Current Systemic Management of Pleural Malignant Mesothelioma

Marjorie G. Zauderer, MD, MS

Marjorie G. Zauderer, MD, MS

Memorial Sloan Kettering Cancer Center

Department of Medicine, Division of Solid Tumor Oncology

Thoracic Oncology Service

300 East 66th Street

New York, NY

Abstract

Malignant mesothelioma remains an uncommon malignancy of the pleura. Standard systemic therapy involves the use of pemetrexed and cisplatin. Recent results of a phase III, randomized clinical trial presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in June 2015 support the addition of bevacizumab to this regimen. The study showed that the addition of bevacizumab improved progression-free survival and overall survival in those without contraindications to vascular endothelial growth factor inhibitor therapy. Second-line therapies yield modest efficacy, but commonly used agents include vinorelbine and gemcitabine, largely based on small phase II trials prior to the first-line use of pemetrexed. Efforts are ongoing to improve systemic options in all lines of therapy. Based on the success in other disease, promising new drugs are being explored that target key aberrant pathways in mesothelioma. Additionally, the advent of immunotherapies has led to some exciting results in mesothelioma. Promising results from a phase IB study of the programmed cell death-1 inhibitor pembrolizumab were presented at the American Association for Cancer Research Annual Meeting in 2015. Moreover, results from a phase I study of live-attenuated bacterial vaccine engineered to express mesothelin (CRS-207) given in combination with standard chemotherapy were presented at the ASCO Annual Meeting in 2015. Furthermore, results from a large randomized trial of the cytotoxic T-lymphocyte—associated protein 4 inhibitor tremelimumab are imminent.

Introduction

Malignant mesothelioma is an uncommon malignancy of the pleura that is usually associated with asbestos exposure. In the United States, there are approximately 3000 new cases annually, and the incidence continues to increase globally, particularly in locations where asbestos use continues.¹While mesothelioma is capable of spreading to distant sites, it typically spreads locally within the chest, invading critical thoracic structures and causing respiratory distress and chest wall pain. While some patients, particularly those with epithelioid histology, can have an indolent disease course, median overall survival (OS) is poor, ranging from 9 to 15 months, depending on the stage at diagnosis.²Even with aggressive multimodality therapy for early-stage disease, the disease recurs and survival is short.

Standard First-Line Therapy

For recurrent disease or disease that cannot be resected, systemic therapies are the mainstay of treatment. However, only one US Food and Drug Administration chemotherapy regimen is approved for the treatment of mesothelioma. In the landmark EMPHACIS trial, 456 patients who were chemotherapy-naïve with unresectable malignant pleural mesothelioma (MPM) were randomized to cisplatin or cisplatin and pemetrexed.³Response rate (RR), progression-free survival (PFS), and OS were all improved. Median OS improved to 12.1 months for the combination compared with 9.3 months with cisplatin alone. Several other phase III trials of cisplatin with and without antifolates have replicated these results (TABLE 1).

Subsequent data support the use of carboplatin with pemetrexed in those unable to tolerate cisplatin.^4-6In the expanded access program for pemetrexed, 861 patients who were chemotherapynaïve received pemetrexed and carboplatin with a response rate of 21.7%.⁶A multicenter, phase II trial further evaluated the efficacy of pemetrexed and carboplatin and found that 19 patients (18.6%) achieved a response and 47% had stable disease.⁵Median OS was 12.7 months in this cohort. Another small phase II trial confirmed these results with a RR with pemetrexed and carboplatin of 25% among 76 treated patients and median OS was 14 months.⁴

For patients who cannot receive pemetrexed, cisplatin in combination with gemcitabine is a viable option. In a multicenter trial of cisplatin and gemcitabine, partial responses were observed in 16% of 25 patients and median OS was 9.6 months. Similarly, another multicenter, phase II study of this combination demonstrated 17 partial responses among 57 previously untreated patients (33%) and 31 (60%) achieved stable disease.⁷Median OS in this study was 17.3 months. As with the combination of cisplatin and pemetrexed, carboplatin can be substituted for cisplatin in combination with gemcitabine based on a multicenter, phase II study in which 50 patients were treated with gemcitabine and carboplatin.⁸In that study, 26% of patients had partial responses and median PFS was 40 weeks.

Table 1. Studies of cisplatin with and without anti-folate therapy.

ITT indicates intention to treat; OS, overall survival; RR, response rate; TTP, time to progression.

