Abstract
Introduction
The PI3K/Akt/mTOR pathway is activated in a majority of malignant pleural mesotheliomas (MPM). We evaluated the activity of everolimus, an oral mTOR inhibitor, in patients with unresectable MPM.
Methods
MPM patients who had received at least one but no more than two prior chemotherapy regimens, which must have been platinum-based, were treated with 10 mg of everolimus daily. The primary endpoint was 4-month progression free survival (PFS) by RECIST 1.1.
Results
A total of 59 evaluable patients were included in the analysis. The median duration of treatment was 2 cycles (56 days). Overall response rate (ORR) was 2% (95%CI: 0%–12%) by RECIST 1.1 and 0% (0%–10%) by modified RECIST for MPM. The 4-month PFS rate was 29% (95% CI: 17%–41%) by RECIST 1.1 and 27% (95%CI: 16%–39%) by modified RECIST. The median PFS was 2.8 months (95%CI: 1.8–3.4) by RECIST 1.1. The median overall survival (OS) was 6.3 months (95%CI: 4.0–8.0). There was no difference in PFS among patients who received 1 or 2 prior chemotherapy regimens (p= 0.74). There was no difference in OS between patients with epithelioid histology versus other types (p = 0.47). The most common toxicities were fatigue (59%), hypertriglyceridemia (44%), anemia (42%), oral mucositis (34%), nausea (32%), and anorexia (32%). The most common grade 3–4 toxicities were fatigue (10.2%), anemia (6.8%), and lung infection (6.8%).
Conclusion
Everolimus has limited clinical activity in advanced MPM patients. Additional studies of single-agent everolimus in advanced MPM are not warranted.
Keywords: malignant pleural mesothelioma, mTOR inhibitor, everolimus, modified RECIST
Background
Multiple signaling pathways are activated in malignant pleural mesothelioma (MPM) including the PI3K-Akt-mammalian target of rapamycin (mTOR) pathway. MPM cell lines1 and tumor samples2–4 frequently exhibit highly activated Akt, leading to phosphorylation of mTOR, 4EBP1, and FKHD, among others.3,4 Inhibition of the Akt pathway by the mTOR inhibitor rapamycin in MPM cells leads to G1 arrest,2 overcomes acquired resistance to apoptosis in MPM,5 and inhibits cell migration on extracellular matrix.6 Sirolimus, another mTOR inhibitor, led to cell death of MPM cell lines alone and to a much greater extent in conjunction with cisplatin.7 Furthermore, temsirolimus alone or in combination with cisplatin inhibited MPM cell growth both in vitro and in vivo xenograft models.8 Thus, mTOR inhibitors demonstrated compelling pre-clinical activity in MPM models.
Everolimus is an orally available inhibitor of mTOR that has been approved for use in renal cell carcinoma, pancreatic neuroendocrine tumors, angiomyolipoma in patients with tubular sclerosis complex, and in combination with exemestane in hormone receptor-positive breast cancer patients after progression on letrozole or anastrozole. 9 Here we report the results of a phase II study investigating the clinical activity of single agent everolimus in advanced MPM patients who have progressed after platinum-based chemotherapy.
PATIENTS AND METHODS
Inclusion criteria
Eligible patients must be 18 years or older with histologically proven epithelioid, sarcomatoid, or biphasic unresectable MPM, zubrod performance status of 0 to 1, adequate hematologic function (absolute neutrophil count ≥ 1500/ml and platelets > 100,000/ml), hepatic function (serum bilirubin < upper limit of normal and transaminases ≤ 1.5 times upper limit of normal), and renal function (serum creatinine < 1.5 times upper limit of normal or a measured creatinine clearance ≥ 50 ml/min).
Patients were required to have failed at least one prior platinum-based therapy but no more than two prior systemic therapeutic regimens (including biologics, targeted and immunotherapies). Pleural space washing with cisplatin was not considered systemic treatment. Neoadjuvant and/or adjuvant systemic therapy was not considered as a prior regimen if more than 12 weeks had elapsed between treatment and disease progression. Patients may have received prior surgery (e.g., pleurectomy) provided that at least 28 days had elapsed and all toxicities surgery had resolved. Patients must not have had any prior mTOR inhibitor therapy or central nervous system metastasis.
Patients were ineligible if they had severe systemic comorbid disease. Pregnant or breast-feeding patients were excluded. Patients who had prior pulmonary emboli could be on therapeutic low molecular heparin. However, patients on coumadin anticoagulation must have had an international normalized ratio (INR) of < 1.5 within 28 days prior to registration to the trial. Patients must not be on chronic, systemic immunosuppressive treatment; however, a stable regimen of topical or inhaled corticosteroids or corticosteroids given at doses equivalent to prednisone < 20 mg/day and given for a minimum of 4 weeks were allowed prior to the first dose of everolimus. The protocol and informed consent document were approved by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) and the institutional review boards of participating SWOG member sites. Written informed consent was obtained from all patients before enrollment.
