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 and an assistant professor at Harvard Medical School. Today I'm joined by two esteemed colleagues and experts in the field and I will let them introduce themself. Dr. Bestvina?
Dr. Christine Bestvina:
Hi. My name is Dr. Christine Bestvina. I'm a thoracic medical oncologist and an assistant professor at the University of Chicago.
Debora Bruno:
And I'm Debora Bruno. I'm a thoracic medical oncologist at Seidman Cancer Center Case Comprehensive Cancer Center and an associate professor at the Case Western Reserve University in Cleveland.
Dr. Narjust Florez:
Thank you to the two of you for being here with me and the team. We know each other, so we're going to be referring each other by first name. So we are going to be discussing the treatment and management of ROS1-mutated non–small cell lung cancer. This is our final case and we're going to be focused on first-line therapy and disease progression after initial treatment.
So we have a 52-year-old male with past medical history of hypertension, depressive disorder, and exercise-induced asthma. He's an avid marathon runner. He started experiencing a cough when running. The cough was attributed to this newly diagnosed exercise-induced asthma. He was training for a marathon in the middle of the New England winter. There was no improvement in the cough, so a chest x-ray was done and showed asymmetric density in the right lower lobe that was attributed to pneumonia, so he was given a course of antibiotics. He has very limited family history, his maternal grandmother had lymphoma and his mother has basal cell skin cancer.
Unfortunately, after the antibiotics were started, the patient presented to the ER with significant shortness of breath and chest pain. You can see on the images that the patient had that show a large concentric pericardial effusion, so the patient had to have emergency pericardiocentesis secondary to cardiotamponade. During the imaging, we also identified a cavitary lesion in the right lower lobe and multiple enlarged hilar metastatic lymph nodes. The pericardial fluid was positive for TTF-1, suggesting adenocarcinoma of lung origin.
Here we have a subsequent imaging of the CT scan, and this tissue biopsy confirmed the metastatic lung cancer (TTF-1 positive). The patient had a brain MRI that showed two small brain lesions, no neurologic symptoms. The patient is very symptomatic in the hospital. Despite the pericardiocentesis, he has significant shortness of breath, chest pain, and biomarker testing is pending. Debora, the patient is still in the hospital. He's required oxygen. What would be your next step as you're waiting for biomarker testing?
Debora Bruno:
Yeah. This is such a difficult situation because in patients with non–small cell lung cancer, the ability of cytotoxic chemotherapy to work fast is limited and different from patients with newly diagnosed, extensive-stage small cell lung cancer where the response to systemic therapy is very fast; with non–small cell lung cancer, not as much. So I try and really optimize as much as I can to see if we can discharge without providing cytotoxic chemotherapy in-house, but sometimes this is the only way to proceed. Usually we can give one round of cytotoxic chemotherapy while we wait for biomarker test results on meeting the use of IO. We’re not using checkpoint inhibitor therapy without knowing biomarker test results because that complicates problems in the future if we identify a biomarker and we want to use a tyrosine kinase inhibitor and the patient has received IO, the rates of toxicity are higher, especially hepatitis and pneumonitis. So it's possible to give one round of cytotoxic chemotherapy while we wait for biomarker test results to be back.
Dr. Narjust Florez:
And that's a good point. So the patient did receive one cytotoxic chemotherapy. No IO, don't let the patients get IO when you're waiting for biomarker testing, regardless of whatever the patient, the aunt, or the Facebook group tells the patient in this case. So the patient got that cytotoxic chemotherapy in the hospital, it improved symptoms, and the biomarker testing came back 3 weeks later from that lung biopsy. Sorry, the circular and tumor DNA came back and the tissue, both revealing ROS1 fusion, with comutations of T53 and others. So we have a patient that's very symptomatic with CNS disease. Christine, what is your first choice for this patient with this ROS1 fusion, and do the presence of these comutations affect your treatment decisions?
Dr. Christine Bestvina:
Currently, I would go with repotrectinib as the drug of choice for this patient. We saw some really impressive results from the TRIDENT study with a progression-free survival of 36 months for newly diagnosed patients with ROS1 fusions. There's also excellent CNS penetration. We saw there an intracranial response of almost 90%, though the numbers were small. So for this patient with known brain metastasis, I would go ahead and I would switch to the TKI despite the fact that they had a good improvement with chemotherapy.
