New Era for Malignant Pleural Mesothelioma: Updates on Therapeutic Options

Abstract

Malignant pleural mesothelioma (MPM) is a rare malignancy with few treatment options. Recent advances have led to US Food and Drug Administration approvals and changes in the standard of care with a novel biomedical device approved for use with platinum-pemetrexed, and also for immunotherapy agents to be included as a frontline treatment option in unresectable disease. Although predictive biomarkers for systemic therapy are not currently in use in clinical practice, it is essential to correctly identify the MPM histology to determine an optimal treatment plan. Patients with nonepithelioid MPM may have a greater magnitude of benefit to dual immunotherapy checkpoint inhibitors and this regimen should be preferred in the frontline setting for these patients. However, all patients with MPM can derive benefit from immunotherapy treatments, and these agents should ultimately be used at some point during their treatment journey. There are ongoing studies in the frontline unresectable setting that may further define the frontline therapy space, but a critical area of research will need to focus on the immunotherapy refractory population. This review article will describe the new developments in the areas of biology with genomics and chromothripsis, and also focus on updates in treatment strategies in radiology, surgery, radiation, and medical oncology with cellular therapies. These recent innovations are generating momentum to find better therapies for this disease.

INTRODUCTION

The field of malignant pleural mesothelioma (MPM) has historically advanced at a slow pace. However, recent technologic and therapeutic advances with US Food and Drug Administration (FDA) approval have occurred that have reshaped the standard-of-care landscape. This following article will review the latest clinically relevant advances in genetics, chromothripsis, radiology, surgery, radiation, and medical oncology in mesothelioma. In addition, future strategies in T-cell therapies and additional therapeutics that have potential to shift the treatment paradigm will also be discussed.

CONTEXT

• Key Objective

• This review article on malignant pleural mesothelioma highlights the main advances in the fields of genomics, radiology, surgery, radiation, and medical oncology.

• Knowledge Generated

• Mesothelioma therapy is now dependent on the histologic subtype, given the differences in survival to treatments. Recent trials have clearly demonstrated the role of immunotherapy in malignant pleural mesothelioma treatment with improved survival.

• Relevance

• The US Food and Drug Administration has now approved dual immunotherapy checkpoint inhibition as a treatment option in frontline mesothelioma. In addition, a novel biomedical device NovoTTF is approved for use with platinum-pemetrexed. Optimal treatment strategies for patients with mesothelioma should be defined by the histologic subtype and stage. Future research must focus on the immune refractory space and on identifying predictive biomarkers for survival. Continued advances in technology may lead to further survival improvements for all stages of malignant pleural mesothelioma.

GENOMICS

The largest genomic studies to date have demonstrated that mesothelioma is primarily defined by loss of function alterations in tumor suppressor genes.^1,2 Despite exposure to the carcinogen asbestos in most cases, mesothelioma has a lower tumor mutation burden than what has been reported for most solid tumors. Rather than single-nucleotide mutations, copy-number alterations seem to dominate the genomic landscape in this malignancy.² The genes most commonly affected by mutations or copy-number alterations include NF2, BAP1, CDKN2A, and others (Fig 1A). Although these tumor suppressor genes are most frequently altered in mesothelioma, there are reports of possibly oncogenic EWSR1 fusions^5,6 and ALK fusions^7,8 in peritoneal mesothelioma. These fusions seem to affect younger patients without known asbestos exposure and arise independent of the more common mesothelioma alterations. A small number of clinical trials are underway with novel targeted therapies for NF2- and BAP1-altered mesothelioma patients.^9,10

FIG 1.

