Combining Angiogenesis Inhibition with Chemotherapy in Malignant Pleural Mesothelioma

Educational Objectives

The goals of this program are to improve diagnosis and treatment of mesothelioma. After hearing and assimilating this program, the clinician will be better able to:

1. Counsel a patient with mesothelioma about the risks and benefits of antiangiogenic agents.
2. Summarize current knowledge about biomarkers in patients with mesothelioma.

Summary

Previous clinical trials: 2 recent trials of antiangiogenic therapies reported positive findings; studies by Byrne and Vogelzang led to adoption of cisplatin and pemetrexed as standard treatment

Vascular endothelial growth factor (VEGF): mesothelioma expresses VEGF-A, VEGF-C, and VEGF receptor (VEGF-R); high concentration of VEGF in tissue, serum, or pleural fluid may be predictive of poor prognosis

Antiangiogenic agents: benefits — normalization of disordered, chaotic vessels; decrease in vascular permeability; reduction in pressure of interstitial fluid allows drugs to permeate tumor; may reduce shedding of cancer cells, invasiveness, and metastasis; tumor may become more susceptible to radio- and chemotherapy; risks — when vasculature normalizes, excessive pruning of vascular supply may lead to necrosis and cell death

Agents: bevacizumab targets VEGF-A; others include nintedanib and other tyrosine kinase inhibitors (TKIs); BNC105P not effective in trials; peptide inhibitors include endostatin; metronomic (low-dose, continuous) chemotherapy targets endothelial cells and angiogenesis; most studies have employed single agents in single-arm trials, sometimes combined with pemetrexed or cisplatin; few drugs studied in randomized trials, because most monotherapies unsuccessful; rate of response often <10%

Tyrosine kinase inhibitors: affect dimerization of VEGF-R, platelet-­derived growth factor (PDGF), its receptor (PDGF-R), and fibroblast growth factor receptor (FGF-R)

Bevacizumab: in one study, rate of response to pemetrexed, carboplatin, and bevacizumab 34%; another study reported rate of response of 40% to pemetrexed, cisplatin, and bevacizumab; although rates of partial response no better with addition of bevacizumab, one study reported longer median survival; first randomized trial of cisplatin, gemcitabine, and bevacizumab found that adding bevacizumab provided no benefit; in MAPS, patients treated with cisplatin and pemetrexed, then observed or treated with bevacizumab; lack of placebo control could have biased assessments of progression and response; difference between arms small (hazard ratio [HR] 0.77) but significant; study included >400 patients, but because only 15 remained at completion of trial, data should be interpreted with caution; HR for progression-free survival (PFS) 0.61; some patients did not progress for 20 mo

LUME-Meso study: nintedanib targets VEGF-R, PDGF-R, FGF-R, Src, and Abl; safety manageable; 87 patients receiving chemotherapy for unresectable epithelioid or biphasic mesothelioma randomized to nintedanib vs placebo; median PFS 9.4 mo in nintedanib arm and 5.7 mo in placebo arm (HR 0.54); difference in overall survival (OS) not statistically significant (18.3 vs 14.2 mo [HR 0.77]), but study not powered to measure OS

Patient selection: antiangiogenic agents used off label for mesothelioma; use of nintedanib premature; contraindications to antiangiogenic therapy include poor performance status, full anticoagulation, cardiac comorbidity, uncontrolled hypertension, recent or planned major surgery, open wound, risk for gastrointestinal (GI) perforation, or active disease in upper GI tract

Planning treatment: insufficient information available to choose patients based on histology; although reports suggest that bevacizumab more effective for sarcomatoid tumors, while nintedanib better for epithelioid tumors, these observations based on few patients; information about combinations of bevacizumab with carboplatin and pemetrexed lacking; patients with peritoneal mesothelioma who undergo aggressive surgeries at risk for GI perforation

Biomarkers: unlikely to be helpful when selecting patients for treatment with bevacizumab; studies report conflicting results; prognostic value of single-nucleotide polymorphisms (SNPs) in VEGF inconclusive; results from several studies showing changes in biomarkers after treatment could not be confirmed; testing of many biomarkers may have led to false-positive results