Dr. Narjust Florez:
Debora, what would be your agent of choice here? We talk about CNS penetration already, but between entrectinib and repotrectinib, did you have a choice?
Debora Bruno:
I agree with Christine. If repotrectinib is available, this is my choice currently. I agree that the PFS is really impressive. 36 months is by far the best PFS we've seen for drugs targeting ROS1, and the intracranial penetration seems to be outstanding as well. So I would certainly start repotrectinib for this patient, doing a stepwise approach for the dosing, of course.
Dr. Narjust Florez:
Thank God I picked the right treatment. As the patient was starting repotrectinib with the appropriate dosing, every time you had a case and there's a new application only a few days away, you're like, "Oh, talking to two experts", so 160 mg once daily for 14 days then increase to 160 mg twice daily. Are either of you have any challenges with this dosing? I think it's very important to our audience that this is different than the other two agents we have talked about in that it requires these dosings that's different for 14 days daily and then to twice a day. Christine?
Dr. Christine Bestvina:
I did have a patient who had pretty significant symptoms on just the once-daily dosing at 160 mg, and so I ended up keeping that patient on the once-daily dosing for an extra few weeks until some of those symptoms subsided. The patient had been having some localized neuropathy that just needed a little bit more time to adjust. Importantly, I was able to get up to the twice-daily dosing, but I think we really have to listen to our patients with this step-up dosing and make sure it's the right time to increase for that particular patient.
Dr. Narjust Florez:
I think that just follows along to what Debora mentioned in the previous case—that she brings the patients quickly to clinic. Debora, would you bring these patients at day 14 to see them right before they go to twice daily?
Debora Bruno:
Yes, I would. I typically see my patients every 2 weeks at the beginning of the therapy, I keep obtaining labs and following them closely so we can tweak toxicities and make sure we adjust accordingly. Two weeks, it's a lot sometimes for these patients, it's very important that they understand that any symptoms that they develop where they can't understand why they are developing those symptoms, they need to call immediately. So I always say, "Let me worry, don't worry about what symptoms you have, just call us and let us grade the toxicity and make sure that we intervene to make you feel better."
Dr. Narjust Florez:
Yeah. I think that's very close follow-up. This is a different dosing compared to the other agents and we need to remember that because this is the new kid in the block, it has more fancy things and that includes dosing. So the patient benefited from therapy for 34 months and that included a marathon in between in those 34 months and the four grandchildren. And he has disease progression on one of the pulmonary nodules and one bone lesion, so one pulmonary nodule is growing and one bone lesion, no other site of disease progression. So Christine, what would you do now? Will you change therapy in this setting of progression?
Dr. Christine Bestvina:
I would actually refer the patient to my radiation oncology colleagues for radiation for oligoprogression. And we've recently seen some results from the CURB trial which showed that for patients who have oligoprogression, radiation can significantly extend that patient's progression-free survival. In that trial, it was upwards of 9 months for patients with non–small cell lung cancer. And so I think using radiation to be able to prolong the lifetime of the TKI can be a really important tool in our toolkit.
Dr. Narjust Florez:
So Debora, will you do the same approach for this pulmonary nodule and one bone lesion?
Debora Bruno:
Yes. I tend to use radiation therapy a lot to try and squeeze as much time as possible out of the targeted therapy. For patients with oligoprogression, I usually send them to radiation oncology and they evaluate. Sometimes a PET scan is also obtained to try to make sure we are not missing some new skeletal lesions that were not picked up by irregular CT scans. And of course, if there is a lot of progression ongoing, I rebiopsy my patients to make sure there are no new on-target or off-target mutations for which we can add another TKI. If it's off-target, that’s to reestablish response to the current regimen and also to rule out transformation to another histology such as small cell lung cancer. But I certainly I agree with Christine, I use radiation a whole lot in situations of oligoprogression.
Dr. Narjust Florez:
I agree with everything. I call this the dandelion approach. Back when I was in the Midwest I used to have a yard—not in Boston anymore—but I remember I just pulled the dandelions and my neighbors were like, "You are going to pull them, they're going to come back again." And I used to tell my neighbor in Rochester, "It's okay, but I don't get to see it for several days." So I call this the dandelion approach and my patients get the analogy, "So we radiate it. It may come back, but you have a time that you don't see it. You can stay in the repotrectinib, we're avoiding the chemotherapy." So not all progressions are the same.