Recent Improvements

Over the past 12 years, there have been no major advances with respect to first-line chemotherapy. However, at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, the results of a phase III, randomized, open-label trial were presented examining the impact of adding the vascular endothelial growth factor (VEGF) inhibitor bevacizumab to standard chemotherapy in patients with MPM.⁹The study enrolled 448 patients with unresectable MPM from 73 centers in France and these patients were randomized to receive cisplatin and pemetrexed or cisplatin, pemetrexed, and bevacizumab. In the intention to treat (ITT) analysis, median OS and median PFS were improved in the group that received bevacizumab, 18.8 months versus 16 months (P= .0127) and 9.6 months versus 7.5 months (P<.0001), respectively. There were, however, additional grade 3 and 4 toxicities among those who received bevacizumab, 71% versus 62% in the standard chemotherapy-alone group (P= .04).

However, a previous multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine and cisplatin with bevacizumab or placebo in patients with mesothelioma did not find a benefit with the addition of bevacizumab.¹⁰In this trial with 108 evaluable patients, response rates were 24.5% and 21.8% (P= .74) for the bevacizumab and placebo arms, respectively. Median PFS and OS also did not demonstrate statistically significant differences. Additionally, a prior multicenter, phase II study of cisplatin, pemetrexed, and bevacizumab did not meet its primary endpoint of a 33% improvement in the PFS rate at 6 months compared with historical controls treated with cisplatin and pemetrexed alone.¹¹Fifty-two evaluable patients who received pemetrexed, cisplatin, and bevacizumab had a PFS of 6.9 months, compared with 5.7 months in historical controls. Finally, a phase II, double-blind, placebocontrolled trial of pemetrexed/cisplatin with nintedanib, an inhibitor of VEGF 1-2, platelet-derived growth factor, and fibroblast growth factor receptor, has completed accrual and results are pending. In this study, 86 patients with unresectable MPM were randomized to either 6 cycles of pemetrexed and cisplatin with nintedanib followed by nintedanib maintenance or pemetrexed and cisplatin alone.¹²The primary endpoint of this trial is PFS with OS as a secondary endpoint.

While the available data are somewhat conflicting, the recent randomized, phase III clinical trial does demonstrate a survival benefit with the addition of bevacizumab to standard pemetrexed and cisplatin chemotherapy and thus justifies its addition to the National Comprehensive Cancer Network&rsquo;s Mesothelioma Guidelines. While there is a modest increase in associated toxicity, the addition of bevacizumab to first-line therapy should be considered in all patients without contraindications to VEGF-inhibitor therapy. Researchers hope that the pending results of the nintedanib study will confirm these findings.

Role of Maintenance Pemetrexed

Given its use as maintenance in non-small cell lung cancer, pemetrexed has also been explored in MPM. In one study, 13 of 27 patients who received induction therapy containing pemetrexed had no progression of disease and were eligible to continue pemetrexed until disease progression.¹³The median number of maintenance cycles received was 4 but ranged from 2 to 14. Therapy was well tolerated and, interestingly, 23% of patients with stable disease after induction therapy achieved a partial response during pemetrexed maintenance. Time to progression and OS were improved among those who received pemetrexed maintenance: 3.4 and 6.0 months versus 8.5 months and 17.9 months, respectively. A randomized, phase II trial of maintenance pemetrexed versus observation in patients with MPM is being conducted by the Alliance for Clinical Trials in Oncology (CALGB 30901) to address this question. In the meantime, until these results are available, it is reasonable to consider maintenance pemetrexed in a very select patient population.

Second-Line Therapy

Unfortunately, there is no proven benefit of secondline therapy. If patients had a good initial response and significant time has elapsed since initial treatment, there are data to support rechallenge with pemetrexed-based therapy from case reports, from the expanded access to pemetrexed program, and from a small observational study.^14-16In the observational study, 31 patients were retreated with pemetrexed-based therapy and 19% achieved a partial response. The disease control rate was 48%.¹⁴Median PFS and OS were 3.8 months and 10.5 months, respectively. It was also noted that those who were retreated less than 12 months after their first-line pemetrexed-based therapy had a median PFS of 2.5 months as opposed to 5.5 months among those who had not received pemetrexed-based therapy in more than 12 months. These findings are corroborated by the report from the expanded access program for pemetrexed in mesothelioma.