Chromothripsis and common alterations in mesothelioma. (A) When both copy-number alterations and mutations are considered, NF2, BAP1, and CDKN2A are the most frequently altered genes according to The Cancer Genome Atlas analysis (TCGA).² Copy-number losses or deletions are more common than single-nucleotide mutations for most of these genes, likely because of underlying structural variants. This circular barplot was created with the R package circlize.³ The percentages of alterations are slightly higher than summarized in the TCGA report since we included both copy-number alterations and mutations regardless of whether the genes were fully inactivated. (B) Sometimes these structural variants are consistent with a pattern of chromothripsis, which likely results from the disordered reassembly of a shattered chromosome. This circos plot represents a pleural mesothelioma specimen from a prior publication.⁴ Copy number is presented as a normalized read depth (NRD) calculated in reference to the diploid level (yellow line, NRD = 2). Regions of the genome calculated to be within the normal diploid level are colored gray, regions of gain are colored blue, and regions of loss are colored red. Dashed lines are provided at increments of NRD = 1 with an upper boundary of NRD = 6. Breakpoint junctions are presented as magenta lines connecting two breakpoints. This circos diagram was made by James Smadbeck, PhD, at Mayo Clinic with a custom R package.

BAP1 is the most frequently mutated gene in mesothelioma and is also affected by copy-number alterations.^11,12 BAP1 alterations can be somatic or germline, and the BAP1 hereditary cancer syndrome predisposes patients to mesothelioma, uveal melanoma, and other malignancies.¹³ Because of discrepancies in the rates of detection of BAP1 alterations, high-density array CGH was used to identify alternating copy-number changes at chromosome 3p21 where BAP1 is located, suggesting that BAP1 is commonly affected by a process known as chromothripsis.¹⁴ Chromothripsis results from numerous double-strand breaks of a large segment of a chromosome or a whole chromosome that has been likened to the shattering of a chromosome (example in Fig 1B).¹⁵ The subsequent repair of these chromosomal breaks results in multiple novel rearrangements that are out of sequence from normal, and oscillating copy-number changes. It appears that the micronuclei that form around lagging chromosomes during cell division are not able to incorporate nuclear pore complexes and other noncore nuclear envelope proteins that protect chromosomes from fragmentation,¹⁶ and the loss of nuclear envelope integrity fosters chromosome fragmentation.¹⁷

More direct evidence for chromothripsis in mesothelioma came from a study that used a form of sequencing that tiles larger fragments of the genome than standard approaches, and is optimized for the detection of structural variants.¹⁸ Among the 22 specimens that were profiled, 1,535 chromosomal rearrangements were detected and many of these rearrangements were in a pattern of chromothripsis that involved arms of chromosomes or full chromosomes. This analysis further suggested that these rearrangements have neoantigenic potential. In short, the genomic landscape of mesothelioma primarily involves tumor suppressor genes that are inactivated through structural variants, mutations, or both.

RADIOLOGY TECHNOLOGY

Imaging suggestive of pleural mesothelioma must always be accompanied by histologic confirmation of the diagnosis. Computed tomography (CT) is presently the standard of care for the diagnosis and monitoring of treatment outcomes in pleural mesothelioma.^19,20 Pleural changes on CT include pleural plaques, diffuse pleural thickening, and pleural effusion. The lobulated pleural encasement of the lung frequently causes lower-lobe collapse.^21,22 Computerized tomography, however, has not proven to be useful for mesothelioma screening in high-risk asbestos-exposed populations.²³ Volumetric analysis as well as other linear approaches for estimating the bulk of disease demonstrated correlations with the prognosis of patients with the disease.²⁴

Metabolic imaging with ¹⁸F-labeled fluorodeoxyglucose-positron emission tomography-CT is also crucial in defining the extent of disease, especially in individuals who are being considered for resection.²⁵ Upward of 10% of patients having preoperative staging for possible mesothelioma resection are found to have extrathoracic disease.²⁶ Magnetic resonance imaging (MRI) with gadolinium enhancement has always been useful for investigation of chest wall and diaphragmatic invasion.²⁷ Recently, there has been interest in the use of diffusion-weighted MRI to further classify benign from malignant pleural diseases as well as histology of mesothelioma^28,29; however, further studies have not validated MRI histologic differentiation of mesothelioma. A variety of novel radiomic algorithms for further image classification of pleural mesothelioma are under investigation,^30-32 with the goal of defining growth of the disease, but these studies are not currently mature.

