Immune checkpoint inhibitor (ICI) therapies have ushered in an exciting new phase of clinical research and treatment for malignant pleural mesothelioma (MPM), offering more effective and less toxic treatment options for patients. The research and clinical oncology communities eagerly await the completion of several upcoming trials focused on refining the role of [ immune checkpoint inhibitor (ICI) therapy ] in the treatment of this rare and deadly disease.
MPM is a rare cancer arising from mesothelial cells that line the pleura. In the United States, physicians diagnose approximately 2000 to 3000 new cases per year. Most cases have been linked to exposures to mineral fibers, particularly asbestos, and the prognosis is quite poor. The median overall survival (OS) is approximately 12 months and varies by histologic subtype.
The epithelioid histologic subtype accounts for an estimated 60% of all MPM diagnoses and portends a slightly more favorable prognosis, with a median OS of 18 months. Conversely, the nonepithelioid (sarcomatoid, biphasic) histologic subtypes are associated with poorer outcomes, with a median OS of 5 to 10 months. Among patients with advanced MPM who are not surgical candidates, oncologists frequently offer palliative systemic therapies. Since 2004, the pemetrexed/ platinum doublet chemotherapy regimen has been recommended as first-line therapy, and until recently was the only FDA-approved systemic treatment for MPM. There has been considerable clinical equipoise regarding recommended regimens for subsequent lines of therapy.
Investigators have recently turned their attention to the immune system’s involvement in mesothelioma pathogenesis. Mesothelioma cancer cells are theorized to be immunogenic because tumor antigens trigger a T-lymphocyte– mediated immune response. This immune response is regulated at 2 critical checkpoints, CTLA-4 and PD-1. Mesothelioma cancer cells have been shown to express PD-L1, which leads to local tumor immunosuppression, allowing malignant cells to evade the immune system.
Investigators began developing [ immune checkpoint inhibitor (ICI) therapy ] targeting both CTLA-4 and PD-1 in the early 2010s to block immune system regulation, thereby enhancing the cytotoxic immune response to cancer cells. As a result, we have seen in a paradigm shift in the treatment of several solid malignancies.
Since 2017, National Comprehensive Cancer Network (NCCN) guidelines have recommended the anti–CTLA-4 agent ipilimumab (Yervoy) and the anti-PD-1 agents pembrolizumab (Keytruda) and nivolumab (Opdivo) for subsequent-line use in patients with MPM. This recommendation was based on the promising early results of the KEYNOTE-028 (NCT02054806), INITIATE (NCT03048474), and MAPS2 (NCT02716272) phase 1 and 2 trials.
Notably, although there is overall moderate expression of PD-L1 in MPM tumors, the nonepithelioid histologic subtypes appear to be associated with relatively higher levels of PD-L1 expression compared to the epithelioid subtype. Accordingly, PD-L1 expression has been demonstrated to be associated with worse survival outcomes. Moreover, a 2018 observational study by Yannis Metaxas, MD, and colleagues included patients with MPM treated with subsequent-line pembrolizumab and demonstrated similar OS by histologic subtype (median OS, 7.0 [nonepithelioid] vs 6.5 months [epithelioid]), suggesting that [ immune checkpoint inhibitor (ICI) therapy ] may offer increased clinical benefit to patients with nonepithelioid disease.
The results of the phase 3 CheckMate743 trial (NCT02899299) comparing first-line nivolumab and ipilimumab with pemetrexed plus carboplatin or cisplatin also suggested a larger effect size for ICI associated with nonepithelioid MPM (median OS, 18.1 vs 8.8 months; HR, 0.46; 95% CI, 0.31-0.68) compared with epithelioid MPM (median OS, 18.7 vs 16.5 months; HR, 0.86; 95% CI, 0.69- 1.08). On the strength of the encouraging CheckMate743 results, the FDA approved ICI for first-line MPM treatment in October 2020.
In our manuscript published May 18, 2021, in JTO Clinical and Research Reports, we sought to evaluate the real-world uptake of off-label second-line [ immune checkpoint inhibitor (ICI) therapy ] among patients with MPM who received traditional first-line chemotherapy and assess the association of MPM histologic subtype on [ immune checkpoint inhibitor (ICI) therapy ] uptake before and after the 2017 NCCN MPM guideline revision.
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