happening?" Now you get hypothyroidism for immune checkpoint inhibitors, you're like, "Okay," and then you move on. We learn from immunotherapy. Rituximab when we were fellows, "Oh, these reactions." Amivantamab, we're learning how to handle these reactions. We can learn how to handle the CNS toxicities. We have done more and that is a tablet. I think the problem here is there's a tablet, so the patient doesn't come to the cancer center as often as somebody on immune checkpoint inhibitor, as somebody on amivantamab, for example. So there's a lot of self-doctoring of the patients and more phone calls and less often visits, but we can do it. Come on. Now we get ICI diarrhea and we're like, "Oh yeah, we know how to do that." So we can do that, we learn lots.
In my opinion. But again, I'm new on the block.
Dr. Bauer:
No, I totally agree. And I think that there's a little bit of comfort level that we've reached, and I don't have to, but I think that you mentioned the number, there were no new safety signals after 18 months on the CROWN trial. One thing that I think was completely stood out to me, so the last data cut for the lorlatinib data for CROWN was at 3 years. So between 3 years and 5 years, there were only six events on the lorlatinib arm suggesting that when you get patients out to that long, you do get this pretty incredible response that you see. And at 5 years on CROWN, we had not seen any, we've not hit median progression free survival yet, so I do believe we can expect more patients like Mr. BK to pop up in our practices.
And I think his case is really important to demonstrate two things. One, you can control CNS adverse events with dose reduction. And two, even at 50% of the reduced dose, you can have response for 6 years basically at that dose. Now, I wish like heck, that he weren't dealing with this side effect and that he were still on the drug, because it makes us feel more comfortable, but I do think it will be from an academic scientific standpoint, be fascinating to see how long does he stay with no evidence of disease progression after having essentially a CR within a few months on the drug and basically 9 full years of maintenance therapy. So that'll be interesting to look at as we go forward.
Dr. Florez:
And I think it's a trade-off. I just told my patients this, "This is the best drug for your cancer but it comes with a price." We don't have any cancer therapies that don't come with any adverse events, even our very beloved pemetrexed will put people in renal failure. So it's a trade-off, but what Ignatius said, know your patients as a whole so you can know if that's the best treatment for them.
Dr. Bauer:
Totally agree. Dr. Ou, any other thoughts on your end?
Dr. Ou:
No, I think I completely agree. Dr. Florez mentioned about we learned to manage side effects and we get better and better. Lorlatinib is not a drug that it's insurmountable. It's actually very easy to manage. If you look at the median dose, relative dose intensity, it's 99%. I mean, we are involved in clinical trials and there is some drug that has remained nameless for now. I mean, my clinic has become a dermatology clinic every day. It's not oncology clinic. And so lorlatinib is very well tolerated. The median relative dose intensity at 5 years is 99%. So the majority of the patients can get close to 100 mg of the dose. We have managed more side effects with more toxicity than lorlatinib.
Dr. Todd Bauer:
Well, thank you both very much for your time. I've really enjoyed the conversation and your insights into these cases. This does bring us to the end of our third and final case. Please see the other segments for further discussion about the latest research in non–small cell lung cancer or visit ascopost.com.