TUMOR RESPONSE RECORDING

To standardize tumor response measurements among mesothelioma trials, considering the complex geometry of the disease, modified RECIST (mRECIST) Guidelines have been validated and adopted.¹⁹ Briefly, the most prominent CT sections have tumor thickness measured at those sites from the outer tumor margin to the inner margin in the appropriate direction that captures tumor direction. These measurements are performed at baseline for up to six pleural measurements with no more than two sites per CT section across sections separated by at least 1 cm. A complete response is disappearance of all pleural and nonpleural diseases, whereas a partial response is a summed measurement decrease by 30% or more at baseline, and progressive disease is a summed measurement increase by at least 20%. Considering the acceleration of studies in the use of immunotherapy in mesothelioma, modification of the immune RECIST criteria³³ and interpretations of fluorodeoxyglucose positron emission tomography-CT will be necessary.³⁴

SURGERY

The surgical management of pleural mesothelioma demands compulsive preoperative staging with imaging and ideally with mediastinoscopy or endobronchial ultrasound, as well as proper selection of patients with a performance status and cardiopulmonary reserve who could tolerate possible extrapleural pneumonectomy (EPP).³⁵ The goal of the surgery remains macroscopic complete resection, which, in reality, is an R1 resection in the majority of cases.³⁶ Whether patients should have attempted macroscopic complete resection with or without induction therapies including chemotherapy or radiation, or whether postoperative adjuvant therapy without induction is preferable remain unanswered questions.^37,38 The extent of the resection for pleural mesothelioma has also evolved from being based chiefly on retrospective case series from large volume centers over the past 30 years.^39,40

EPP, except in a specific protocol, ie, Surgery for Mesothelioma after Radiation Therapy, has largely been replaced by the use of either pleurectomy decortication or extended pleurectomy decortication, but remains as an option for good-risk patients for whom a satisfactory lung-sparing procedure cannot be performed. Although the mortality for EPP has decreased to as low as 1%-4% in high-volume centers, the pleurectomy options are associated with consistently lower mortality and morbidity. This is especially demonstrated in centers in which the same mesothelioma surgeon performed both procedures.^41-43 Recent data suggest that tumor T status may discriminate which patients are the best candidates for lung-sparing procedures.⁴⁴ T1 and T2 tumors have been associated with median survivals approaching 69.8 months in patients with epithelial tumors, whereas results of pleurectomy/decortication for T3 and T4 tumors have not had the same long-term survival outcomes except in selected series.

Despite these long-term survivals, there is still significant attrition of presumed surgical candidates, with the best series demonstrating that only 60%-80% of patients planned for surgery will go on to complete a resection. Moreover, a significant portion of these patients are found to have unresectable disease. Upstaging at the time of surgical resection is unfortunately a common occurrence in up to 70%-80% of patients with clinical stage I or II and 23% with clinical stage III malignant pleural mesothelioma.⁴⁵ Lymph node disease and biphasic/sarcomatoid histology have classically been associated with poorer survival in the majority of surgical series with recurrences occurring chiefly locally after pleurectomy decortication procedures and systemic recurrences after EPP.⁴⁶ The role of surgery for diagnostic biopsies confirming sarcomatoid disease is controversial. The 2018 ASCO Guidelines do not recommend maximal surgical cytoreduction for known sarcomatoid histology based on intermediate-quality evidence,⁴⁷ whereas the 2019 National Comprehensive Cancer Network guidelines state that surgery in patients with sarcomatoid or mixed histology should only be reserved for those with early-stage, minimally bulky disease without lymph node involvement.⁴⁸ Perhaps, the best compromise is that recommended by the International Association for the Study of Lung Cancer Mesothelioma Committee, which advises that patients with sarcomatoid histology should be offered clinical trials considering their poor outcome.³⁹