Other options include vinorelbine and gemcitabine based on first-line data and other small trials. In an open-label, phase II trial among 63 patients who were pemetrexed na&iuml;ve, there was a 16% response rate with vinorelbine, but more than 50% of these patients also experienced severe toxicity.¹⁷Also, in an exploratory subgroup analysis of a firstline multicenter, randomized trial comparing active symptom control plus chemotherapy with mitomycin, vinblastine, and cisplatin or weekly vinorelbine, there was a suggestion of a survival advantage with weekly vinorelbine.¹⁸One retrospective study examined the efficacy of vinorelbine in 59 patients with MPM who had previously received pemetrexedbased chemotherapy and found a RR of 15% and median PFS of 2.3 months.¹⁹

Clinical Pearls

• The addition of bevacizumab to standard first-line pemetrexed-based therapy should be considered in patients without contraindication to VEGF inhibitor therapy.
• Second-line therapies are limited, but vinorelbine and gemcitabine are the most commonly used agents with the most robust data.
• Whenever possible, patients should be enrolled in clinical trials for this rare and almost universally lethal disease.

Gemcitabine&rsquo;s efficacy in MPM was initially demonstrated in a phase II screening of drugs; 27 patients who were chemotherapy na&iuml;ve received weekly gemcitabine and there was a RR of 7% and median OS was 8 months.²⁰Additional analysis of the poststudy treatment of patients who participated in the EMPHACIS trial identified gemcitabine as the most commonly used agent.²¹In a CALGB phase II trial, 17 patients who were chemotherapy na&iuml;ve received gemcitabine. While there were no complete or partial responses, median OS was 4.7 months.²²

However, the efficacy of these agents was not confirmed in a recent retrospective analysis of the Memorial Sloan Kettering Cancer Center experience.²³Among 56 patients treated with vinorelbine or gemcitabine after pemetrexed-based therapy, only one patient had a partial response to treatment. However, 46% did achieve stable disease. While these data certainly support the use of vinorelbine and gemcitabine as second-line and beyond therapies, their efficacy is modest at best and, whenever possible, patients should be treated on clinical trials.

Research Challenges

Because of the rarity of this disease and the nihilism about outcomes, clinical research in this area has historically been challenging. It was long believed that large, randomized, clinical trials would be difficult to execute and take many years to complete. Consequently, there was a lack of interest from pharmaceutical companies and funding agencies to support studies in this orphan disease. Yet, the recent brisk accrual to several large multinational studies has debunked this belief, and interest has exploded in pursuing clinical trials to explore novel agents against a wide range of targets in mesothelioma.

One way to try to break past the current therapeutic plateau is to improve our understanding of the biology of this disease so that it can be exploited with novel agents, an approach that has been successful in other malignancies. That work is ongoing in mesothelioma and is being translated into clinical trials with several novel agents that have strong biologic rationale, such and phosphatidylinositol-3 kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors, focal adhesion kinase (FAK) inhibitors, mesothelin-directed therapies, and other small molecules that target commonly aberrant pathways (TABLE 2). Additionally, the advent of immunotherapy has brought some exciting preliminary results to mesothelioma research and further investigations are ongoing (TABLE 2). At the American Association for Cancer Research Annual Meeting in 2015, results from a phase IB study of pembrolizumab demonstrated that this PD-1 inhibitor was safe and tolerable for patients with MPM.²⁴A disease control rate of 76% among 25 patients with MPM was achieved. At the ASCO Annual Meeting in 2015, results were presented from a single-arm study of vaccination with live-attenuated Listeria monocytogenes engineered to express mesothelin in combination with pemetrexed and cisplatin in patients who were chemotherapy na&iuml;ve. Not only was the combination safe, but an amazing disease control rate of 92% was achieved.²⁵A large, randomized, phase II trial of the cytotoxic T-lymphocyte-associated protein--4 (CTLA- 4) inhibitor tremelimumab versus placebo recently completed accrual and results are imminent. Clearly, additional studies are needed but this represents a promising new avenue for advances.

Table 2. Partial List of Ongoing Trials in MPM With Novel Agents and Immunotherapies

Anti-PD-1 indicates anti-programmed cell death 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; FGFR, fibroblast growth factor receptor; FAK, focal adhesion kinase; pem/cis, pemetrexed and cisplatin; PDGFR, platelet-derived growth factor receptor; PI3K/mTOR, phosphatidylinositol-3 kinase/mammalian target of rapamycin inhibitors; TNF&alpha;, tumor necrosis factor &alpha;; VEGF, vascular endothelial growth factor.

Conclusion

The current treatment options for mesothelioma are limited and advances have been slow and incremental. However, many new drugs and novel approaches are being investigated. Therefore, whenever possible, patients should be treated in clinical trials. Yet, with the abundance of ongoing studies, vigilance is needed to design trials that have a strong biologic rationale and the greatest potential for meaningful clinical impact. This is the only way the bar of therapy in this almost universally lethal disease will be raised.

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