Dr. Narjust Florez:
Welcome to the ASCO Post Roundtable series on clinical considerations in the treatment of metastatic ROS1-positive non–small cell lung cancer. I'm Dr. Narjust Florez, a thoracic medical oncologist at Dana-Farber Cancer Institute, and assistant professor at Harvard Medical School. Today, I'm joined by two of my esteemed colleagues, and I will let them introduce themselves.
Dr. Christine Bestvina:
Hi, my name is Dr. Christine Bestvina. I'm a thoracic medical oncologist at the University of Chicago and an assistant professor.
Dr. Debora Bruno:
Hi, I'm Debora Bruno. I'm a thoracic medical oncologist at Seidman Cancer Center, Case Comprehensive Cancer Center, and an associate professor at Case Western Reserve University in Cleveland.
Dr. Narjust Florez:
I'm delighted to have these two esteemed colleagues here. We know each other, so we're going to be referring to each other by first name. Today we'll be discussing the treatment and management of ROS1-mutant non–small cell lung cancer. In our second installment, we focus on the management of CNS metastasis and ROS1 non–small cell lung cancer. Let's start with a case.
We have a 54-year-old female. She presents to her primary care doctor with a dry cough for around 4 weeks. No relevant past medical history. No previous tobacco use.
After antibiotics and five different COVID tests, she did not have any improvement. A chest X-ray showed a right middle lobe opacity. That prompted further testing, which led to a PET scan that showed an avid lesion with mediastinal lymph nodes.
She underwent a biopsy with EBUS, or the mediastinal lymph nodes, revealing adenocarcinoma of the lung, cribriform features TTF-1 positive, P40 negative, and a PD-L1 less than 1%. Biomarker testing was ordered, is pending. Her clinical stage so far is a T2N3.
Christine, what will you do as you're waiting for this biomarker testing for this newly diagnosed patient?
Dr. Christine Bestvina:
The last part of the workup that's still pending for this patient is an MRI of the brain. We do do that for all patients who have this stage of disease, but it's particularly important to make sure that patients don't have metastasis to the brain or stage IV disease.
Dr. Narjust Florez:
Very good point. We need to scan the brain. Regardless of the subtype of non–small cell lung cancer, patients can have limited disease in the chest and still have brain metastasis. So the brain MRI showed multiple supratentorial and infratentorial lesions. The patient only reports some mild headaches, no visual changes, no seizures or other neurologic deficits. Debora, should we refer this patient right away to start whole-brain radiation? She has over 30 brain lesions.
Dr. Debora Bruno:
Most recently with the FDA approval of so many tyrosine kinase inhibitors that have intracranial activity, for patients who are asymptomatic who have brain metastasis and are asymptomatic, I tend to wait for results of biomarker testing before I refer them for radiation therapy. Because if we identify an actionable alteration for which we have an FDA-approved agent that has high intracranial activity, most of those patients that start taking the medication have substantial response, intracranially. So I typically don't do that until biomarker testing is out.
Dr. Narjust Florez:
Christine, what is your approach in this patient with over 30 brain lesions?
Dr. Christine Bestvina:
Yeah, I'm similar to Deb. I'm also going to wait for the molecular testing. I think, fortunately, our radiation oncology colleagues are also recognizing the importance of molecular profiling. Sometimes I'll have a patient who has just one brain lesion that's large with edema but a few smaller lesions. My radiation oncologist is now reaching out to me saying, "Is the molecular testing back?" Because maybe I'll just do SRS to the big one and watch the small ones.
Dr. Narjust Florez:
I think that's something that's new over the last few years, I think less than 5 years, we are considering that these new agents have very good CNS penetrance, and this is a younger woman. Some of the issues I have about whole-brain radiation is that after you give it, you cannot take it away from patients. Their quality of life significantly gets affected and even overall survival may get affected because some patients may not be able to get to next lines of therapy, so whole-brain radiation doesn't come without a price.
Let's see. Then we got the results of the drugs and the patient has a ROS1 fusion. Before we start talking about treatment, Debora, this is a ROS1 fusion. Is it tricky to diagnose when it comes to biomarker testing in NGS, or is it the same as the most traditional mutations like EGFR?
Dr. Debora Bruno:
Yes, it's not just NGS. Rearrangements, fusions are a bit tricky to pick up and detect with certain types of NGS testing platforms, because we have many breakpoints in those genes and different fusion partners, and the breakpoints are located in introns. So it makes it difficult sometimes with DNA NGS sequencing to be able to detect those alterations. It is common practice, if you don't detect any actionable alteration, to reflex with RNA sequencing to make sure you are potentially detecting fusions, alterations that were missed by regular DNA NGS testing.
Dr. Narjust Florez:
I think this is very important. Sometimes you may rule out a tissue and you only have DNA testing. That is not enough, particularly for ROS1. So you may have to rebiopsy to get enough tissue for RNA. I have been there way too many times and it comes with an odd mutation in our ROS1 fusion and you're like, "Hey, the second biopsy was worth it."
Christine, now we know that we have a ROS1 fusion. We have multiple brain lesions where we were waiting for these results. Do the brain lesions affect your treatment decision for the agent that you would pick for ROS1?
Dr. Christine Bestvina:
We have three FDA-approved agents for patients with ROS1 fusions. The one agent that I would take out of the discussion now would be crizotinib. Crizotinib, one of its biggest problems when it was the only option we had, historically, was failure in the brain and lack of good CNS penetration.
