ASCO Updates Guidelines for Malignant Pleural Mesothelioma Treatment

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Earlier in 2025, the American Society of Clinical Oncology (ASCO) released its first updated guidelines for the treatment of patients with malignant pleural mesothelioma (MPM) since 2018.¹ The updated guidelines emphasize a more nuanced approach to surgery, the integration of immunotherapy, the importance of genetic testing, and refined pathologic insights.

These new recommendations were informed by 110 peer-reviewed studies that were conducted between 2016 and 2024. Each update reflects significant advancements in the understanding and management of this aggressive, asbestos-related cancer.

“The ASCO Guideline Update is not advocating for a “reduced role of surgery.” We do need to be more selective about which patients are offered surgical cytoreduction. However, just because it is anatomically feasible to resect does not mean one should do so,” explained Hedy Lee Kindler, MD, professor of medicine, section of hematology/oncology, associate dean for clinical science research, human subjects, The University of Chicago, Biological Sciences Division, in an interview with Targeted Oncology^TM.

“The challenge is to identify which patient might benefit from resection. This would include appropriately staged patients with early-stage epithelioid disease who are evaluated by a multidisciplinary team. Optimally, cytoreduction should be performed at experienced centers with a documented history of low morbidity and mortality,” she added.

Hedy Lee Kindler, MD

The Evolving Role of Surgery

Surgery has long been a cornerstone of MPM treatment, but the updated guidelines suggest a more limited role. The phase 3 MARS-2 trial (NCT02040272) performed in the United Kingdom showed that at a median follow-up of 22.4 months, patients treated with chemotherapy alone had a longer median overall survival of 24.8 months (interquartile range [IQR], 12.6-37.4) compared with those who underwent surgery followed by adjuvant chemotherapy at 19.3 months (IQR, 10.0-33.7). The difference in restricted mean survival time at 2 years was -1.9 months (95% CI, 3.4 to -0.3; P =.019). Additionally, chemotherapy was linked with better quality of life and lower costs in the study.²

As a result of this study and other published data, ASCO now recommends surgery only for carefully selected patients with early-stage disease and the epithelioid subtype, which is associated with a better prognosis. Surgical cytoreduction should not be routinely offered to all patients based solely on anatomic resectability, and surgery should be performed exclusively at high-volume mesothelioma centers with extensive expertise.¹

Advances in Systemic Therapies With Immunotherapy

Some of the key updates in the guidelines pertain to systemic therapies, particularly immunotherapy. The combination of ipilimumab (Yervoy) and nivolumab (Opdivo), approved by the FDA in 2020, is now recommended as a first-line treatment for non-epithelioid MPM, based on data from the CheckMate 743 trial (NCT02899299).³ In the study, a significant survival benefit was seen among treatment-naive patients with MPM.

For patients with non-epithelioid tumors, the median overall survival (OS) was 18.1 months (95% CI, 12.2-22.8) in the nivolumab plus ipilimumab arm compared with only 8.8 months (95% CI, 7.4-10.2) in the chemotherapy arm (HR, 0.46; 95% CI, 0.31-0.68). The 2-year OS rates were also superior among those given immunotherapy, at 41% vs 27%. Further, OS was improved with nivolumab plus ipilimumab vs chemotherapy across histologic subtypes.

“When choosing between chemotherapy [pemetrexed plus cisplatin or carboplatin with or without bevacizumab], doublet immunotherapy [ipilimumab/nivolumab] or chemo-immunotherapy [pembrolizumab (Keytruda), pemetrexed, carboplatin], key factors are histology, disease burden, comorbidities, and patient preference,” said Kindler. “Because histology is both predictive and prognostic in this disease, it is essential that the pathologist ascertain the histologic subtype—epithelioid, sarcomatoid, or biphasic [mixed]. Patients with sarcomatoid, or sarcomatoid predominant biphasic disease should receive doublet immunotherapy with ipilimumab/nivolumab, due to the substantial survival benefit with this regimen, unless there are medical contraindications to immunotherapy.”

