In recent years, angiogenesis inhibition, and VEGFR inhibition in particular, has been the most promising therapeutic target in advanced ovarian cancer, and the VEGF-targeted monoclonal antibody Avastin® (bevacizumab, Roche/Genentech) has been the major player in drug development for this tumor type. With Phase III trials conducted in multiple settings in ovarian cancer, Avastin has demonstrated a progression-free survival (PFS) benefit in first-line1,2,3, recurrent platinum-sensitive4, and recurrent platinum-resistant5,6 patients, and in the past two years, it has received regulatory approval in the European Union for use in the first-line/maintenance and recurrent platinum-sensitive settings. Other small molecule VEGFR inhibitors have followed Avastin into late stage development in ovarian cancer; Votrient® (pazopanib, GlaxoSmithKline) and cediranib (AstraZeneca, development discontinued) have demonstrated positive results in Phase III trials in the first-line maintenance and recurrent platinum-sensitive settings, respectively7, and an ongoing Phase III trial is evaluating Vargatef™ (nintedanib, Boehringer Ingelheim) as first-line/maintenance therapy.
Trebananib (Amgen) is a first-in-class agent that inhibits angiogenesis through a different pathway: the angiopoietin axis. Trebananib, a recombinant peptide-Fc fusion protein (peptibody), prevents the interaction of ligands angiopoietin 1 and 2 (Ang1 and Ang2) with the Tie2 receptor, thereby inhibiting a signaling pathway that is normally involved in vascular growth, remodeling, and stabilization. Amgen has initiated a comprehensive Phase III development program for trebananib in ovarian cancer, with the TRINOVA-1 and TRINOVA-2 trials in recurrent patients with platinum-resistant or partially platinum-sensitive disease and the TRINOVA-3 trial in the first-line/maintenance setting.
The results of the TRINOVA-1 trial were presented on Tuesday, October 1 at the 2013 European Cancer Congress (ECC)8. This double-blind Phase III trial (NCT01204749) randomized 919 recurrent patients with advanced ovarian, primary peritoneal, or fallopian tube cancer to receive weekly paclitaxel (80 mg/mg2) plus placebo or trebananib (15 mg/kg). Patients could have received up to 3 prior regimens and must have had a platinum-free interval (PFI) of less than 12 months after their most recent line of therapy; about half of patients in each arm had a PFI of less than 6 months, a threshold which is often used to define platinum resistance. The primary endpoint of the trial was PFS, and secondary endpoints included OS, ORR (using RECIST criteria), CA-125 response rate, and quality of life (FACT-O, OCS, and EQ-5D measurements).
The trial met its primary endpoint, with the addition of trebananib to paclitaxel significantly increasing PFS (see Table 1, mPFS: 7.2 vs. 5.4 months, HR: 0.66, p<0.001), and this benefit was consistent across multiple subgroups, including patients with a PFI less than 6 months as well as those with a PFI between 6 and 12 months. Patients with prior anti-angiogenic therapy (e.g. Avastin) were allowed in the study, but due to the large degree of variability in the PFS results for those patients (HR: 0.69, with 95% CI of 0.41 – 1.17), the efficacy results in that subgroup are inconclusive based on the data presented. In addition to PFS, the overall response rate was also improved in patients who received trebananib plus paclitaxel (38.4% vs. 29.8%, p<0.0071). However, although there was a slight numerical improvement, an interim analysis did not find a statistically survival benefit of adding trebananib to paclitaxel (mOS: 19.0 vs. 17.3 months, HR: 0.86, p=0.19); mature survival data are expected in 2014. Interestingly, the dose of trebananib used in TRINOVA-1 (15 mg/kg) was increased from the highest Phase II dose (10 mg/kg) in the hopes of improving drug efficacy. An analysis of the Phase II data found a trend toward an increased PFS in patients with a higher drug exposure (AUC of at least 9.6 mg*h/mL) that was not routinely reached in patients who received the 10 mg/kg dose9.
