Updates in Immunotherapy for Advanced Thoracic Malignancies - Episode 12

Mesothelioma: A Look at DREAM3R and PrECOG Trial

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Suresh Ramalingam, MD: When we think about mesothelioma, 1 of the early observations was how high the patient’s VEGF circulating levels are and that led to the evaluation of bevacizumab-based regimens. Martin mentioned the MAPS study. Steve, where does bevacizumab fit in the mesothelioma-treatment landscape?

Stephen Liu, MD: Until CheckMate743 at World Lung [World Conference on Lung Cancer 2020], this was my standard of care. I admit that it was not FDA approved, though it is approved in other parts of the world. The addition of bevacizumab improved survival. It’s very tolerable, and I continue that as maintenance. Until recently, that was my preferred standard of care, with a modest but real improvement in outcomes. But I agree with my colleagues: We’ve been looking for much better. CheckMate743 offers another option, another line of therapy, and while the outcomes were best in the PD-L1 positive, they were best in the nonepithelioid subsets, which were, by the way, the subsets with the worst prognosis overall. Even in patients who were PD-L1 negative or in the epithelioid, this becomes my preferred option. It allows me to move platinum-pembrolizumab-bevacizumab to second line for patients who don’t get that response. I’m a little nervous about when people don’t respond. Are they going to become increasingly symptomatic?

There are a lot of parallels between mesothelioma and non–small cell lung cancer. We’ve got a dual checkpoint blockade strategy, which seems to be very effective, in certain subsets clearly better, in others comparable, and you have to wonder if there’s a role to combine strategies.

Suresh Ramalingam, MD: Talking about parallels between non–small cell lung cancer, as we think about ipilimumab-nivolumab it’s hard not to think about chemotherapy plus I/O [immuno-oncology] strategies in mesothelioma. Steve, we have 2 studies. Why don’t you talk about the DREAM3R study that was recently published.

Stephen Liu, MD: The DREAM3R trial was an Australian study led by Anna Novak, looking at patients with mesothelioma, with a combination of durvalumab with cisplatin-pemetrexed. What we saw was the outcomes in that study were quite impressive. It’s difficult to know, though, how much durvalumab was adding really as opposed to just the passage of time. When we compared the initial EMPHASIS trial with the MAPS study, that even those same arms of platinum-pemetrexed improved over time because of better supportive care and better lines of therapy. In a single-arm phase 2, there’s only so much you can learn, but still the outcomes in DREAM3R with durvalumab and chemotherapy were quite impressive, with the majority of patients, almost 60%, still alive and progression-free at 6 months. That’s certainly a clear signal that we need to build on.

Suresh Ramalingam, MD: I would also add that the PrECOG study, which also looked at the same approach—chemotherapy plus durvalumab for first-line treatment of mesothelioma—was reported at ASCO [American Society of Clinical Oncology Annual Meeting] by Dr Patrick Forde, and the results were very impressive. The median survival was upward of 20 months for this group of patients. When we specifically looked epithelioid type of patients, the median survival was even better in that subgroup. Patrick also showed some biomarker work in this patient population that’s early, that needs to be developed further. But certainly it gives some insights that could potentially lead to benefit for this chemotherapy-immunotherapy approach. The good news is there is a follow-up study planned that hopefully will launch very soon. This will be a phase 3 trial of chemotherapy plus durvalumab compared with chemotherapy alone, and it will be done globally in collaboration between PrECOG and the Australasian Lung Cancer Trials group. Hopefully that trial will help us answer this question in mesothelioma. A lot of excitement with the integration of immunotherapy in mesothelioma, with ipilimumab-nivolumab now becoming an option. Hopefully it will get approved soon so we can use it in our clinics.

One continuing question is what happens when patients progress on first-line therapy? If they get chemotherapy, what is your go-to regimen? I want to hear briefly from our panel on that.

Stephen Liu, MD: There are not a lot of great options, right? We look at the comparators with the pembrolizumab data. The standard chemotherapy is vinorelbine or gemcitabine, and those are our standards now with very modest outcomes and a low ceiling for both regimens. I use vinorelbine in those settings, but this is a case in which you need to find a trial. If 1 is not nearby, then you need to refer to a specialty center, because the standard treatments are not very good.

Firas Badin, MD: I agree completely. I don’t think we have great options or we have a standard of care for those patients. A lot of us believe mesothelioma is a surgical disease. I’m interested in neoadjuvant approaches. I’d like to see maybe adopting some immunotherapy in the neoadjuvant setting with chemotherapy, hoping that we can resect more patients and maybe cure more patients. In subsequent lines of treatments, I don’t have great success. You can try different kinds of single-agent chemotherapy agents, but really it doesn’t add much.

Suresh Ramalingam, MD: Thank you. Does anyone consider reintroducing platinum-pemetrexed if the patients did well in the frontline setting? I’ve done that for a couple of patients, and at least you get stable disease out of it for a few months and results in some improvement in their overall quality of life.

Stephen Liu, MD: There’s some activity there. You notice we don’t talk a lot about reintroducing platinum or revisiting those doublets in non–small cell, because we have better options. The fact that we’re revisiting those older treatments in mesothelioma and small-cell lung cancer reflects the lack of other better alternatives. But I’ve been in similar situations, and if patients had good tolerability, good outcomes, and it’s been a little while, then I’ll absolutely revisit those just for lack of anything better.

Transcript Edited for Clarity