Studies on biomarkers: NVALT 5 — study of thalidomide reported better outcomes in patients with increases in IL-6 and nonepithelioid tumors; NGR015 — showed that shorter treatment-free interval may be best for patients with aggressive disease; MAPS — on­going study assessing levels of serum VEGF in patients treated with cisplatin, gemcitabine, and bevacizumab; Kindler et al — among patients treated with gemcitabine and cisplatin, those with lower levels of circulating VEGF-A more likely to benefit from treatment with bevacizumab; lower levels may allow bevacizumab to saturate VEGF-A; LUME-Meso — panel of 58 putative angiogenic factors and SNPs studied in patients with epithelioid tumors; angiogenic factors available for 71 patients, and genomic data available for 67 patients; weak associations discovered for plasma endoglin and 3 SNPs of VEGF; these markers to be evaluated in phase 3 study

Future of antiangiogenic therapy: neither antiangiogenic agents nor TKIs alone likely to prevent angiogenesis; combining these agents may be more effective; role for maintenance with bevacizumab or nintedanib should be explored; number of patients available to study limited, so investigators should consider information gained through treatment of other types of cancers and be selective when planning clinical trials

Ongoing trials: NEMO — nintedanib may have antitumor and antiangiogenic effects; in double-blinded trial, patients who complete chemotherapy randomized to maintenance with nintedanib vs placebo; Karmanos Cancer Institute — evaluating nintedanib in recurrent malignant pleural mesothelioma; Southwest Oncology Group — evaluating pemetrexed and cisplatin with or without cediranib; early results similar to those reported in trials of bevacizumab and nintedanib; LUME-Meso — phase 3 trial similar to phase 2 trial; although study limited to epithelioid tumors, patients with sarcomatoid and biphasic tumors may benefit

Summary: bevacizumab not likely to be approved for mesothelioma because MAPS not regulatory trial; if trials of TKIs positive, further comparisons with antiangiogenic agents unlikely; oral agents have low toxicity; future studies should evaluate combinations of antiangiogenic and immune therapies

Readings

Buikhuisen WA et al: Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomised phase 3 study. Lancet Oncol 2013 May;14(6):543-51; Ceresoli GL et al: Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma. Br J Cancer 2013 Aug 6;109(3):552-8; ClinicalTrials.gov: Nintedanib as switch maintenance treatment of pleural malignant mesothelioma (NEMO). Available at: https://clinicaltrials.gov/ct2/show/NCT02863055. Accessed January 15, 2018; ClinicalTrials.gov: Pemetrexed disodium and cisplatin with or without cediranib maleate in treating patients with malignant pleural mesothelioma. Available at: https://clinicaltrials.gov/ct2/show/NCT01064648. Accessed January 15, 2018; Gaafar et al: Phase III trial (NGR015) with NCR-hTNF plus best investigator choice (BIC) versus placebo plus BIC in previously treated patients with advanced malignant pleural mesothelioma (MPM) [abstract]. May 30, 2015. Available at: https://meetinglibrary.asco.org/record/109653/abstract. Accessed January 15, 2018; Grosso F et al: Nintedanib plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma: phase II results from the randomized, placebo-controlled LUME-Meso trial. J Clin Oncol 2017 Nov 1;35(31):3591-600; Kindler HL et al: Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma. J Clin Oncol 2012 Jul 10;30(20):2509-15; 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 2016 Apr 2;387(10026):1405-1414. Erratum in: Lancet 2016 Apr 2;387(10026):e24.

Disclosures

For this program, the following has been disclosed: Dr. Nowak has received funding from Boehringer Ingelheim GbmH and is on the advisory board for Hoffmann-La Roche. The planning committee reported nothing to disclose. In her lecture, Dr. Nowak presents information that is related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Nowak was recorded at the 7th International Symposium on Malignant Pleural Mesothelioma, presented by the David Geffen School of Medicine of the University of California, Los Angeles, and held September 30, 2017, in Los Angeles, CA. To learn about CME opportunities from the University of California, Los Angeles, please visit cme.ucla.edu. The Audio Digest Foundation thanks the speakers and the University of California at Los Angeles for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

ON090602

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.