Novel research approaches include the use of preoperative radiation therapy before EPP have had encouraging results in a subgroup of patients with epithelioid histology and no involved lymph nodes at resection with a median overall survival of 66 months; however, the overall median survival of 24 months remains soberingly similar to results from other trials in the literature.⁴⁹ Additional novel approaches that are just beginning to be reported include the use of dual checkpoint induction therapy followed by resection, include intriguing data regarding the tumor microenvironment and response to therapy (NCT02592551). Finally, standardization of reporting of procedures in the future will hopefully help define which procedure provides the maximum of benefit and minimum of morbidity for each individual patient.⁵⁰

RADIATION ONCOLOGY

Radiotherapy (RT) plays an important role in the management of MPM and can be delivered in the adjuvant, neoadjuvant, and palliative settings. In early-stage resectable MPM, RT is typically delivered to the hemithorax before or after non–lung-sparing surgery (ie, EPP) or to the involved pleural space after lung-sparing surgery. Adjuvant conventionally fractionated hemithoracic RT after EPP to 54-60 Gy is safe and associated with low rates of locoregional recurrence.^51,52 Hence, it is recommended to use modern techniques (ie, 3D conformal RT, intensity-modulated radiotherapy, or proton therapy) to minimize radiation doses to surrounding normal tissues, especially the heart and contralateral lung.^53-55 A randomized trial on the use of hemithoracic RT following EPP closed early to accrual and thus did not meet its primary end point of locoregional relapse-free survival.⁵⁶ Its use should therefore remain limited to centers with significant experience in treating MPM with RT.

The Surgery for Mesothelioma after Radiation Therapy radiotherapy regimen, referenced earlier in the surgical section, consists of a short, neoadjuvant, hypofractionated course of hemithoracic intensity-modulated radiotherapy delivered to 5-6 Gy for five fractions followed by complete resection of the lung via EPP to avoid the development of radiation pneumonitis in the ipsilateral hemithorax. This multimodality treatment approach has resulted in impressive long-term disease control with a median survival of 24.4 months overall, but 42.8 months in a subset of patients with epithelioid MPM.^49,57,58 However, the 30-day perioperative grade 3-4 toxicity rate was 49%, indicating that this aggressive treatment approach should only be offered to appropriately selected patients at a tertiary care center with significant expertise in mesothelioma treatment.

Adjuvant hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) after lung-sparing pleurectomy decortication to a total dose of 50-60 Gy in conventional fractionation is safe and feasible, as shown in multiple phase II studies.^59-61 Figure 2 illustrates the IMPRINT radiation fields after lung-sparing surgery. Arc therapy and proton therapy may further improve normal tissue dosimetry and target coverage.^62,63 A single-center phase III randomized trial comparing palliative RT with radical hemithoracic radiation therapy demonstrated an improvement in 2-year overall survival from 28% to 58%. NRG LU-006 (NCT04158141) is an ongoing cooperative group multicenter phase III randomized trial designed to evaluate the survival benefit of adjuvant IMPRINT using photon or proton therapy following lung-sparing surgery and systemic therapy.

FIG 2.

Right-sided hemithoracic intensity-modulated pleural radiation therapy plan to a total dose of 5,040 cGy in 28 fractions. The red line represents the planning target volume.

RT can be used for palliation of pain, eg, from tumor invasion into chest wall or spine, spinal cord compression, superior vena cava syndrome, and other obstructive symptoms. Some studies have described better response rates with fraction sizes of ≥ 4 Gy.⁶⁴ A prospective single-arm phase II study demonstrated 47% pain improvement with a relatively low dose of 20 Gy in five fractions.⁶⁵ A randomized study (SYSTEMS-2; ISRCTN12698107) is currently evaluating the palliative effect of higher doses of 36 Gy in six fractions.