Study Design and protocol treatment
The S0722 treatment protocol (ClinicalTrials.gov_identifier:NCT00770120) consisted of single-agent everolimus administered orally at 10 mg once daily until disease progression or unacceptable toxicity. Adverse events were graded according to the NCI CTC Version 3.0. Patients who experienced > grade 3 nonhematologic and/or grade 4 hematologic toxicities were allowed two sequential dose modifications to 5 mg once daily and 5 mg once every other day. Treatment was held until all toxicities resolved to < grade 1.
Patient history, physical examination, laboratory analyses were performed within 28 days before cycle 1 and on day 1 of each subsequent treatment cycle. Radiographic tumor measurements were performed after every two treatment cycles. Tumor responses were determined by RECIST 1.1 and modified RECIST.10 Patients were withdrawn from the study due to disease progression, unacceptable toxicity, treatment delay of >2 weeks for pneumonitis, treatment delay of >3 weeks for any other reason, or if >2 dose reductions were required.
Statistical considerations and statistical analysis
The primary objective of this study was 4-month progression-free survival (PFS) rate using RECIST 1.1.11 It was assumed that if the true 4-month PFS is ≤ 30%, everolimus would not warrant further investigation, while if the true 4-month PFS is ≥ 50% it will be of considerable interest. Using a two-stage design, initially 20 patients would be enrolled. If ≥ 5 of those 20 patients were alive and progression-free at 4 months, additional 35 patients would be enrolled. If 23 out of 55 patients were alive and progression-free at 4 months, everolimus would be considered as having potential activity in MPM. This design had 91% power to detect an increase from a 4-month PFS of 30% to 4-month PFS of 50% using a one-sided significance test of 4%. Secondary objectives included evaluating overall response rate (ORR) and overall survival (OS) using RECIST 1.1, and ORR and PFS using the modified RECIST for pleural tumors. PFS and OS estimates were calculated using the method of Kaplan-Meier. Confidence intervals for median PFS and median OS were constructed using the method of Brookmeyer-Crowley.12
RESULTS
Patients
The protocol was activated on December 1, 2008 and completed accrual on September 15, 2010. Sixty-one patients were enrolled. One patient was ineligible due to having an elevated baseline INR (> 1.5). Another patient refused treatment and is not evaluable for any of the study endpoints. The majority of the 59 evaluable patients were male, Caucasian, had epithelioid histology and multiple sites of metastases, with weight loss < 5%, and performance status of 1. An almost equal number of patients had received either one or two prior chemotherapy regimens (Table 1).
Table 1.
Clinicopathologic Characteristics of Advanced MPM Patients
| N (%) | |
|---|---|
| Median age (yrs) (range) | 67.0 (45.8–81.3) |
| Sex | |
| Male | 45 (76) |
| Female | 14 (24) |
| Race | |
| White | 55 (93) |
| Black | 1 (2) |
| Unknown | 3 (5) |
| Histology | |
| Epithelial | 36 (61) |
| Biphasic | 4 (7) |
| Sarcomatous | 0 (0) |
| NOS | 17 (29) |
| Not reported | 2 (3) |
| Prior systemic regimens | |
| 1 | 34 (58) |
| 2 | 25 (42) |
| Zubrod PS | |
| 0 | 13 (22) |
| 1 | 46 (78) |
| No. of metastatic sites | |
| None | 5 (8) |
| Single | 23 (39) |
| Multiple | 31 (53) |
| Weight loss past 6 months | |
| < 5% | 47 (80) |
| 5% – <10% | 6 (10) |
| 10% – 20% | 6 (10) |
| > 20% | 0 (0) |
NOS: not otherwise specified
Treatment
The median number of treatment cycles administered was 2 (range, 1–12), with 25% of patients receiving at least 4 cycles. During the first two cycles, 50% of the patients received at least 88% of the planned dose, with 18 patients (31%) receiving 100%.
Response and survival
Forty-five patients had measurable disease per RECIST 1.1. There was only one confirmed partial response (ORR=2%, 95% CI: 0%–12%) that lasted 7 months. Pleural thickness measurements were not performed so this patient could not be assessed for response by the modified RECIST criteria. An additional 24 of these 45 (53%) patients had stable disease by RECIST 1.1 for a disease control rate (DCR) of 55% (95% CI: 40%–70%). Of the 36 patients evaluable for response by the modified RECIST criteria, there were no responders and 20 patients had stable disease for a DCR of 56% (95% CI: 38%–72%). The 4-month PFS rate was 29% (95%CI: 17%–41%) by RECIST1.1 and 27% (95%CI: 16%–39%) by modified RECIST. A one-sided test of the null hypothesis of a 4-month PFS of 30% has a p-value of 0.59. The median PFS was 2.8 months (95%CI: 1.8–3.4 months) by both RECIST 1.1 (Figure 1A) and modified RECIST (95%CI: 1.8–3.5 months) (Figure 1A). The median overall survival was 6.3 months (95%CI: 4.8–8.0 months) (Figure 2). There was no difference in median PFS among patients who had received 1 or 2 prior regimens, p=0.74. The median OS of patients with epithelioid histology (6 months; 95%CI: 4.7–9.1) was not significantly different than in patients with non-epithelioid histologies (7.6 months; 95%CI: 3.4–8.1; p=0.47).