Particularly since this patient has CNS disease upfront and needs a good intracranial response, that limits the discussion to either entrectinib or repotrectinib.
Dr. Narjust Florez:
That's a very good point. We need drugs that will get to the brain, particularly for this patient. This patient was started on entrectinib at 600 mg daily for the treatment of ROS1 adenocarcinoma. That was before the approval of repotrectinib.
So the patient came back after she was on therapy for approximately 12 weeks, and she had a repeat brain MRI which showed two remaining brain lesions. I think it's very important to show these pictures of the same patient because we were talking about how brain radiation can be avoided.
So this patient had over 30 lesions and now we have 2 remaining in the picture. She cried, I cried, we all cried of happiness with the scans. Will you radiate the remaining lesions, Debora?
Dr. Debora Bruno:
It's a great question. This is a much-changed scan from the previous one obtained at baseline. I typically keep following my patients with scans every 3 months as they're responding and some of the responses deepen with time.
If and when we see progression, then I recommend SBRT to the lesions, or SRS to the lesions that are growing. I think radiation therapy has a very important role in the treatment of oligoprogression in patients with actionable alterations being treated in the first-line setting. It allows for patients to remain on targeted therapy longer. So I typically follow them closely, and when needed, I refer for SRS to the brain.
Dr. Narjust Florez:
I think it's good to continue to follow because sometimes patients can have disease progression in the CNS when everything is still looking good from the neck down. So 9 months had happened, she's back to full-time work. But she comes to you reporting that she's having a lot of lower-extremity edema, and she has gained approximately 15 pounds. In addition, you can see an elevated AST and ALT in the lab. And during examination, she tells you that her attention span has significantly decreased. When you do finger-to-nose examination, she has mild ataxia. Christine, what will you do next? Brain MRI or proceed with dose reduction of the medication?
Dr. Christine Bestvina:
I probably would do a brain MRI while holding and potentially dose-reducing. I think these cognitive side effects of both entrectinib and repotrectinib are some of the most challenging to manage.
Several of the patient examples we're discussing today are young people who are still working who may be caregivers in their family. They have a lot of responsibility, and so those cognitive side effects can really be challenging for their life. Typically, I'll start with dose interruption and potentially dose reduction depending on the severity.
Dr. Narjust Florez:
I think that's a very good point. Debora, would you do something different when this patient has these symptoms?
Dr. Debora Bruno:
No, I agree with what Christine said. I would probably check an MRI of the brain once again to rule out intracranial progression while I hold the medication depending on the severity of the side effects. And after discussing with the patient in great detail, potentially, once the symptoms resolve, consider reintroducing the drug at a lower dose level.
Most of those symptoms, interesting to see that they tend to occur early on, so it is really important to keep following those patients closely and make sure they understand that those symptoms can occur and report to you soon enough, so they don't have to be hospitalized because of such complications.
Dr. Narjust Florez:
I think those are two very good important points here. One is the dose interruption or the medication interruption, so the patient can go back to baseline before the dose reduction. I think that allows the symptoms to improve faster instead of going right to dose reduction. It's just stop, image, and when the patient reports that some of these symptoms have improved, then consider the dose reduction. The second thing I think is important is that these side effects come from the benefits that we just talked about. We can avoid the whole-brain radiation, but then the drug gets to the CNS and now we have these new side effects that we haven't seen before. The fancier the drug, the more it gets to the CNS, the more I'm doing finger-to-nose. I didn't use to do that too much with carboplatin and etoposide and now with these other drugs I'm like, "Okay, here, let's do it."
I have a patient that she just knows when I put the finger, and she knows right away. But the point is that also teaching caregivers is important because the patient may not notice some of these CNS side effects. And the caregiver—the spouse, partner, an older son or daughter—can identify these symptoms. So we provide education to the patient and the family, which I think is very important, because otherwise the patient may not notice some of these symptoms.
I had a patient that forgot his wife's name and the family used to joke about it. But the wife was like, "I don't think this is normal." And it wasn't. So I think it's very important.
We're coming to the end of this case. It's important that we break down some of these clinical takeaways. When we're talking about ROS1 fusion–positive non–small cell lung cancer, so up to 36% of patients with ROS1 non–small cell lung cancer will present with metastatic disease to the brain.
In terms of efficacy of systemic therapy, we favor entrectinib and repotrectinib because these drugs have great intracranial penetration. In certain patients, like this patient, whole-brain radiation can be avoided. We wait for the biomarker testing and we consider these new TKIs that have adequate CNS penetration but something very important since we have to do short-term follow-up with brain MRI. If we decide not to do radiation and start the TKI, we cannot do the MRI in 3 to 4 months, which usually tends to be a short interval.
For entrectinib, we have long-term follow-up data when it comes to CNS response—particularly higher progression-free survival, 7.4 months. And in terms of the CNS for treatment-naive patients, the progression-free survival was less in patients that were previously treated.
But if the patient has experienced any significant adverse events, we look to medication interaction, imaging if required, and then have a conversation with the patient and consider a dose reduction.
That is our summary about the management of CNS metastasis in patients with ROS1 fusion–positive non–small cell lung cancer. Please see the other segments for further discussion about ROS1 and other data in non–small cell lung cancer, or visit ascopost.com.
