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Page 4 of 11 Fitzgerald et al. J Cancer Metastasis Treat 2021;7:54 https://dx.doi.org/10.20517/2394-4722.2021.97

More recently, encouraging data have also been reported with a VEGF monoclonal antibody plus
chemotherapy combination in the second-line setting [Table 2]. The results of the phase II RAMES trial
[8]
were presented at the ASCO virtual meeting in 2020 ; patients with unresectable MPM who had progressed
after standard first line chemotherapies were randomized to gemcitabine plus ramucirumab (a monoclonal
antibody targeting VEGFR2) vs. gemcitabine alone. The addition of ramucirumab yielded a significant
overall survival benefit, with HR of 0.70 favoring the addition of ramucirumab with a mOS of 13.8 months
vs. 7.5 months with chemotherapy alone. However, patients in the RAMES trial had not received
bevacizumab in the first line, and it is unclear if patients who progress on the MAPS regimen would derive
similar benefit. Notably, the authors reported no increase in grade 3-4 thromboembolism or hematologic
toxicity with ramucirumab vs. placebo; however, the authors did report an increase in grade 3-4
hypertension.

Hopes of a class effect have not borne out, as trials with VEGF TKIs have not replicated the survival benefit
seen in MAPS and RAMES. In 2018, a collaborative group randomized phase II trial (SWOG S09505)
examined the addition of cediranib vs. placebo to CP . The trial met its primary endpoint of RECIST
[9]
progression-free survival (PFS), with PFS increased to 7.2 months for CP plus cediranib vs. 5.6 months for
CP plus placebo. Despite statistical significance, this PFS benefit was modest in absolute terms, and there
was no corresponding difference in overall survival (10 months vs. 8.5 months, P = 0.44). Moreover,
toxicities were significantly higher in the cediranib arm including GI symptoms, hypertension, and
epistaxis. Similarly, the double-blind, randomized, placebo-controlled phase III LUME-MESO trial
investigated the addition of nintedanib to doublet chemotherapy. Nintedanib has been shown to target
VEGF receptors, PDGF receptors α and β, FGF receptors 1-3, and Src and Abl kinases; it had performed
well in early phase trials and the targeting of multiple related angiogenic pathways was hypothesized to
increase anti-tumor efficacy. Despite encouraging data from the randomized Phase 2 portion of the trial, the
Phase 3 did not meet its primary endpoint of increased PFS.

INTO THE IMMUNOTHERAPY ERA
To date, the most favorable results improving on historical chemotherapy outcomes in MPM have come
from immunotherapy. The recently published Checkmate 743 trial demonstrated significant overall survival
benefit with combination nivolumab/ipilimumab when compared to platinum/pemetrexed chemotherapy,
leading to the first new FDA approval for the treatment of MPM in nearly 20 years [10,11] .

Immunotherapy in the second-line setting
For many years, MPM was considered to be a relatively immunologically inert tumor type; Tumor
Mutational Burden, a predictor of immunotherapy outcomes in other tumor types, is generally low in
MPM [12,13] .

However, the past two years have seen the maturation of practice-changing immunotherapy trials
throughout multiple settings in the treatment of MPM. Early data demonstrated promise with
immunotherapy for MPM, starting in the second line.

KEYNOTE-028 provided an early signal of immunotherapy activity in MPM; this study enrolled multiple
disease cohorts in an open-label phase 1b trial . The MPM cohort enrolled 25 patients with previously
[14]
treated disease and tumor PD-L1 expression ≥ 1%. The safety profile was tolerable, and the authors reported
a strong signal towards anti-tumor activity, with a 20% objective response rate and a further 52% of patients
experiencing stable disease. Anti CTLA-4 monotherapy also exhibited strong anti-tumor activity in single
arm phase II trials, with single-agent tremelimumab after progression on standard chemotherapy yielding a