Checkpoint Inhibitors, Electrical Fields Provide New Options for Mesothelioma

Maurizio D’Incalci, MD

Despite an outsized reputation fueled by late-night commercials from personal injury lawyers, mesothelioma is a rare disease. There are approximately 3000 new diagnoses every year in the United States.¹

Malignant mesothelioma is a highly malignant disease that most often occurs in the pleura of the thoracic cavity. The disease also affects the peritoneum, pericardium, or tinea vaginalis testis. Although mesothelioma is often mistaken for lung disease, it affects the serous membranes lining the lungs rather than the organs themselves.²

“Malignant pleural mesothelioma is notable to be distinct from lung cancer although it does many times affect lung function as it can encase the lungs,” said Roger Y. Kim, MD, a clinical fellow with the University of Pennsylvania Health System in Philadelphia.

The American Cancer Society reported that incidence grew from the 1970s through the 1990s but has declined slightly since investigators identified asbestos exposure as the primary cause of mesothelioma. The last United States asbestos mine closed in 2002. However, the United States Geological Survey reported in its 2020 Minerals Yearbook that the United States imported 305 metric tons of asbestos that year, up from 172 metric tons in 2019.³

The prognosis is poor for these patients. The 5-year relative survival for those diagnosed with malignant pleural mesothelioma, the most common form of the disease, from 2010 to 2016 was just 10% overall.⁴

“For most patients with pleural mesothelioma, unfortunately, within 2 years from diagnosis [they] generally die,” said Maurizio D’Incalci, MD, head of the Laboratory of Cancer Pharmacology and professor of pharmacology at Humanitas Research Hospital in Pieve Emanuele, Italy.

The unmet need is clear but, as with many rare cancers, it is difficult to get drug developers interested in investigating new treatments.

“Certainly, there is very little interest in pharmaceutical companies, because of course, it is a relatively rare disease,” D’Incalci said. “For any rare disease, it is always difficult to find great support from big companies. Although, I will say, in the field of oncology, there is growing interest in mesothelioma.”

Checkpoint Inhibitors Offer New Hope

The introduction of checkpoint inhibitors provided a new avenue of investigation for a field desperate for new options. Recent findings suggest that checkpoint inhibitors, alone or in combination, may do more for patients than chemotherapy, the current standard of care.

In results published in Cancer Discovery in July, the combination of atezolizumab (Tecentriq) plus bevacizumab (Avastin) elicited encouraging, durable responses in patients with advanced malignant peritoneal mesothelioma, irrespective of tumor mutational burden (TMB) and PD-L1 expression status, according to data from a phase 2 trial (NCT03074513).⁵

The combination induced an objective response rate (ORR) of 40% (95% CI, 19.1%-64.0%; n = 8/20) per independent radiology review (IRR) and RECIST v1.1 criteria. The median duration of response (DOR) with the regimen was 12.8 months. Notably, 75% of responses (n = 6) persisted for longer than 10 months.

In October 2020, the FDA approved ipilimumab (Yervoy) plus nivolumab (Opdivo) as first-line treatment for adult patients with unresectable malignant pleural mesothelioma. In the randomized, open-label CheckMate 743 trial (NCT02899299), treatment-naïve patients were randomly assigned to the combination for up to 2 years (n = 303) or 6 cycles of combination chemotherapy with cisplatin or carboplatin plus pemetrexed (Alimta; n = 302). The median age was 75 years.

The median overall survival (OS) was 18.1 months for ipilimumab/nivolumab compared with 14.1 months for chemotherapy (HR, 0.74; 95% CI: 0.61-0.89; P = .002).⁶

Kim published results from a retrospective, real-world study on July 17, 2021, demonstrating a survival benefit of checkpoint inhibitors in this population. Investigators examined outcomes for 176 adults treated for malignant pleural mesothelioma collected in the Flatiron Health database.⁷

Patients received second-line chemotherapy with gemcitabine and/or vinorelbine or checkpoint inhibitor therapy with pembrolizumab (Keytruda) or nivolumab with or without ipilimumab.

The median OS was significantly longer for those who received checkpoint inhibitors vs chemotherapy, respectively (8.7 vs 5.0 months, P = .001; adjusted HR, 0.52; 95% CI, 0.34-0.81). The estimated 12-month OS probability was 36.7% (95% CI, 27.6%-45.8%) in the checkpoint inhibitor groups vs 15.6% (95% CI, 7.7%-26.1%) in the chemotherapy group.

