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. My name is Dr. Narjust Florez. I'm a thoracic medical oncologist at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School. I have the pleasure to moderate this roundtable with esteemed colleagues and experts in the field. I will pass it to Dr. Bestvina.
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 of medicine at Case Western Reserve University.
Dr. Narjust Florez:
Thank you for introducing yourselves. We are colleagues and friends, and we are going to be using first names for this recording. Today, we'll be discussing the treatment and management of ROS1-mutant non–small cell lung cancer with three patient case studies.
Our first case is going to be about a newly diagnosed metastatic ROS1-positive non–small cell lung cancer. So I'm going to get straight to the case. We have a 49-year-old Hispanic White female. She's a busy wife and mother with two young kids, works as an accountant, and is an avid runner. No significant past medical history. She had previous tobacco use during college, less than 10 pack-years.
She presented to her primary care doctor with a dry cough for the last 4 weeks. After a round of antibiotics and no improvement of the cough, a chest x-ray was obtained that showed a left lower lobe shadow and, again, she was treated with another course of antibiotics without improvement of symptoms.
This led to a CT of the chest that showed extensive reticulonodular and tree-in-bud opacities throughout the left lung associated with peribronchovascular thickening, mucus plugging, and a small left pleural effusion.
This was suspicious for lung cancer, which prompted a PET scan that confirmed the lung findings with significant FDG activity and a new-found liver metastasis, also FDG uptake. So now we have this case and I'm going to go to Dr. Bruno. So what is next for this patient?
Dr. Debora Bruno:
Yeah, so certainly the finding of an FDG-avid liver lesion raises a suspicion for a malignant and metastatic process and this patient certainly needs a biopsy. I would say it's preferable in the setting of potentially oligometastatic disease to biopsy the metastatic site because in doing so, you can—at the same time—diagnose and stage the patient.
So if possible, I would recommend biopsy for what seems to be a liver metastasis in this patient. But sometimes, you have to really look into the tissue procurement teams that you have available. At our institution, for instance, a lot of times our pulmonologists will be the ones at front lines obtaining tissue for us. So sometimes a bronchoscopy is the best way to go as well.
Dr. Narjust Florez:
And in this case, the metastatic lesion tends to be a little bit perimedial, so it may be hard to get to that portion of the liver, but yes, this is right. We always go for what will confirm the metastatic disease.
So the left lower lobe biopsy shows a papillary carcinoma with psammoma bodies. The tumor was positive for TTF-1 and napsin and a PDL-1 of 100%; a brain MRI to complete staging was negative for metastasis. So Dr. Bestvina, where are the next steps, right? We have a high PDL-1 here. Should we go right to immunotherapy? The patient is eager to start treatment as soon as possible.
Dr. Christine Bestvina:
Yeah, I think this is one of the harder parts in the journey for the patient, which is waiting for the molecular profiling to come back, which is absolutely the right thing to do for this patient. One of the advantages of ctDNA is that it does offer a quicker turnaround time. In my practice, I typically am sending ctDNA at diagnosis in addition to tissue. But waiting for those results prior to starting any immunotherapy or chemoimmunotherapy is important here.
Dr. Narjust Florez:
So how do you explain this to the patient? She went on Google and she put in “PD-L1 100%,” so immunotherapy came out as the best treatment option.
Dr. Christine Bestvina:
Yeah, I think with the growing body of work about how immunotherapy does not benefit patients with targetable alterations, we've recently seen KEYNOTE-789, which showed that chemo plus pembrolizumab did not show a benefit for patients with EGFR mutations. I think it's just a conversation with the patients about how even though immunotherapy is great for some patients, it's not great for all, particularly if you have one of these targetable alterations. And so the important thing is for us to sit tight so that we know your exact map forward.
Dr. Narjust Florez:
So like I told my patients—"hurry up and wait.” So circulating tumor DNA or liquid biopsy was obtained for this patient and it was negative or no target mutations were identified. Now you have part of the results and they're negative. Dr. Bruno, what do you do with these results? Do you throw them away or do you tell the patient they don't have a target mutation? What do we do when this happens? Like you mentioned, she has oligometastatic disease.
Dr. Debora Bruno:
Right. So the sensitivity of ctDNA plasma genotyping is approximately 70% to 80% and is certainly lower in patients with less tumor burden and disease that is confined to the chest, central nervous system. This patient only has one small liver metastasis, so a negative result must be followed through with tissue NGS. So I'll certainly try and rebiopsy the patient and explain to the patient that we need to be certain that there are no actionable alterations that we can target with a drug that can be taken orally with less side effects and higher efficacy hopefully than chemotherapy.
Dr. Narjust Florez:
So can I say the cheesy phrase “tissue is the issue” if the liquid biopsy is still negative?
Dr. Debora Bruno:
I would agree with that 100%.
