Angiogenesis Inhibitor Tested in Mesothelioma Trial

Nicholas J. Vogelzang, MD

Nintedanib, an angiogenesis inhibitor, is being investigated as a first-line treatment for patients with unresectable malignant pleural mesothelioma (MPM). Although it is estimated that malignant mesothelioma represents less than 1% of all cancers, it is a fatal asbestos-associated malignancy¹ , and patients with MPM tend to be difficult to treat.

The drug, which targets multiple receptors including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF), is being administered in combination with pemetrexed and cisplatin in the phase III, multicenter, international LUME-Meso clinical trial (NCT01907100).

“The current median survival of epithelioid MPM is about 15 months for most patients. Other trials have shown an improvement in overall survival, perhaps partially due to improved supportive care and secondary therapy,” said Nicholas J. Vogelzang, MD, a medical oncologist at the Comprehensive Cancer Centers of Nevada, the medical director for the Genitourinary Research Committee through US Oncology Research, and the vice chair of SWOG, a clinical trials network.

Vogelzang, who is the primary investigator for LUME-Meso in the United States, noted that there are no secondary therapies approved by regulatory agencies to treat patients with epithelioid MPM.

Currently, the only approved treatment regimen is combined pemetrexed and cisplatin; however, the prior MAPS study showed that the addition bevacizumab (Avastin), an anti-VEGF monoclonal antibody, improved survival in patients with MPM² , which prompted investigators to look into other combination treatments with VEGF-inhibitors.

For the LUME-Meso trial, which is currently enrolling, eligible patients must have epithelioid subtype MPM; patients with biphasic or sarcomatoid subtype will be excluded. Participants in the trial will be randomized in a 1:1 ratio to receive either oral nintedanib twice daily at 200 mg per dose combined with intravenous pemetrexed and cisplatin, or pemetrexed and cisplatin with a placebo, followed by maintenance therapy (Figure). Notably, patients will also receive vitamin supplements, including daily oral folic acid and vitamin B-12 given every 8 to 9 weeks.

Figure. Nintedanib in Malignant Pleural Mesothelioma

The FDA has approved nintedanib under the trade name Ofev for the treatment of idiopathic pulmonary fibrosis. As a small-molecule, nintedanib binds competitively to the ATP binding pocket of the VEGF and PDGF receptors, blocking intracellular signaling needed for the proliferation, migration, and transformation of fibroblasts that are essential to the growth of MPM. It also inhibits the Lck, Lyn, and Src nonreceptor tyrosine kinases.³

Data from the phase II LUME-Meso trial demonstrated improved PFS with nintedanib therapy in patients with MPM. For the overall population, the median progression-free survival (PFS) was 9.4 months with the nintedanib combination versus 5.7 months with pemetrexed and cisplatin alone (HR, 0.54; 95% CI, 0.33-0.87; P = .010). The median overall survival (OS) was 18.3 months with nintedanib versus 14.2 months with chemotherapy alone; however, this finding was not statistically significant (HR, 0.77; 95% CI, 0.46-1.29; P = .319).4 The objective response rate was 57% with nintedanib and 44% with chemotherapy (odds ratio, 1.66; 95% CI, 0.72-3.92).

A greater benefit was observed in patients with epithelioid histology, the target population of the phase III study. Among these patients, the median OS was 20.6 months with nintedanib versus 15.2 months with chemotherapy (HR, 0.70; 95% CI, 0.40-1.21; P = .197). The median PFS was 9.7 months with nintedanib versus 5.7 months with chemotherapy (HR, 0.49; 95%CI, 0.30-0.82; P = .006).⁴

In terms of adverse events (AEs), nintedanib has a profile similar to that of other VEGF inhibitors. In the phase II study, the most common grade ≥3 AEs were neutropenia, increased gamma-glutamyl transferase, increased alanine aminotransferase, and electrolyte imbalance. Febrile neutropenia was experienced by 2.3% of patients in the nintedanib arm versus none of those in the placebo group.⁴

There are also some risks of bleeding, gastrointestinal toxicities such as diarrhea and bowel perforation, and thrombosis. However, these AEs are familiar to those who have used other VEGF inhibitors. “I don’t think there’s a single medical oncologist who has not used sunitinib, sorafenib, axitinib, this cluster of drugs. Nintedanib is expected to be similar,” Vogelzang commented. Standard dosereduction criteria and the time off the drug, if needed, are built into LUME-Meso’s trial design.

Should this trial be successful, nintedanib could secure a new indication, because it is a registrational trial for the FDA and the European Medicines Agency. It also could be tested n other tumor types, particularly in non—small cell lung cancer. Nintedanib is being developed by Boehringer Ingelheim, which is also sponsoring the trial.

References

1. Moore AJ, Parker RJ, Wiggins J. Malignant mesothelioma. Orphanet J Rare Dis. 2008;3:34. doi: 10.1186/1750-1172-3-34.
2. Zalcman G, Mazieres J, Margery J, et al; French Cooperative Thoracic Intergroup (IFCT). Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial [published correction in Lancet 2016;387(10026):e24). Lancet. 2016;387(10026):1405-1414. doi: 10.1016/S0140-6736(15)01238-6.
3. Ofev [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2017.
4. Nowak AK, Grosso F, Steele N, et al. Mature overall survival (OS) results from the LUME-Meso study of nintedanib (N) + pemetrexed/cisplatin (PEM/CIS) vs placebo (P) + PEM/CIS in chemo-naïve patients (pts) with malignant pleural mesothelioma (MPM) [ASCO abstract 8506]. J Clin Oncol. 2017;35(suppl). http://meetinglibrary.asco.org/ record/153088/abstract.