In the surgical resectable setting, the standard practice currently consists of four cycles of neoadjuvant or adjuvant cisplatin-pemetrexed therapy. In general, it is not recommended to provide neoadjuvant platinum-pemetrexed-bevacizumab because of the high risk of bleeding during surgical resection. Recent perioperative research efforts have primarily focused on immunotherapy and chemoimmunotherapy combination trials. SWOG1619 (S1619) is a feasibility trial with the primary end point of safety conducted in patients with treatment-naïve resectable (stage I-III) MPM (epithelioid or biphasic). Twenty-five patients received four cycles of neoadjuvant cisplatin-pemetrexed-atezolizumab, followed by resection, adjuvant radiation (in EPP cases only), then 1 year of maintenance atezolizumab. This strategy met the safety criteria but only 60% of eligible patients completed all therapy and received maintenance atezolizumab. Additional follow-up will assess efficacy and long-term toxicity outcomes.
There are several ongoing studies that are designed to further our understanding of MPM with translational correlates that seek to predict clinical benefit with immunotherapy. A window of opportunity trial (NCT02592551) treated patients with durvalumab and tremelimumab both via intravenous infusion once per day for every 28-day cycles (+7 days). Participants received tremelimumab for up to four cycles and then continued to receive durvalumab monotherapy until disease progression. This study has completed enrollment. An additional neoadjuvant nivolumab and ipilimumab-nivolumab neoadjuvant trial (NCT03918252) is currently open and accruing patients. These window-of-opportunity trials and the translational research generated are vital foundational studies to advance the field.
Until recently, the systemic standard of care in the United States was platinum-pemetrexed with and without bevacizumab for four to six cycles of therapy followed by bevacizumab maintenance therapy. There were no specifications for histologic subtype nor any biomarker or molecular profiling requirements to determine treatment. Over the past decade, several unsuccessful strategies explored maintenance therapies and combining targeted or antiangiogenic small molecule inhibitors with chemotherapy. The phase II CALGB 20901 showed that maintenance pemetrexed was not beneficial, and outside of the United States and France, many countries did not adopt the use of bevacizumab via the MAPS I study. Also, despite early promising results from phase II randomized trials,[77,78] combining antiangiogenic tyrosine kinase inhibitors with frontline chemotherapy failed to improve overall survival (OS) in larger phase III trials (Table 1). It was therefore heartening for the field to have two recent FDA approvals affecting the frontline therapeutic setting.
On May 23, 2019, the NovoTTF system based on the phase II STELLAR trial received FDA approval (Humanitarian Device Exemption Pathway) in combination with platinum-pemetrexed in MPM. NovoTTF is a portable biomedical device that produces alternating electrical fields (tumor treatment fields, TTFields) within the torso. Patients use adhesive bandages to hold transducer arrays to their chests for 18 hours a day. The TTFs are believed to disrupt cancer cell division and cause apoptosis. STELLAR was a single-arm trial that enrolled 80 patients with MPM from Europe and treated them with cisplatin-pemetrexed and TTFields to 150 kHz to the torso. The main toxicity associated with TTFields was 66% grade 1–2 skin reaction and 5% grade 3. Of note, the NovoTTF system cannot be used in patients who have implanted electronic devices such as pacemakers or defibrillators. The median OS was 18.2 months, and median progression-free survival was 7.6 months. An important caveat is that TTFields have yet to demonstrate benefit for the treatment of mesothelioma in a randomized setting. Additional trials evaluating this technology with immunotherapies are ongoing in non–small-cell lung cancer (KEYNOTE B36 NCT04892472) that may expand the indication for TTFields and have applicability to mesothelioma.
The second regulatory approval was for the CheckMate 743 trial, which compared platinum-pemetrexed to ipilimumab-nivolumab in treatment-naïve patients with mesothelioma. This frontline trial showed an OS benefit in the intent-to-treat population leading to FDA approval for all histologic subtype regardless of programmed death ligand 1 (PD-L1) expression in October 2020 (median OS 18.1 months with ipilimumab-nivolumab v 14.1 months with chemotherapy, hazard ratio [HR], 0.74; P = .002). This overall survival benefit at 2 years was 41% ipilimumab-nivolumab versus 27% platinum-pemetrexed, suggesting significant duration of response benefit. Although the FDA approval is for all histologies, CheckMate743 showed that patients with biphasic or sarcomatoid histology had the greatest magnitude of survival benefit with the immunotherapy combination (HR 0.46, median OS 18.1 months with ipilimumab-nivolumab v 8.8 months with chemotherapy). This was an exciting finding as patients with nonepithelioid histology are associated with a worse prognosis and limited benefit to chemotherapy. Hence, it is highly recommended to treat patients with biphasic/sarcomatoid mesothelioma with frontline ipilimumab-nivolumab.
