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Treatment of Mesothelioma

This is Part 5 of Appropriate Management of Challenging Cases in Lung Cancer, a five-part video roundtable series. Scroll down to watch the other videos from this Roundtable.

Hear from thoracic oncology experts Drs. Ramaglingam, Brahmer, and Wakelee about the current and emerging treatment landscape for mesothelioma. In this video, they discuss first-line treatment data from the DREAM, PrECOG, and CheckMate 743 trials, as well as second-line gemcitabine plus ramucirumab in the RAMES trial.


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Transcript

DR. RAMALINGAM: Hello. Welcome to The ASCO Post Roundtable Series on the Appropriate Management of Challenging Cases in Lung Cancer. I'm Dr. Suresh Ramalingam, Deputy Director of the Winship Cancer Institute of Emory University. Today I'm joined by two of my esteemed thoracic oncology colleagues, Dr. Julie Brahmer and Dr. Heather Wakelee. DR. BRAHMER: Hi, I'm Dr. Julie Brahmer. I’m a professor of oncology at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. DR. WAKELEE: Hi, I'm Dr. Heather Wakelee. I'm a professor of medicine and interim chief of the Division of Oncology at Stanford University in California. DR. RAMALINGAM: Thank you both for joining us. Today we will be discussing the latest in emerging data on the treatment of mesothelioma. So meso is a rare tumor. The treatment advances in mesothelioma have been rather slow. For almost two decades now, for patients with unresectable mesothelioma, the platinum-pemetrexed combination has remained as the standard of care. With the emergence of immunotherapy, there is a lot of interest in studying these drugs in patients with advanced mesothelioma. So Julie, the first question I want to pose to you is, what's the current status of immunotherapy in mesothelioma? DR. BRAHMER: So for mesothelioma, the immunotherapy right now is approved in – or does have an indication per the NCCN compendia guidelines that pembrolizumab does have activity. And nivolumab also has been shown with activity, as well as others, but right now, at least here in the U.S., we do have access to single-agent PD-1 antibodies in that setting, and there is a 10 to 20% response rate in that setting. I think clearly we want to try to move these agents up front, since there particularly is a subset of patients that can respond, and so there's been data out of Australia combining immunotherapy with chemotherapy, as well as other studies. And certainly at ASCO this year, we also were able to show some of that data. So kind of going back to the DREAM study from Australia that was presented last year, this was a single-arm study combining durvalumab with the standard chemotherapy pemetrexed and platinum or cisplatin. And the response rate was 48%, and the progression-free survival at six months was 57%. Now, PrECOG, or based through ECOG, Dr. Ford, a junior faculty at my institution, presented the data this year at ASCO, showing again a very interesting – the primary endpoint of this study combining durvalumab with the standard pemetrexed and cisplatin showed an overall survival of 20 months, or 20.4 months. So again, compared to what we've seen with chemotherapy alone, which is much less, around 12 to 14 months, and then with combining pemetrexed/platinum with bevacizumab, that's closer to 18 months, at least in this single-arm phase II study that is showing consistent results with the Australian DREAM study as well. And again, this is actually leading to a larger study. The response rate in the U.S. study presented at ASCO this year showed a response rate of approximately 56%. Again, very consistent with data from the other side of the world in Australia. So I think – again, I think IO in combination with chemotherapy for mesothelioma is potentially something that we have to pay attention to, but it would be great to see a larger phase III study done, and a lot of those studies are ongoing. DR. RAMALINGAM: Absolutely. Two phase II studies showing very promising data in the frontline setting of chemo plus durva sets the stage nicely for further interrogation in a phase III trial. Heather, what we did not hear about ASCO but we've seen a press release are the results with ipi-nivo in the frontline setting. Can you provide us with a background for that combination and what the audience has to look forward to in an upcoming meeting when those data are presented? DR. WAKELEE: Sure. So there was some phase II data where the response rate for nivolumab and ipilimumab was close to 30%. It was 29%. And so that was encouraging to lead to a big phase III trial, the CheckMate 743. We haven't seen the data yet, but we saw the press release, and this was looking at first-line nivolumab/ipilimumab versus chemotherapy, and the press release said that it met its endpoint and was positive with an OS benefit. So I think we're eagerly awaiting the presentation of that data, which hopefully should be at one of the upcoming virtual meetings. We have a few of those over the summer and early fall. So, excited for that. That could potentially change practice, but we need to be mindful that, where do the angiogenesis inhibitors fall into all of this? So we haven't seen the chemo anti-angiogenesis inhibitor plus IO data, and so when we're comparing without that aspect of things, we're always going to have some questions. We had a bit more anti-angiogenesis data. At ASCO this year, there was a