And I think Debora brought up a very important point, which is biopsy at the time of disease progression, because that will help us understand not only the patient's disease but improve the learning that we have about ROS1, which overall is still a new drug target and repotrectinib is the newest kid in the block. So we don't know fully long-term what mechanisms or resistance patients may develop fully with these drugs, so two reasons to do that. My last question before we go to our clinical takeaways is for the both of you. Christine, let's say the patient has significant progression. We're talking that you radiated, patient got 9 months, another grandkid, and then it's full progression. Will you add chemotherapy according to TKI or what will your next line of therapy be?
Dr. Christine Bestvina:
I would transition to chemotherapy. I think the question of combining TKIs with chemotherapy is always a great one. We have more data in the EGFR space about the safety of combining osimertinib with chemotherapy. I will say despite how much I like repotrectinib, I do think the toxicity of the drug can be more difficult to manage than some of the other TKIs, particularly the dizziness. About 60% of patients will have some degree of dizziness on this drug among other side effects. And so this may be one where I do chemotherapy first and see how they tolerate the carboplatin plus pemetrexed as opposed to adding it on top of the repotrectinib.
Dr. Narjust Florez:
Debora, what will you do in this case? We have to mention if there's a clinical trial, we'll proceed with the clinical trial, but let's say there is no clinical trial for ROS1-resistant mechanisms—what will you do next?
Debora Bruno:
I don't get to disagree with Christine at all today, so I would do the same. I, of course, would repeat NGS to make sure there are no off-target mutations that can be, perhaps, managed with the addition of another TKI—like a MET amplification, for instance, and so forth. And if there are none and if there is no transformation to small-cell histology, I would move on to a platinum-based chemotherapy using pemetrexed, which tends to be still very active in these patients. Of course, clinical trials are the go-to option if available but when they are not, cytotoxic chemotherapy is certainly reasonable.
Dr. Narjust Florez:
An extra bonus question. Debora, to identify the resistant mechanism, do you do ctDNA or you go for the tissue?
Debora Bruno:
So it depends. I say that for patients who have overt progression in certain areas—so you have a mass that is growing quite fast—certainly that's the area to be biopsied. And with the biopsy, again, you assess histology and you do NGS at the same time. But sometimes the progression is in places where it's not easy to biopsy, it's not an easy procedure to be performed, and there is significant disease burden for you to be able to be sure that a liquid biopsy would be sensitive enough to pick up any new mechanisms of resistance that the patient may be developing, So a liquid biopsy is certainly something that you can do. I don't use it to monitor disease, I don't use to preview potential progression on scans, but once there is progression and biopsy is challenging, certainly plasma genotyping is of help for those patients.
Dr. Narjust Florez:
Thank you. Christine, anything you would like to add before we go to our takeaways?
Dr. Christine Bestvina:
I agree with Deb. I do tend to do both ctDNA and tissue at time of progression. Unlike in the newly diagnosed setting where those two tests have a high rate of concordance, at time of progression, there's been a few papers published that showed that the concordance is about 50% or less at time of progression. And so I do think you get better bang for your buck out of using both testing modalities after the patient's already been on targeted therapy.
Dr. Narjust Florez:
That's a very good point. So with that, we're going to go to our clinical takeaways for this case.
So repotrectinib has been used in 71 treated patients with an overall response rate of 79% and a median progression-free survival of 36 months. And patients that were treated with previous TKIs, their overall response rate was 35%. We have a progression-free survival of 9 months. When we look at the pool safety analysis and all patients treated with repotrectinib, the most common adverse events included dizziness, peripheral neuropathy, constipation, dyspnea or shortness of breath, ataxia, and cognitive disorders, so in order to get the drug to the CNS, you have the side effects from the CNS. Local therapy can be used for limited disease progression. We talked about radiation and when the patient has one pulmonary nodule and one bone lesion. And when we have frank progression, it's important to rebiopsy to understand mechanisms or resistance.
Tissue is the gold standard where it can be supplemented. With ctDNA or liquid biopsy, as Christine mentioned, you tend to have some difference in concordance when it's at the time of disease progression, so both approaches are recommended. If there is not a clinical trial available, then we use chemotherapy with a platinum-based regimen. Chemotherapy could be started first to see how the patient responds, and maybe the TKI can be added. But repotrectinib is still very new, so we don't have a lot of data about the tolerability of the combination.
So this brings us up to the end this case. Please see other segments for further discussion about the latest data in ROS1-positive non–small cell lung cancer or visit ascopost.com. Thank you.
