Dr. Todd Bauer:
Welcome to The ASCO Post Roundtable Series on ALK-Positive Metastatic Non–Small Cell Lung Cancer. I'm Dr. Todd Bauer based in Nashville, Tennessee, working at Tennessee Oncology and the Greco-Hainsworth Centers for Research. I'm delighted to be joined this evening by Dr. Ou and Dr. Florez, who I'll allow to introduce themselves now.
Dr. Sai-Hong Ignatius Ou:
Thank you for the invitation, I'm Ignatius Ou, I'm at the University of California Irvine School of Medicine, located in Orange, California. Thank you for the opportunity.
Dr. Narjust Florez:
Thank you for the opportunity as well. My name is Dr. Narjust Florez and I'm a thoracic medical oncologist at Dana-Farber and an Assistant Professor at Harvard Medical School.
Dr. Bauer:
Guys, great to have you both here. Today, we're going to be discussing the treatment and management of ALK-positive metastatic non–small cell lung cancer with three patient case studies. Our first patient will focus on the management of first-line ALK-positive non–small cell lung cancer with CNS metastases at baseline.
Ms. FC was 38 years old in 2021 when she presented for evaluation of headaches. Unfortunately, her head CT did reveal two lesions with some surrounding edema but no midline shift. These were concerning for metastatic disease. CT scan of the chest, abdomen, and pelvis revealed a 4-cm left upper lobe mass, hilar adenopathy, and a 2-cm liver lesion. A biopsy of this liver mass did confirm metastatic non–small cell lung cancer.
So NGS was sent but of course that took probably 2 to 3 weeks, 3 years ago, to get back. So she was started on carboplatin and pemetrexed and referred for radiation to the CNS lesions. Next-generation sequencing did return with an EML4-ALK variant 1 translocation and alectinib was started posthaste. She underwent stereotactic radiosurgery to the CNS lesion about 1 week after alectinib started, and initial restaging scans demonstrated partial response in all of her lesions. So let's pause there. Dr. Ou and Dr. Florez, what are your thoughts on this case?
Dr. Florez:
I think this patient reveals the real-life case. These are patients without rearrangements, who tend to be very young, and they tend to have CNS disease. So many of us have been in this position in which the NGS is still pending, and I think it's very important to remember that we still have carboplatin and pemetrexed. Today in clinic, I started a patient on that because the disease is rapidly progressing and we're still waiting for NGS.
Dr. Ou:
So I agree, this is a very young patient, 30-some years old, I assume it's a nonsmoker, it's not specified in the slide. Pretty aggressive tumor with brain metastases, a 4-cm primary that is moderate in size, very suspicious of very strong driver mutations in the background. So I would put ALK very high in a differential diagnosis. Liquid biopsy probably will be able to detect a fusion because of the tumor burden. So I would probably send off a liquid biopsy too, which probably takes about 7 days. And then whether the patient has symptoms or not depends on whether we go ahead with the SRS or not, but the brain mets need to be treated.
Dr. Florez:
That is a good question I have for you, Todd. Right? This is 2021. So let's say February of 2021, before March of 2021. So with these patients on alectinib, we knew that was the first line. Would you take in these patients or are we taking these patients right to SRS compared to monitoring knowing that the benefit is not as good?
Dr. Bauer:
Yeah, I think at that point we probably felt there was still benefit in doing so. And in fact, one of the sessions at ASCO just a couple of weeks ago, the TURBO-NSCLC did demonstrate that benefit in EGFR- and ALK-positive populations. Now, 80% of the patients were EGFR-positive treated with osimertinib and 20% were ALK-positive and treated with alectinib, that there was benefit in duration of response in the brain or time to progression. There wasn't a difference, however, in overall survival in those groups.
So I think when we look at alectinib and brigatinib in the second-line ALK agents, there's probably still good rationale for utilizing SRS in these groups. And our colleagues down in the basement in the radiation oncology suite will tell us that SRS has no long-term toxicity, it's wonderful; so, not many of our patients have the chance to be alive 5 or 10 years after SRS, so though we think the long-term side effects aren't bad, we don't know that to be true. So it'd be interesting to see how this evolves as the out-therapy options evolve as well.
Now, Ignatius, one thing I will go back to, you mentioned this is a young patient and a never-smoker and so probably a oncogene-driven cancer. I'll agree with you, but I will also, because I practice in middle Tennessee where we have more smokers than never-smokers, remind you and share with everyone, smoking doesn't protect people from these alterations. So I don't care if they've smoked four packs a day since they were 4 years old, they still get NGS to look for these because it's a needle in a haystack, but we can find them.
