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Page 2 of 11 Fitzgerald et al. J Cancer Metastasis Treat 2021;7:54 https://dx.doi.org/10.20517/2394-4722.2021.97

resection by pleurectomy or extra-pleural pneumonectomy can be offered, but recurrence and progression
typically occur. Unfortunately, most patients present with advanced disease, and treatment is
predominantly palliative. Traditional chemotherapy, up until recently the international standard of care for
unresectable disease, provides only limited benefit. MPM is generally categorized as epithelioid or non-
epithelioid, with sarcomatoid and mixed histologies falling under the non-epithelioid categorization.
Epithelioid histology can respond somewhat better to treatment with traditional chemotherapy and has
slightly better prognosis, while non-epithelioid histology is chemoresistant and progresses rapidly. Beyond
histology, the field still lacks predictive biomarkers to identify patients who will derive the most benefit from
a particular therapy or combination. Fortunately, recent studies with anti-VEGF monoclonal antibodies
have demonstrated benefit when added to chemotherapy, and, even more significantly, the advent of
immunotherapy has sparked a paradigm shift in the treatment of MPM. This review will contextualize the
substantial impact of these therapies which will improve the treatment outcomes and quality of life for
patients with MPM who previously had limited treatment options. Other targeted approaches will also be
discussed in this issue of the journal. Continued support of robust clinical research will be indispensable in
integrating these advances into the evolving standard of care and addressing the ongoing unmet need for
these patients.

CHEMOTHERAPY AND ANTI-ANGIOGENESIS
Until recently, platinum-based chemotherapy with pemetrexed was the established standard for
unresectable MPM; cisplatin plus pemetrexed remained the only FDA approved first-line treatment for
MPM until 2020. This practice was founded largely on the results of the phase III EMPHACIS trial reported
in 2003, in which 456 patients were randomized to receive pemetrexed in combination with cisplatin (CP)
[1]
vs. cisplatin alone . The combination provided a nearly 3-month survival benefit with a median OS at 12.1
months for CP vs. 9.3 months with cisplatin monotherapy. Response rate in the intention to treat
population was also superior for the combination, at 41.3% vs. 16.7% for the cisplatin alone and time to
progression improved to 5.7 months from 3.9 months. Although outcomes were better with combination
chemotherapy, the fact that less than half of the patients treated with cisplatin plus pemetrexed had
objective responses to treatment, and only 50% of the intervention arm survived to 1 year demonstrated the
continued need for improved or adjunctive therapy options.

VEGF receptor inhibitors
Strategies utilizing the addition of a third agent to platinum-based chemotherapy have had mixed success.
Twenty years ago, a series of pre-clinical studies provided compelling evidence suggesting a pivotal role for
the VEGF/PDGF pathway in the pathogenesis of MPM, primarily by demonstrating that VEGF/VEGFR
[2,3]
levels correlate with angiogenesis in MPM cell lines . Armed with this rationale, trials incorporating the
anti-VEGF monoclonal antibody bevacizumab were designed [Table 1]. Following promising anti-tumor
efficacy in phase II trials, the combination of bevacizumab plus CP was evaluated in the Mesothelioma
Avastin Cisplatin Pemetrexed Study (MAPS), a large, phase III randomized controlled trial conducted by
[4,5]
the French thoracic oncology cooperative group, IFCT . This study recruited patients with unresectable
MPM who had not received prior chemotherapy. The primary endpoint of median overall survival (mOS)
was significantly longer with the addition of bevacizumab to chemotherapy at 18.8 months vs. 16.1 months
with chemotherapy alone, with a hazard ratio (HR) 0.77 favoring bevacizumab, despite a longer mOS in the
CP arm than was seen in the EMPHACIS trial. Although a trend towards decreased benefit from
bevacizumab addition was observed in patients whose tumors had epithelioid histology, no population
identified by the authors within the subgroup analysis reliably predicted which patients benefit from the
addition of bevacizumab to chemotherapy. The benefit in mOS in the bevacizumab arm of MAPS came at a
cost of expected adverse events related to bevacizumab, including hypertension (56.3%, 23% ≥ grade 3),
cardiovascular events (61.7%), thrombotic events (7.2%), proteinuria (16.7%) and hemorrhage (41.0%).