Recurrences in the chest wall along prior diagnostic or therapeutic procedure tracks have been observed in patients with MPM. Therefore, prophylactic radiotherapy to prevent procedure-tract metastases was previously advocated based on initial promising data.^66,67 However, no consensus could be reached in several systematic reviews of this topic.^68,69 More recently, two large randomized trials showed no benefit of prophylactic radiotherapy to diagnostic or therapeutic procedure tracks. A multicenter, phase III, randomized controlled trial of 203 patients investigated immediate versus deferred radiotherapy (21 Gy in three fractions) to large-bore pleural intervention sites.⁷⁰ Although radiotherapy was well tolerated, there was no significant difference in development of procedure-tract metastases. Another even larger phase III, randomized trial of 375 patients compared prophylactic radiotherapy within 42 days of a procedure versus no radiotherapy.⁷¹ This study also failed to detect a significant difference in the incidence of chest wall metastases at 6 months. Thus, there is no role for the routine use of prophylactic radiotherapy to prevent chest wall recurrences.

SYSTEMIC THERAPY

Resectable Disease

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)⁷² 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.⁹ 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.

Unresectable Disease

Until recently, the systemic standard of care in the United States was platinum-pemetrexed⁷³ with and without bevacizumab⁷⁴ for four to six cycles of therapy followed by bevacizumab maintenance therapy.⁷⁵ 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 20901⁷⁶ 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.⁷⁴ 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 trials⁷⁹ (Table 1). It was therefore heartening for the field to have two recent FDA approvals affecting the frontline therapeutic setting.

TABLE 1.

Selected Frontline Therapy Trials for Unresectable Malignant Pleural Mesothelioma

On May 23, 2019, the NovoTTF system based on the phase II STELLAR trial⁸¹ 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. STELLAR⁸¹ 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.⁹

The second regulatory approval was for the CheckMate 743 trial,⁸⁰ 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).⁸⁰ 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).⁸⁰ 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).⁸⁰ 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 trial⁸⁰ 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.⁹ 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 DREAM⁸² 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.⁹ These trials may again redefine the frontline treatment landscape by incorporating immunotherapy with and without an antiangiogenic into the frontline chemotherapy regimen.

TABLE 2.

Frontline Therapy Trials With Potential to Alter the Treatment Landscape

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.⁸³ 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 trial⁸⁸ was the world's first study to obtain regulatory approval for a salvage checkpoint inhibitor, and the tremelimumab monotherapy trial (DETERMINE)⁸⁴ demonstrated that single-agent anti–cytotoxic T-cell lymphocyte-4 blockade was not beneficial in mesothelioma. Although the PROMISE-Meso⁸⁷ 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 trial⁸⁹ 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.

TABLE 3.

Recent Salvage Immunotherapy Studies in Malignant Pleural Mesothelioma

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)⁹⁰ 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.

NOVEL AND CELLULAR THERAPIES

With the rare exception of case reports⁹¹ of patients with tumors that harbor ALK fusions that are responsive to ALK inhibition, the genomic landscape of mesothelioma is difficult to target. The loss of tumor suppressor genes suggests that synthetic lethality or collateral lethality may be a more appropriate strategy than that of direct kinase inhibition of oncogenes used in other tumor types. To that end, poly (ADP-ribose) polymerase (PARP) inhibitors have been explored in mesothelioma. One investigation that tested 10 mesothelioma cell lines that were characterized for BAP1 did not identify a correlation between BAP1 status and PARP inhibitor sensitivity.⁹² A clinical trial at the NIH suggested that the PARP inhibitor olaparib had minimal activity in MPM, and that patients with germline BAP1 mutations had worse outcomes than those who were wild-type for BAP1.¹⁰ By contrast, the Mesothelioma-Stratified Therapy study group just reported encouraging activity with the PARP inhibitor rucaparib in BAP1-deficient mesothelioma,⁹³ suggesting that further investigation of this strategy is warranted.