randomized phase II trial of a second-line gemcitabine with or without ramucirumab, and again, it was phase II, but it was a big phase II. It was over 160 patients. And that study showed a survival benefit of adding the ramucirumab to gemcitabine. Overall survival hazard ratio 0.7, and the median OS in that group was almost 14 months when they got both drugs, versus under eight months without the ramucirumab. So again, reinforcing that anti-VEGF therapy—in this case, anti-VEGFR therapy—does actually have an important role in mesothelioma. So as we delve into the enthusiasm with the checkpoint inhibitors, we don't want to leave the potential additive benefit with anti-VEGF agents behind. DR. RAMALINGAM: Absolutely. You highlight the point that mesothelioma is a very vascular tumor, and these patients have among the highest circulating VEGF levels compared to other tumor types. So it could be an additional strategy, even if we go at an immunotherapy-based approach in one setting, in another setting using an anti-angiogenetic approach could be helpful. But the prospect of having an IO-IO combination in the frontline setting is exciting, and what that means is, you could still use platinum and pemetrexed as another line of therapy for these patients. That's an indication where we've not seen any active drugs. You've mentioned the ramucirumab/gemcitabine combination, so finally beginning to see some options emerge. But Julie, in your institution, when you have a patient with mesothelioma, how do you determine who is a resectable patient and who is not? Who makes that decision? Talk to us about that. DR. BRAHMER: Certainly we have a multidisciplinary clinic, just like a lot of other institutions, where we sit down and see these patients all together and come up with the best treatment strategy. Clearly, if they have mediastinal adenopathy or lymph node involvement with their tumor, then these patients cannot undergo resection, or it's not recommended to at least start with resection. Sometimes we will consider neoadjuvant chemotherapy, which has some phase II data behind it, and then consider resection. And clearly, though, resection, or the idea around resection, has kind of varied over time based on some of the surgical data comparing extra-pleural pneumonectomy compared to pleurectomy, really the outcomes were similar, and so most of the time we'll consider pleurectomy in those patients with only local disease without lymph node involvement. Clearly, if the chest wall is involved or significant lung involvement that can't be resected, these patients aren't recommended to undergo surgery. Clearly, if the disease is growing into the abdomen through the diaphragm, those patients typically can't undergo resection either. DR. RAMALINGAM: Those are very important points for our audience. Multidisciplinary setting is critical to make decisions, and if a patient is deemed a candidate for surgery, it's important that a thoracic surgeon with experience in resecting mesothelioma be the one who is performing the surgery. Heather, the histology of mesothelioma is not uniform, right? We have epithelial, sarcomatoid. One of the things I was happy to see in the PrECOG trial was the response rates were consistent whether the patient had sarcomatoid or epithelial mesothelioma. How does that factor into your treatment decision for frontline chemo, which is what we have right now? DR. WAKELEE: That's a great question. I mean, the sarcomatoid tumors are bad actors in mesothelioma, and so the fact that we were seeing good responses even in that subset when we add in the immune checkpoint inhibitors, is really encouraging that we'll have a better pass forward for those folks. Obviously, use of chemotherapy plus immune checkpoint inhibitor is not yet the standard, but it's going to be – it's going to increase our enthusiasm as we try to enroll into the phase III, knowing that it's gonna hopefully be a better choice for the sarcomatoid patients also. DR. RAMALINGAM: Great. Julie, you mentioned the upcoming phase III plans for chemo-immunotherapy approach. Are there any other exciting advances that you're looking forward to in 2020 and 2021 for meso patients? DR. BRAHMER: Well, I think some of the local therapy. I think infusing certain drugs into the pleural space certainly may show us some promise. And certainly different IO combinations. You know, it'd be great to see some of this data for these patients. And again, these patients need options, and so, you know, particularly some of these second-line options I'm excited to see. DR. RAMALINGAM: Great. Thank you. So the key takeaway messages for our audience from this section is that the treatment of mesothelioma, which has been primarily driven by chemotherapy approaches, may be changing with the immunotherapy integration. We will see the data soon with the ipi-nivo combination and figure whether that would become the new frontline treatment for patients with mesothelioma. The chemo plus IO combinations are also showing promise, and more recently the ASCO data with gemcitabine and ramucirumab in the salvage therapy setting may prove to be a helpful approach for second-line treatment of mesothelioma. A lot of great information. Thank you very much to both Drs. Brahmer and Wakelee for joining us. And I want to thank our audience for participating with us today. Don't forget to watch the other videos in this ASCO Post Roundtable Series. Thank you.
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