In the past few years, several studies have addressed the possibility of using immunotherapies to treat patients with mesothelioma. Herein, we discuss two recent trials, one testing the immune-checkpoint inhibitor nivolumab and the other testing a mesothelin-directed therapeutic vaccine, and reflect on the advances and challenges remaining in this research area.
Refers to Okada, M. et al. Clinical efficacy and safety of nivolumab: results of a multicenter, open-label, single-arm, Japanese phase 2 study in malignant pleural mesothelioma (MERIT). Clin. Cancer Res. 25, 5485–5492 (2019) | Hassan, R. et al. Clinical response of live-attenuated, Listeria monocytogenes expressing mesothelin (CRS-207) with chemotherapy for treatment of malignant pleural mesothelioma. Clin. Cancer Res. 25, 5787–5798 (2019).
Malignant pleural mesothelioma (MPM) is an orphan disease (~30,000 patients were estimated to be diagnosed worldwide in 2018) with a devastating prognosis. MPM is also largely preventable, with the majority of cases attributable to exposure to asbestiform fibres. Of three major histological subtypes, epithelioid mesothelioma is the most common (60–70%) and has the most favourable prognosis, sarcomatoid mesothelioma (10–15%) has the least favourable prognosis, and biphasic mesothelioma (remainder of patients) has an intermediate prognosis and is more frequently identified with extensive sampling. The standard-of-care systemic treatment for MPM has not changed substantially since 2003 and remains combination chemotherapy with cisplatin and pemetrexed1. In the pivotal trial of this combination, the median overall survival (OS) duration was 12.1 months compared with 9.3 months with cisplatin alone. In 2016, the addition of bevacizumab to this combination demonstrated a further incremental benefit in OS; however, the use of bevacizumab is predominantly confined to jurisdictions in which this therapeutic agent is approved or reimbursed2. No second or subsequent line treatment options are approved, and numerous agents tested in clinical trials in this setting have failed to progress through the drug development pipeline for MPM, owing to a lack of clinical activity. As with many other cancers, immunotherapy has been an area of active clinical research in MPM over the past 5 years. Two recent publications in Clinical Cancer Research highlight the potential of immunotherapy approaches to improve the outcomes of patients with MPM but also act as a salutary reminder that clinical researchers still have much work to do.
Okada et al.3 report the results of the single-arm phase II MERIT trial of monotherapy with the immune-checkpoint inhibitor (ICI) nivolumab in the second or subsequent line of therapy for patients with MPM, which led to the regulatory approval of nivolumab in this setting in Japan3. Thirty-four patients with advanced-stage MPM resistant and/or refractory to standard-of-care chemotherapy were recruited and received treatment in this trial. A total of 10 patients (29%) had an objective response to treatment according to the modified RECIST criteria for MPM, with responses observed across all disease subtypes4. With a median progression-free survival (PFS) of 6.1 months, duration of response of 11.1 months and OS of 17.3 months, the results of the MERIT study strengthen the emerging role of ICI treatment in this disease. The toxicity profile was as anticipated for nivolumab: 4 patients required treatment discontinuation owing to adverse events (AEs), including 2 patients with interstitial pneumonia (one of grade 2 and one of grade 3) and 2 patients with grade 3 pneumonitis. These toxicities highlight that patients with a pulmonary malignancy and consequent pre-existing respiratory compromise might not tolerate additional pulmonary toxicities from immunotherapy.
In the MERIT study, patients with tumours expressing programmed cell death 1 ligand 1 (PD-L1) at levels ≥1% (according to staining with the Dako 28-8 antibody) were more likely to have a response than those with PD-L1 levels <1% (objective response rate 70% versus 33%). The correlation between treatment outcomes and PD-L1 expression has been more difficult to demonstrate with confidence in patients with MPM than in those with other tumour types (such as non-small-cell lung cancer). In the KEYNOTE-028 trial of pembrolizumab in patients with MPM, in which patients with PD-L1-negative tumours were excluded, the objective response rate was 20% and no relationship was found between the levels of PD-L1 expression and outcomes5. Of note, however, researchers do not currently fully understand how PD-L1 expression changes over time and in the context of other treatments (such as prior chemotherapy); nor can they be confident that PD-L1 expression is uniform throughout an individual tumour — usually, PD-L1 determination in these trials is made on a small tumour sample from a biopsy performed before first-line treatment. More recently, the single-arm INITIATE study6, which combined nivolumab and ipilimumab as a second-line therapy for MPM, showed data supporting that tumoural expression of PD-L1 (stained with the 22C3 pharmDx antibody) is predictive of benefit from ICIs in patients with MPM; the difference between this study and MERIT is that biopsies were performed during the trial, enabling contemporaneous analysis of PD-L1 status6.
What is the current situation for treatment with ICIs in MPM? Response rates of 20–29% have been reported with single-agent treatment using anti-programmed cell death protein 1 (PD-1) agents such as pembrolizumab5 or nivolumab3,7, although the results observed in real-world clinical practice have not been as promising8. Dual checkpoint blockade, including combinations with anti-cytotoxic T lymphocyte protein 4 (CTLA-4) agents such as ipilimumab or tremelimumab, seems to bring response rates closer to 30%, but at the cost of toxicities (38% of patients in INITIATE had grade ≥3 AEs)6,7,9. The results of well-powered randomized controlled trials that are expected to be reported over the next few years will begin to clarify if any survival benefit can be derived from ICI treatment, identify which patients benefit most from this therapeutic class, and how to optimize combination therapy. Single-agent checkpoint blockade therapy is most likely a step forward, but patients with MPM still need better treatments that substantially improve outcomes.