The toxicity profile of the trebananib and paclitaxel combination was manageable, and the addition of trebananib barely increased the incidence of Grade 3+ adverse events (56%) compared to paclitaxel alone (54%). Adverse events (of all grades) that were increased in the paclitaxel plus trebananib arm included localized edema (57% vs. 26%), peripheral neuropathy (21% vs. 16%, thought by the presenter to be related to increased paclitaxel exposure), ascites (20% vs. 12%), pleural effusion (13% vs. 4%), upper abdominal pain (12% vs. 7%), and generalized edema (11% vs. 3%). There was little to no increase in the incidence of typical VEGFR inhibition-related adverse events, such as hypertension (6% vs. 4%), proteinuria (3% in both arms), arterial thrombotic events (<1% in both arms), impaired wound healing (<1% in both arms), and GI perforation/fistula (1% vs. <1%), in the paclitaxel plus trebananib arm compared to pacliltaxel alone.
Considering these data, what will be trebananib’s regulatory and commercial fate? This question is best viewed through the prism of Avastin’s experience. To date, all Phase III trials evaluating Avastin in ovarian cancer have shown a significant PFS benefit, but no OS benefit. Based on these data, Avastin has been approved by the European Medicines Agency (EMA) for use in the first-line/maintenance setting as well as the recurrent platinum-sensitive setting; however, Roche has not yet filed for approved in Europe in the recurrent platinum-resistant setting. In contrast, Roche has not filed for approval in the U.S. in any setting in ovarian cancer, strongly suggesting that the FDA has provided guidance that a PFS benefit without an OS benefit would not be approvable. If trebananib’s experience with the European and U.S. regulatory agencies reflects that of Avastin, then it will likely be approved by the EMA with only the current PFS benefit, but if the mature OS data do not show a significant survival benefit, then it is unlikely to be approved by the U.S. Federal Drug Administration (FDA). However, it is possible that the high unmet need in platinum-resistant patients and the reasonable toxicity profile of trebananib might sway U.S. regulators in favor of the drug.
If approved, how will trebananib fare against Avastin, which will be its primary competitor in the recurrent setting? Based on the fact that the TRINOVA-1 trial include recurrent patients who were platinum-resistant as well as those who were partially platinum-sensitive, the patient population in this trial is not directly comparable to either the AURELIA or OCEANS trials of Avastin in recurrent platinum-resistant and platinum-sensitive patients, respectively. In general, however, the 1.8 month PFS benefit seen in the TRINOVA trial is somewhat smaller than the 3.3 month and 4.0 month PFS benefits observed in the AURELIA and OCEANS trials, respectively (see Table 2). Therefore, it is unlikely that physicians would routinely prefer trebananib over Avastin.
Due to their different mechanisms of action, however, Avastin and trebananib do have very distinct safety profiles, and this distinction could easily lead to the two agents being used in slightly different patient populations. Avastin administration generally results in typical VEGFR-related toxicities such as hypertension, proteinuria, and in rare cases, GI perforation and bleeding. In contrast, trebananib does not cause these VEGFR-related side effects, but does increase the incidence of edema, ascites, and pleural effusions. These side effect profiles, combined with recent data presented at the 2013 ECC suggest that first-line Avastin is more effective in higher-risk patients3, and also suggest that Avastin will be more likely to be utilized in high risk or highly symptomatic patients who already have baseline ascites and other similar symptoms. In contrast, trebananib might be more likely to be used in patients with co-morbidities that increase the risk of serious side effects from Avastin, such as a history of cardiovascular disease.
The data from the TRINOVA-1 trial also raise several additional questions about the use of these two agents. For example, how should these agents be sequenced? In patients who receive Avastin in the first-line setting, re-treatment with Avastin is unlikely, and that may be the primary opportunity for trebananib. Considering the non-overlapping safety profiles, another major outstanding question is whether trebananib and Avastin (or other VEGFR-targeted agents) should be used in combination. Although these questions will not be answered conclusively anytime soon, the results of the ongoing TRINOVA-2 and TRINOVA-3 trials of trebananib should become available within the next few years, and these results should provide a better understanding of how trebananib will best fit into the treatment paradigm for ovarian cancer.
By: Stephanie Hawthorne, PhD, Director, Clinical and Scientific Assessment, Kantar Health and Cory Blaiss, Analyst, Clinical and Scientific Assessment, Kantar Health
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