Interview – Malignant mesothelioma: implementation of immunotherapy-based standards

Paul Baas, MD, PhD, Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands

Which outcomes can be expected in European patients with malignant mesothelioma who receive the current standard treatment?

After 4 to 6 courses of standard chemotherapy with platinum and pemetrexed, we can expect a median overall survival of around 15 or 16 months. This has hardly changed over the last 15 years. Due to patient selection, the results are a bit better than when we started with this chemotherapy regimen in 2004, but there is an urgent need to improve survival.

Where are we today regarding first-line checkpoint inhibitor treatment of mesothelioma?

Exploration of the combined modality treatment with immune checkpoint inhibitors and chemotherapy has just been started, so we are in the process of building up evidence. In the first-line setting, CheckMate 743 is the first positive phase III study for checkpoint inhibition in patients with unresectable mesothelioma. The data presented at the WCLC Presidential Session in August 2020 showed an overall survival benefit with nivolumab plus ipilimumab compared to the standard chemotherapy in an all-comer population [1]. Nivolumab plus ipilimumab led to a median OS of 18.1, while this was 14.1 months with cisplatin or carbo­platin plus pemetrexed, translating into a reduction of the risk of death of 26 %. At 2 years, 41 % compared to 27 % of patients were alive. This was the first actual prove of efficacy of an immunotherapy-based regimen over chemotherapy. Phase II trials investigating durvalumab and chemotherapy have shown encouraging results, reinforcing the value of immunotherapy as a first-line approach in malignant mesothelioma [2, 3].

What can be said about later-line immunotherapy?

If the first-line treatment was chemotherapy, there is the possibility to use an immune checkpoint inhibitor as monotherapy or as part of a combination treatment. Single-agent nivolumab has demonstrated clinical benefits in patients with mesothelioma and has been approved in Japan in 2018 for second-line use based on the MERIT trial [4]. This was the first approval of an immuno-oncological agent in the second or later lines.

After first-line treatment with checkpoint inhibitors, especially nivolumab plus ipilimumab, the next step depends on the condition of the patient, duration of the previous response and the availability of a study. I think that at present, after first-line combination treatment with immune checkpoint inhibitors, the patient should preferably be treated in a study.

Which regimens are currently being assessed?

Several ongoing phase III trials are evaluating immunotherapy plus chemotherapy as first-line treatment. Over the next 4 years, we can expect the results for at least 3 studies. Pembrolizumab is investigated together with cisplatin and pemetrexed (NCT02784171), as is durvalumab (NCT04334759), while atezolizumab is tested in addition to carbo­platin, bevacizumab and pemetrexed (NCT03762018). The underlying biology of the disease remains to be elucidated further, and future translational studies may help to address this knowledge gap.

What is new regarding other immunotherapeutic approaches in mesothelioma?

Much research has been conducted in mesothelioma over the last 5 to 6 years. It has focused first on immunotherapeutic treatment, but of course this is not restricted to checkpoint inhibition but also includes CAR-T cells and antibody-drug conjugates containing antibodies of mesothelin that are linked to a payload, which can be thorium or killer T cells. Also, vaccines are being developed. An example of this is the randomized phase II/III DENIM study that is run in Europe [5]. Immature dendritic cells are harvested from patients who have not progressed during first-line chemotherapy. These cells are exposed to epitopes of malignant mesothelial cell lines and are reinfused, in the hope that there will be an immune response. The DENIM trial is comparing dendritic cell therapy to best supportive care.

For many years, we have struggled to improve outcomes in this patient population where it was difficult to contain the disease. I think one of the strong points to arise from the CheckMate 743 study in the future might be the emergence of a tail of the overall survival curve. This will indicate that some patients can be successfully treated for many years, just like we see it with melanoma and in some cases with NSCLC. We have to identify these patients, which is the real trick. Thus, we might not be able to actually cure mesothelioma, we might turn it into a chronic disease with considerably improved outcomes.

REFERENCES

1. Baas P et al., First-line nivolumab + ipilimumab vs chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743. WCLC Presidential Session 2020, abstract 3
2. Nowak A et al., DREAM – a phase 2 trial of durvalumab with first line chemotherapy in mesothelioma: final results. WCLC 2018, OA.08.02
3. Forde PM et al., PrE0505: Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (MPM) – A PrECOG LLC study. J Clin Oncol 38: 2020 (suppl; abstr 9003)
4. Okada M et al., Clinical efficacy and safety of nivolumab: Results of a multicenter, open-label, single-arm, Japanese phase II study in malignant pleural mesothelioma (MERIT). Clin Cancer Res 2019; 25(18): 5485-5492
5. Belderbos RA et al., A multicenter, randomized, phase II/III study of dendritic cells loaded with allogeneic tumor cell lysate (MesoPher) in subjects with mesothelioma as maintenance therapy after chemotherapy: DENdritic cell Immunotherapy for Mesothelioma (DENIM) trial. Transl Lung Cancer Res 2019; 8(3): 280-285

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