Dr. Narjust Florez:
Tissue is the issue. And it's a gold standard, and it remains the gold standard, even when we have new technology. So, surprise behold, the tissue came back on a Friday 3:30 PM and it was a ROS1 fusion, the most common, CD74. So, ROS1 fusion and the tissue from the lung biopsy. So let's discuss a little bit. So Christine, what was your first-line therapy for this patient with oligometastatic ROS1 fusion?
Dr. Christine Bestvina:
So fortunately we're at a point where we now have three different options for patients with ROS1 fusion. We have crizotinib, we have entrectinib, and then most recently, we have repotrectinib. I do think that this is a time where you'll want to explain to the patient what the different side effects are, but also what the efficacy is.
For me, I am going to be choosing repotrectinib as my front-line agent just because of the improved progression-free survival as well as the intracranial responses that we're seeing with this drug. But I think it certainly is still a discussion with the patient.
Dr. Narjust Florez:
So, Debora, the patient says, “Why don't we start with crizotinib and then we can use the other drugs later.” How can we explain to the patient that maybe crizotinib was very good in 2009 or 2014 and now, it may be good to use another agent? How do we explain that?
Dr. Debora Bruno:
So I try and trace parallels with prior drug approvals that occurred for other targets in the past. So at some point, drugs such as osimertinib were approved only in the second-line setting. And we saw that when they were brought in and tested in the first line, there was a very substantial progression-free survival benefit that was noted for that drug compared to first-generation TKIs.
And I think something similar is happening here. I tend to say that for patients who have actionable alterations, progression-free survival is important because the longer you stay progression-free on a medication that has manageable side effects without needing cytotoxic chemotherapy, the better it is, because you give more time for newer drugs to become approved and every day counts, every day you survive a cancer. Taking a drug that is active is important to you. So this is how I usually explain to my patients.
Dr. Narjust Florez:
And I think a good important aspect of these agents is that they're oral. And I have young patients who are very active, like this patient, an avid runner, and I never had a patient run a marathon in chemotherapy. They're always in targeted therapy. My ladies that run the marathon—I don't run, I just go there, we’re assigned to support them every year at the Boston Marathon. So Christine, the patient has started the ROS1 therapy, no crizotinib. What time do you proceed with the restaging scans? When is the right time to do that?
Dr. Christine Bestvina:
I typically do my restaging scans every 3 months. Although I must admit for my first restaging scan on therapy, I'll do it a little bit earlier, somewhere around the 6-to-8-week timeframe. I think it's both reassuring to know that the patient is headed in the right direction, and I also think psychologically, that first scan is so important for these patients to know that they're now taking a therapy that has their cancer under control.
Dr. Narjust Florez:
Debora, when do you do those scans?
Dr. Debora Bruno:
I agree with Christine. I tend to do my first set of scans within 6 weeks of treatment initiation. The first weeks when patients start targeted therapies, a lot of the side effects associated with these drugs, they tend to occur early. So I see them quite often.
Every couple of weeks they're in the office getting labs and being checked. And I think 6 weeks after initiation, to have those scans—and most of the time, we see responses—is really good and important. Psychologically speaking, they feel better about putting up with the side effects they're developing. And then after we establish that the patient has achieved a partial response, then we keep following them with CT scans every 12 weeks.
Dr. Narjust Florez:
Yeah. I tend to do 6 weeks as well. I think that's very helpful for the patients. In targeted therapy, you may have a faster response than when they start their cytotoxic therapy and immunotherapy, so you can see that. So we're coming to the end of this case, so let's talk about the clinical takeaway.
So first, we have seen an increase in incidence of lung cancer in younger patients. Remote smoking history like this patient in college should not be exclusion criteria for biomarker testing.
Features associated with ROS1-positive non–small cell lung cancer include adenocarcinoma histology, younger patients as mentioned before, and neversmokers or a very limited smoking history. ROS1 is a translocation and identified by a FISH break-apart assay similar to what we use for all translocations. And it will be present in most of the NGS panels. Circulating tumor DNA vs tissue and negative circulating tumor DNA or liquid biopsy does not exclude the presence of a biomarker.
So if you have a negative result, you need to go there for the tissue. So no tissue, no issue, still. ROS1 tyrosine kinase are highly sensitive to ROS1 inhibitors. The first was crizotinib, initially. Then in 2014, the results were published, then entrectinib, and repotrectinib. All of these agents are FDA-approved in patients with ROS1 translocations.
And these patients should receive targeted therapy first line in the first-line setting, because, as Debora mentioned, it's about quality of life. It is about adverse events, and progression-free survival really matters to our patients.
So this brings us to the end of this case. Please see the other segments for further discussion about the latest data in non–small cell lung cancer, particularly with ROS1 mutations, and also visit ascopost.com.
