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Page 8 of 11 Fitzgerald et al. J Cancer Metastasis Treat 2021;7:54 https://dx.doi.org/10.20517/2394-4722.2021.97

Chemo-immunotherapy combinations
The success of front-line immunotherapy has raised interest in studying combination chemo-
immunotherapy approaches, which hope to combine the prompt action of cytotoxic chemotherapy
regimens with the durable responses of immunotherapy. This approach has been practice-changing in non-
small cell lung cancers, where the combination of carboplatin and pemetrexed with the anti-PD-1 drug
pembrolizumab has become front-line standard of care based on the results of the landmark Keynote-189
trial . Early phase data in MPM are promising; The phase II US PrECOG LLC run PrE0505 study and the
[25]
Australian DREAM trial each evaluated a single cohort of patients treated with combination CP
chemotherapy plus the anti PDL-1 antibody durvalumab [26,27] . PrE0505 reported a mOS of 20.4 months, with
DREAM reporting a mOS of 18.4 months.

In contrast to Checkmate 743, the DREAM study enrolled primarily patients with epithelioid histology,
including only 6 patients with biphasic and 1 patient with sarcomatoid histologies. In a post-hoc analysis the
authors noted responses across subtypes however are careful to report that the patient with sarcomatoid
disease experienced stable disease as a best radiographic response. Therefore, it is unclear based on these
phase II results if the immunotherapy benefit for patients with sarcomatoid histology with ipilimumab and
nivolumab will carry over to chemo-immunotherapy combinations.

Although these trials were non-comparative, the reported survival data are significantly better than what
might be expected from chemotherapy alone. Moreover, the prospect of meaningful long-term benefit for
significant proportion of patients is raised by these data, with nearly 40% of patients in the DREAM study
alive at 2 years. These benefits appear to be agnostic of tumor PD-L1 expression. In parallel with the
Checkmate 743 results, the 53% of patients with PD-L1 scores ≥ 1% demonstrated similar PFS when
compared to their low PD-L1 score counterparts.

The DREAM and PrECOG LLC run PrE0505 trials had very similar designs but were performed
independently in different countries. Despite this, the comparable outcomes raised hope that the findings
may be further confirmed when the design is translated to a phase III comparative setting. A follow-up
international phase III (DREAM3R) trial is currently recruiting , and plans to compare 4-6 cycles CP
chemotherapy plus durvalumab followed by durvalumab maintenance with 4-6 cycles of CP chemotherapy
2
followed by observation (NCT04334759). Pembrolizumab (200 mg/m IV q3 weeks) in combination with
CP is also being studied in an ongoing phase Ib trial (NCT04153565), and a separate phase II/III trial
sponsored jointly by the Canadian Cancer Trials Group and the NCI will randomize more than 500 patients
to chemotherapy, pembrolizumab monotherapy, or chemotherapy plus pembrolizumab (NCT02784171).
Currently, the only ongoing trial combining immunotherapy with chemotherapy and bevacizumab is the
phase III BEAT-MESO trial currently recruiting in sites across Europe which plans to complete in 2024
(NCT03762018). This trial will be powered for dual primary endpoints of progression free and overall
survival and will randomize patients to receive atezolizumab 1200 mg IV plus bevacizumab 15 mg/kg with
carboplatin plus pemetrexed every 3 weeks vs. chemotherapy plus bevacizumab alone.

CONCLUSION AND FUTURE DIRECTIONS
The breadth and scope of clinical trials which have recently been reported and are currently ongoing for
such a rare disease as MPM provide reason for optimism. The success of several large-scale well-designed
trials proves that ambitious clinical trials to answer urgent questions about the treatment of MPM are not
only exigent but feasible, and there is reason to believe that outcomes for patients with MPM will continue
to improve rapidly over the next decade. OS remains the gold standard for establishing benefit, as ORR and
PFS are difficult to measure in MPM and may not correlate as evidenced from phase I-II studies that have