For patients with epithelioid MPM, options now include immunotherapy, chemotherapy, or a newly approved chemoimmunotherapy regimen combining pembrolizumab with pemetrexed and platinum-based chemotherapy. The guidelines stress the importance of individualizing treatment decisions, taking into account patient comorbidities, toxicity tolerance, and treatment goals.¹

“For patients with epithelioid disease, the 3 regimens have similar activity, so additional factors come into play. Highly symptomatic patients, or those with a large disease burden, may benefit from chemoimmunotherapy, which has a response rate of 62%, nearly double the other regimens. Patients with autoimmune disease or other contraindications to immunotherapy should receive chemotherapy, while those with a low creatinine clearance that precludes pemetrexed should receive doublet immunotherapy,” said Kindler.

“Patients with germline mutations have superior survival if they receive a platinum-based regimen, so chemotherapy or chemoimmunotherapy are preferred in these patients. And, of course, there are the usual patient preferences applicable to any disease, related to duration of treatment and pattern of side effects that helps to decide upon a treatment regimen,” she added.

Pathologic Insights

Accurate diagnosis and subtyping of MPM remain key for guiding treatment among patients with MPM. According to the updated guidelines, the terminology for what the diagnosis of mesothelioma is has been simplified, replacing “malignant mesothelioma” with “mesothelioma.” The term “mesothelioma” now covers only malignant tumors.¹

“This cancer is no longer called malignant pleural mesothelioma. All mesotheliomas are now considered malignant, so the prefix “malignant” is no longer required. Just call it “pleural mesothelioma,” Kindler explained.

Additionally, mesothelioma must now be classified into 1 of 3 subtypes: epithelioid, sarcomatoid, or biphasic. Making this distinction is crucial, as the cell type influences treatment decisions, with epithelioid mesothelioma generally responding better to systemic therapies.

Genetic Testing

The guidelines also now recommend germline genetic testing for all patients with MPM upon diagnosis. Genetic mutations, particularly in the BAP1 gene, have been linked to both the development of mesothelioma and patient prognosis. Identifying these mutations can inform treatment decisions and provide insights into familial cancer risks.

“Since up to 14% of mesothelioma patients will have a germline mutation, ASCO recommends that all mesothelioma patients should be offered germline testing. The most important thing is simply to recognize that this is a disease where genetic testing is necessary. A unique issue facing mesothelioma patients, which needs to be included in genetic counseling of these individuals, are medicolegal considerations related to asbestos litigation,” Kindler added.

The guidelines also highlight the role of inherited BAP1 mutations, which have been associated with longer survival in patients with MPM. These updates underscore the potential for genetic testing to not only guide therapy but also offer prognostic information to oncologists and their patients.

Implications for Clinical Practice

The 2025 ASCO guidelines for malignant pleural mesothelioma mark a transformative moment in the field of oncology. By incorporating the latest research and clinical trial data, these recommendations offer a roadmap for optimizing patient care.

For oncologists, staying abreast of these updates is essential to providing the most effective and individualized treatment for patients with this rare and aggressive cancer. As the field continues to evolve, collaboration and adherence to these guidelines will be key to improving outcomes for patients with mesothelioma worldwide.

REFERENCES:

1. Kindler HL, Ismaila N, Bazhenova L, et al. Treatment of Pleural Mesothelioma: ASCO Guideline Update. J Clin Oncol. Published online January 8, 2025. doi:10.1200/JCO-24-02425

2. Lim E, Waller D, Lau K, et al. Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial. Lancet Respir Med. 2024;12(6):457-466. doi:10.1016/S2213-2600(24)00119-X

3. Peters S, Scherpereel A, Cornelissen R, et al. First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743. Ann Oncol. 2022;33(5):488-499. doi:10.1016/j.annonc.2022.01.074