For the epithelioid patients, there is more equipoise on sequencing the immunotherapy combination and chemotherapy. For the epithelioid patients, the median OS was 18.7 months with ipilimumab-nivolumab versus 16.5 months with chemotherapy (HR 0.86). Since immunotherapies can take longer to see an antitumor effect, some epithelioid patients with more bulky disease or who are imminently threatened may need to be considered for chemotherapy with or without bevacizumab first. The CheckMate743 trial highlights the importance of identifying the mesothelioma patient's histology and its impact on therapeutic choice.
Although these two regulatory approvals have changed the frontline treatment space, the field remains dynamic and will likely transform again once three key trials (BEATMeso [NCT03762018], DREAM3R [NCT04334759], and the Canadian Cancer Trials Group [NCT02784171]) seen in Table 2 are reported. The Canadian Cancer Trials Group is evaluating the use of pembrolizumab, a programmed death protein 1 (PD-1) inhibitor, combined with platinum-pemetrexed, whereas the BEAT-Meso trial is combining platinum-pemetrexed-bevacizumab with and without atezolizumab, a PD-L1 inhibitor. The phase II PrECOG0505 (NCT02899195) and DREAM trials were recently presented and provided the foundation for the DREAM3R trial, which is an international phase III trial comparing cisplatin-pemetrexed with and without durvalumab, a PD-L1 inhibitor. These trials may again redefine the frontline treatment landscape by incorporating immunotherapy with and without an antiangiogenic into the frontline chemotherapy regimen.
Although there has been high activity in the salvage setting over the past decade with immunotherapies, progress for regulatory approvals has been far slower. In addition, the recent approval of the CheckMate743 regimen has nullified the applicability of many of the salvage immunotherapy trials that were previously only conducted in chemorefractory patients. As in many other tumor types, the immune-refractory population of patients do not have many options beyond chemotherapy at this time. Table 3 depicts the results from recent salvage immunotherapy trials over the past few years in mesothelioma that have been conducted in immunotherapy-naïve patients. These studies are still valuable in a historic sense, as to our knowledge, the Japanese MERIT trial was the world's first study to obtain regulatory approval for a salvage checkpoint inhibitor, and the tremelimumab monotherapy trial (DETERMINE) demonstrated that single-agent anti–cytotoxic T-cell lymphocyte-4 blockade was not beneficial in mesothelioma. Although the PROMISE-Meso trial did not show a survival benefit when comparing pembrolizumab in PD-L1–positive patients to the investigator's choice of gemcitabine or vinorelbine, the CONFIRM trial recently demonstrated that nivolumab improved progression-free survival and OS over placebo. In essence, it is reasonable to conclude that there is a population of patients with mesothelioma who derive significant benefit to immunotherapies and that until better predictive biomarkers are developed, all patients with mesothelioma should receive an immunotherapy regimen at some point in their therapeutic journey.
There are clearly outstanding clinical questions that remain with regard to the optimal treatment sequence, whether to use combination therapies, and which treatment to use in the immune-refractory setting. An Italian trial (RAMES, EudraCT Number 2016-001132-36) in 164 salvage mesotheliomas demonstrated that ramucirumab-gemcitabine improved overall survival compared with gemcitabine alone, with a median overall survival of 13.8 months compared with 7.5 months. If this is confirmed in a larger more inclusive trial, this regimen may be a viable salvage treatment after immunotherapy and platinum-pemetrexed failure.
In addition, the utility of tumor biomarkers with immunotherapies remains elusive as the trials demonstrate limited and often contradictory correlations of outcomes with PD-L1 detected by immunohistochemistry (Appendix Table A1, online only).[80,83,87,89] It is possible that these inconsistent results could be because of tumor heterogeneity. However, there are no definitive studies to date that justify the use of PD-L1 as a predictive biomarker in mesothelioma for checkpoint inhibitors. Many mesotheliomas are considered cold tumors without robust immune infiltrates. Hence, tumor mutation burden, which is used as a surrogate for tumor neoantigens and is associated with benefit from immune checkpoint inhibitors, is reportedly low in mesothelioma.[1,2,80] Further exploration of alternative biomarkers is critically needed and emphasizes the essential need to support window-of-opportunity trials and translational research.
J Clin Oncol. 2022;40(6):681-692. © 2022 American Society of Clinical Oncology