Hassan and colleagues10 took a different approach to modulating antitumour immunity and tested a live, attenuated Listeria monocytogenes-based vaccine construct, CRS-207, encoding the human mesothelin gene, in a single-arm phase Ib trial10. Mesothelin is commonly overexpressed in both epithelioid mesothelioma and in the epithelioid component of biphasic tumours, and thus is a therapeutic target for many novel agents, including bispecific antibodies, vaccines and adoptive cellular therapies. Preclinical data supported the immunogenicity of CRS-207, and early clinical trials in other tumour types, most notably metastatic pancreatic adenocarcinoma, have shown promising survival and toxicity outcomes11. The study by Hassan and colleagues10 involved 37 eligible patients with surgically unresectable epithelioid-predominant biphasic or epithelioid mesothelioma who received two priming doses of CRS-207 over 1 month before commencing a standard course of cisplatin plus pemetrexed treatment. Two further booster doses of CRS-207 were planned to be administered after completion of chemotherapy (86% of patients who received priming doses also received booster doses) followed by maintenance treatment for patients who had radiographically stable disease or an objective response. Among 35 evaluable patients, 20 (57%) had an objective response (according to the modified RECIST criteria for MPM); the median duration of response was 5.0 months. An apparent immune-related response pattern, comprising an initial increase in tumour size followed by eventual regression, was noted in a substantial percentage (69%); however, owing to the sequential design whereby CRS-207 was administered before and after chemotherapy, this effect might have been attributable to a differential response to immunotherapy and cytotoxic therapy. The median PFS duration (7.5 months) compares favourably with historic data for cisplatin plus pemetrexed in similar patient populations (4.7–7.0 months), although the reported median OS duration (14.7 months) is relatively modest given the promising PFS. The grades and frequency of AEs related to CRS-207 infusion (chills, fever and nausea) were consistent with those previously reported11, with no evidence of a synergistic effect with the toxicities of chemotherapy. Multiplex immunofluorescence staining of tumour biopsy samples from three patients taken before and after treatment showed increased infiltration of CD8+ Ki67hi T cells and natural killer cells, consistent with the effects of CRS-207 noted in preclinical studies. Taken together, these results support the concept of mesothelin-directed immunotherapy as a promising approach that warrants future investigation in patients with MPM. Of note, CRS-207 is no longer in clinical development owing to the negative results of a later phase clinical trial (NCT01675765).
“Ongoing investment in research and clinical trials must be a high priority…”
The incidence of MPM keeps increasing worldwide, and the use of asbestos remains unabated in many countries. Ongoing investment in research and clinical trials must be a high priority to improve the outcomes for people with this almost invariably fatal cancer. Although this cancer type is uncommon, the recruitment of patients in phase III clinical trials in mesothelioma conducted in the past few years has been rapid, showing that patients and clinicians are comfortable with participating in a randomized study. Challenges in the interpretation of the results of single-arm phase II studies in mesothelioma include the interpretation of reported PFS when imaging schedules vary between trials, and a bias towards long OS durations that is apparent when selected patients seek treatment at single centres of excellence. Randomized phase II studies in MPM, particularly if chemotherapy is a component of the combination tested, would facilitate the interpretation and decision-making processes involved in the continuous development of therapeutic agents. The next generation of clinical trials includes novel strategies such as CAR T cells, DNA repair targeting agents and immunotherapy combinations. Researchers need to carefully consider trial designs that will provide clear information regarding the contribution of novel agents to chemotherapy or immunotherapy regimens.
Vogelzang, N. J. et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J. Clin. Oncol. 21, 2636–2644 (2003).
Zalcman, G. et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 387, 1405–1414 (2016).
Okada, M. et al. Clinical efficacy and safety of nivolumab: results of a multicenter, open-label, single-arm, japanese phase II study in malignant pleural mesothelioma (MERIT). Clin. Cancer Res. 25, 5485–5492 (2019).
Byrne, M. J. & Nowak, A. K. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann. Oncol. 15, 257–260 (2004).
Alley, E. W. et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol. 18, 623–630 (2017).
Disselhorst, M. J. et al. Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma (INITIATE): results of a prospective, single-arm, phase 2 trial. Lancet Respir. Med. 7, 260–270 (2019).
Scherpereel, A. et al. Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial. Lancet Oncol. 20, 239–253 (2019).
Metaxas, Y. et al. Pembrolizumab as palliative immunotherapy in malignant pleural mesothelioma. J. Thorac. Oncol. 13, 1784–1791 (2018).
Calabro, L. et al. Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study. Lancet Respir. Med. 6, 451–460 (2018).
Hassan, R. et al. Live-attenuated, listeria monocytogenes expressing mesothelin (crs-207) with chemotherapy for treatment of malignant pleural mesothelioma. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-19-0070 (2019).
Le, D. T. et al. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J. Clin. Oncol. 33, 1325–1333 (2015).
The research of A.K.N. is supported by the National Health and Medical Research Council Centre for Research Excellence Grant.
A.K.N. has been a paid consultant or adviser for Bayer, Boehringer Ingelheim, MSD and Roche; has been a consultant or adviser with fees to her institution for Atara, Douglas and Pharmabcine; has received travel funding from AstraZeneca and Boehringer Ingelheim; and her institution receives research funding to institution from AstraZeneca and Douglas Pharmaceuticals. P.M.F. has been an unpaid consultant or adviser for Abbvie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb (BMS), EMD Serono, Inivata, Janssen, Merck and Novartis, and his institution receives research funding from AstraZeneca, BMS, Corvus, Kyowa and Novartis.
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Nowak, A.K., Forde, P.M. Immunotherapy trials in mesothelioma — promising results, but don’t stop here. Nat Rev Clin Oncol 16, 726–728 (2019). https://doi.org/10.1038/s41571-019-0291-4
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