Dr. Florez:
And I have found, I have a few patients I have to say that are ALK-positive, maybe because I tend to see most of the outpatients here. But I have found these patients with previous tobacco history, but the large majority don't. But I confirmed that especially that come from rural areas of Massachusetts and when I was in Mayo, I also saw it and something that we forget too, are second-hand smokers are very common in this group of patients.
They don't have active tobacco use but they have occupational exposure. So I have for some unclear reasons, I have three flight attendants from Pan Am, that have second-hand smoke. They never smoked, but they were exposed to second-hand smoke, and two out of the three have a target mutation. And we haven't been able to collect second-hand smoke data adequately, but that also is not exclusion criteria for testing.
Dr. Ou:
I agree completely. What I want to say is yes, you definitely need to do NGS on everybody, but this patient has a high chance of getting or having ALK, a very aggressive driver mutations. She's pretty young, 38 years old. So what I'm trying to say is, with liquid biopsy you can probably wait a week or so before starting the SRS. That's my only point.
You definitely do NGS on smokers. So I do ask my patient, "How much have you smoked?" They say 30 years. And I ask them, "You're 70 years, so 30 years. That means you started in your 20s," and then they started to go back to their teens.
But the fact is that if you profile every smoker, the chance of finding a driver mutation is much less. That's what I'm trying to say is you can probably wait a week, give it a week maybe to convince the patient to wait and wait for the liquid biopsy. So that's my point. But definitely profile on everybody. Yes, we do that.
Dr. Bauer:
And I think most patients is we can talk them through the rationale for let's get all the information to make the best treatment decisions for you. I'm going to throw you on steroids, so don't worry about that edema, that'll go away, you're not having symptoms. Their headaches get better in 2 days and so they do feel more comfortable with it. But I think one thing that does bear bringing is one of the takeaways from this case is that if you do feel the need to start treatment, we know from the EGFR data that it's much better to delay the start of immunotherapy for that first cycle so that you don't increase their risk of TKI-associated pneumonitis if they've been exposed to immunotherapy previously.
Dr. Florez:
I just want to support what Ignatius said about liquid biopsy, because I think they're complementary now. In 2021, we were still in the peak of the pandemic and I think liquid biopsies at that time saved many of us because patients were able to get phlebotomy. But at this point I found it complementary and the person that gets tissue and gets liquid DNA in these patients, not only because of the results but also the heterogeneity of the samples. I had a patient that has truly adenosquamous and then the tissue and then the liquid biopsy and then we ended it, but I think they're very complementary and now they're getting more into the clinic, I think in 2021 they're still early, but more and more also, I think we're getting both at the same time.
Dr. Bauer:
And I agree, that's my standard practice as well, that I'll request NGS on the tissue specimen and await the liquid biopsy to come back at the same time. It's not been a problem for patients from a reimbursement or copay standpoint. And I'll say that literally, three times in the past month, I've had QNS come back on the solid tumor only to have something actionable come back on the liquid biopsy. So certainly, I'm sure there are some health-care economics people who would argue strongly against me, but if that's your mom or your grandma who has that situation, it is a world of difference for that patient. So I think it's worthwhile.
Dr. Florez:
Yeah, I still get the tickles when I see the liquid biopsy result and I'm clicking on it, because I mostly focus on young patients and I'm like praying to whatever God like, "Please send me something I can target in these four young women."
Dr. Bauer:
The lab clear-through is sort of like Christmas and you don't know if it's going to be a good year or a bad year until you open it. And so the other thing is, we talked about this patient was diagnosed and started treatment 3 years ago, 3 years and 4 months ago, according to Dr. Florez, which I agree with. So things have evolved and we know that the CROWN data just got presented at ASCO and that has some, I think, some impactful information that I'd like to look at with the next couple cases.
So to sum up this case, guys, I think that three clear points came to mind as we talk through it. One, we starting treatment prior to having NGS results. We should avoid immunotherapy agents to decrease the risk of TKI-associated pneumonitis. Based on the TURBO-NSCLC data produced at ASCO this year, stereotactic radio surgery in combination with TKI is superior to TKI alone from a PFS standpoint, both equivalent survival in an osimertinib and alectinib treated group. And as data evolves, there are ongoing choices in the ALK-positive lung cancer and ongoing debate about those.
This brings us to the end of the first case, please continue watching the other cases for further discussion.