“We did find a significant benefit with immunotherapy, noting that overall, even in the immunotherapy arm in our study, the median OS was 8.7 months, which is still lower than the 12-month median OS that was cited in the PROMISE-meso trial [NCT02991482],” Kim said. “But this is really reflective of our real-world cohort of patients, which was sicker, older, and had more comorbidities than might be included in a clinical trial.

“Overall, our conclusion was that there’s a possible benefit of second-line immunotherapy in this patient population. But certainly, more work needs to be done to better [understand] the role of immunotherapy, both in the first or second line.”

Electricity To Treat Mesothelioma

In May 2019, the FDA approved the NovoTTF-100L System in combination with pemetrexed (Alimta) plus platinum-based chemotherapy for the first-line treatment of patients with unresectable, locally advanced or metastatic malignant pleural mesothelioma. NovoTTF-100L is a non-invasive, antimitotic cancer treatment that delivers tumor-treating fields (TTFields) to the tumor and the first treatment for this patient population in more than 15 years to receive FDA approval.⁸

The FDA granted the approval based on findings from the prospective, single-arm STELLAR trial (NCT02397928). TTFields plus chemotherapy demonstrated a median OS of 18.2 months (95% CI, 12.1-25.8) in patients with unresectable, locally advanced or metastatic malignant pleural mesothelioma.

“OS data appear to be better than expected,” D’Incalci. “This phase 2 study data is not definitive––they require confirmation by a controlled clinical trial––but the results are encouraging, and were so encouraging to deserve the approval of this therapy.”

D’Incalci is a leading investigator exploring the use of TTFields for mesothelioma. TTFields are a cancer treatment modality that uses alternating electric fields of intermediate frequency and low intensity to disrupt cell division.⁹ Earlier this year, he was 1 of 6 investigators worldwide who received an AACR-Novocure Grant for Tumor Treating Fields Research grant and the only one using the grant to study pleural mesothelioma.

“We want to investigate the mechanisms by which TTFields really work in mesothelioma and how this mechanism can be applied in the most rational way to combine drugs with TTFields,” he said. “The scientific basis for this is already there because we know already that TTFields have many biological effects on these cells. The ultimate goal of our research is to achieve a better mechanistic knowledge in preclinical systems that will be applied to optimize the effects of TTFields in patients with mesothelioma, in combination with pharmacological and possibly immunological therapies.”

References

1. Key statistics about malignant mesothelioma. American Cancer Society. Revised January 9, 2019. Accessed August 27, 2021. https://www.cancer.org/cancer/malignant-mesothelioma/about/key-statistics.html
2. Levý M, Boublíková L, Büchler T, Šimša J. Treatment of malignant peritoneal mesothelioma. Klin Onkol. 2019;32(5):333-337. doi:10.14735/amko2019333
3. 2020 minerals yearbook. United States Geological Survey. Published August 26, 2021. Accessed August 27, 2021. https://bit.ly/3mypPJw
4. Survival rates for mesothelioma. American Cancer Society. Revised January 21, 2021. Accessed August 27, 2021. https://bit.ly/3sSrR8f
5. Raghav K, Liu S, Overman MJ, et al. Efficacy, safety and biomarker analysis of combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade in advanced malignant peritoneal mesothelioma. Cancer Discov. Published online July 14, 2021. Accessed August 27, 2021. doi:10.1158/2159-8290.CD-21-0331
6. FDA approves nivolumab and ipilimumab for unresectable malignant pleural mesothelioma. News release. FDA. October 2, 2020. Accessed August 27, 2021. https://bit.ly/3sQ9912
7. Kim RY, Li Y, Marmarelis ME, Vachani A. Comparative effectiveness of second-line immune checkpoint inhibitor therapy versus chemotherapy for malignant pleural mesothelioma. Lung Cancer. 2021;159:107-110. doi:10.1016/j.lungcan.2021.06.017
8. FDA approves the NovoTTF-100L system in combination with chemotherapy for the treatment of malignant pleural mesothelioma. News release. Novocure. May 23, 2019. Accessed August 27, 2021. https://bit.ly/3yhXrxz
9. Wenger C, Miranda PC, Salvador R, et al. A review on tumor-treating fields (TTFields): clinical implications inferred from computational modeling. IEEE Rev Biomed Eng. 2018;11:195-207. doi:10.1109/RBME.2017.2765282