Figure 1.
A. Progression-free survival by RECIST 1.1
B. Progression-free survival by modified RECIST for pleural tumors
Figure 2.
Overall survival of the entire advanced MPM population.
Adverse events
One death due to dyspnea was deemed possibly related to the study drug by the treating investigator. Two other patients experienced grade 4 adverse events (dyspnea and lung infection respectively). Eleven patients discontinued treatment early due to adverse events. The three most common adverse events were fatigue (59%), hypertriglyceridemia (44%), and anemia (42%). The three most common grade 3–5 adverse events were fatigue (10%), anemia (7%), and lung infection (7%) (Table 2).
Table 2.
Number of Patients with Treatment-Related Adverse Events
| All (>15%) | ≥ Grade3 | |||
|---|---|---|---|---|
| Fatigue | 35 | 59.3% | 6 | 10.2% |
| Hypertriglyceridemia | 26 | 44.1% | 2 | 3.4% |
| Hemoglobin | 25 | 42.4% | 4 | 6.8% |
| Mucositis, clin: oral cavity | 20 | 33.9% | 2 | 3.4% |
| Anorexia | 19 | 32.2% | 1 | 1.7% |
| Nausea | 19 | 32.2% | 0 | 0% |
| Cholesterol | 17 | 28.8% | 0 | 0% |
| Hyperglycemia | 17 | 28.8% | 3 | 5.1% |
| Diarrhea | 15 | 25.4% | 1 | 1.7% |
| Platelets | 15 | 25.4% | 0 | 0% |
| Weight Loss | 13 | 22.0% | 0 | 0% |
| Rash | 11 | 18.6% | 1 | 1.7% |
| Dyspnea | 10 | 16.9% | 3 | 5.1% |
| Leukocytes | 10 | 16.9% | 0 | 0% |
| Mucositis, funct: oral cav. | 10 | 16.9% | 1 | 1.7% |
| Creatinine | 9 | 15.3% | 0 | 0% |
| Dehydration | 2 | 3.4% | ||
| Lung Infection | 4 | 6.8% | ||
| Lymphopenia | 2 | 3.4% | ||
| Muscle weakness: whole body | 2 | 3.4% | ||
| Pneumonitis | 2 | 3.4% | ||
| INR | 1 | 1.7% | ||
| Left vent. systolic dysfunct. | 1 | 1.7% | ||
DISCUSSION
In this phase II study in patient with advanced MPM, who failed at least 1 platinum-containing regimen. we reported a 4-month PFS rate of 29% with single agent everolimus which is less than the pre-specified 50% needed to recommend single-agent everolimus for further investigations in MPM. The ORR was 2% with everolimus and the median OS was 6.3 months for all the evaluable patients. The ORR, the 4-month PFS rate, and the media PFS were not different using RECIST 1.1 or modified RECIST criteria. The 4-month PFS rate of this trial was less than the target goal of 50% expected from first line treatment for advanced MPM as estimated by EORTC 14 indicating single-agent mTOR inhibition lacks sufficient clinical activity in advanced MPM to warrant further study.
Inactivation of the tumor suppressor gene (Merlin/NF2) is found in up to 40% of advanced mesothelioma 13 and can lead to the activation of the mTOR pathway and may serve as a sentivitiy biomarker to everolimus.14 We have not investigated the prevalence of inactivations of Merlin/NF2 in our patients’ sample but another trial (NCT01024946) with everolimus in advanced mesothelioma with Merlin/NF2 loss as a sensitivity biomarker has been completed and results are pending. Alternatively combination strategy inhibiting both PI3K and mTOR may prove to be more successful in treating mesothelioma. 15
Acknowledgments
SUPPORT: This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102, CA38926, CA105409, CA14028, CA13612, CA58723, CA35090, CA63848, CA45808, CA27057, CA45377, CA42777, CA67575, CA86780, CA11083, CA45807, CA35261, CA20319, CA76462, CA16385, CA77429, CA114047 and in part by Novartis Pharmaceuticals, Inc.
Footnotes
Results presented in part at the 48th Annual Meetings of the American Society of Clinical Oncology (June 1–5, 2012, Chicago, Illinois)
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