In a similar fashion, Mesothelioma-Stratified Therapy also has an ongoing treatment arm with the CDK4/6 inhibitor abemaciclib for patients with tumors that lack p16 (which is encoded by CDKN2A). While these novel therapeutics are being explored in mesothelioma, BAP1 may affect the benefit with our current approved therapies. It was recently shown that patients with loss-of-function mutations in BAP1 or other DNA repair genes had improved overall survival with platinum-based therapy compared with patients whose tumors did not have these mutations.⁹⁴

Cellular therapies are also in development with both dendritic cells (DCs) and chimeric antigen receptor T cells (CAR-Ts). DCs are antigen-presenting cells that are critical to modulating immune responses against antigens. Upon collection and differentiation, DCs can be trained to promote an immunostimulatory response against selected antigens (Fig 3A). Although autologous DCs are used in most ongoing clinical trials, the choice of antigen sources differs widely: some use autologous tumor lysates, others use allogenic tumor lysates, and peptide loading, or transfection strategies are also possible. As genomic and bioinformatics approaches improve the identification of neoantigens, personalized vaccination strategies might become feasible with DCs.

FIG 3.

Examples of cellular therapies. (A) In most clinical trials with dendritic cell vaccines, monocytes are removed by leukapheresis and matured, then loaded with tumor lysates or peptides, and administered to patients. (B) Similarly, to construct CAR-T cells, lymphocytes are isolated after leukapheresis and then undergo DNA or RNA transfection, or viral transduction, of a chimeric antigen receptor against a specific antigen, and are then administered. While the CAR-T cells are being created, patients typically undergo lymphodepletion to reduce immunosuppressive regulatory T cells. CAR-T, chimeric antigen receptor T cells; DC, dendritic cell. Used with permission of Mayo Foundation for Medical Education and Research, all rights reserved.

By contrast, most CAR-T trials that have included patients with mesothelioma have targeted the tumor-associated antigen mesothelin that is broadly expressed by epithelioid variants of mesothelioma. CAR-T cells are generated by DNA or RNA transfection, or viral transduction, of a chimeric antigen receptor that recognizes a specified antigen into T cells ex vivo (Fig 3B).⁹⁵ CAR-T trials typically involve lymphodepletion before treatment to reduce immunosuppressive regulatory T cells and potentially improve the efficacy of the CAR-T cells.⁹⁶ Most studies to date have demonstrated limited efficacy with poor infiltration of tumors, limited persistence of the CAR-T cells, and in some cases, anaphylactic reactions.^97,98 Hopefully, the humanization of the CAR-T constructs, expansion of targets, inclusion of suicide switches, combinations with immune checkpoint inhibitors, and other innovations will improve the therapeutic index with this approach.⁹⁹ As our understanding of the vulnerabilities in mesothelioma improves, so will the therapeutic strategies we implement against it.

SUMMARY

In summary, the field of mesothelioma has gained momentum with recent therapeutic advances and innovative devices. For clinical practice, it is now essential to know the histologic subtype of mesothelioma and factor this into the decision-making process for frontline systemic therapy. Several ongoing trials in the frontline unresectable setting may soon provide additional treatment options but a key area of need for research remains in the immunotherapy refractory population. In time, it is possible that predictive biomarkers will refine the optimal systemic treatment sequence and justify novel therapies for the patient. These recent advances in adjunct biomedical devices, immunotherapy combinations, and molecular research have generated excitement and hopeful momentum in the field of mesothelioma.

APPENDIX

TABLE A1.

Correlation of PD-L1 IHC to Clinical Outcomes by trial

AUTHOR CONTRIBUTIONS

Conception and design: Anne S. Tsao, Andreas Rimne, Aaron S. Mansfield

Collection and assembly of data: All authors

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

New Era for Malignant Pleural Mesothelioma: Updates on Therapeutic Options 2021

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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