Votrient POIZEd to become a new option for maintenance therapy in advanced ovarian cancer
| Jun 1, 2013
Co-authored by Cory Blaiss, PhD, Analyst
Although first-line combination chemotherapy with a platinum (carboplatin or cisplatin) plus a taxane (primarily paclitaxel) is very successful at producing high response rates in first-line advanced ovarian cancer patients, the vast majority (up to 70%1) of these patients still experience a recurrence. Based on this high unmet need to extend progression free survival (PFS) in these first-line patients, maintenance therapy in now utilized in some advanced ovarian cancer patients. Maintenance therapy was initially introduced to ovarian cancer in the Phase III SWOG-9701/GOG-178 trial that found a significant PFS benefit of 12 cycles versus 3 cycles of paclitaxel in patients who had received a platinum-paclitaxel regimen as first-line therapy2,3. However, other trials evaluating maintenance chemotherapy in ovarian cancer have shown no benefit4, creating a controversy regarding whether maintenance chemotherapy is effective or not. Several years later, two Phase III studies evaluated the ability of anti-angiogenic agents to improve outcomes when used in the induction and maintenance settings. The GOG-0218 trial5 and the ICON7 trial6, evaluated the addition of Avastin® (bevacizumab, Genentech/Roche) to standard first-line carboplatin-paclitaxel combination chemotherapy along with continued Avastin maintenance therapy compared to carboplatin-paclitaxel chemotherapy alone with no maintenance therapy. Both trials found a significant PFS benefit with Avastin as first-line induction therapy and maintenance therapy, although interim analyses to-date have failed to show an overall survival (OS) benefit.
Although the concept of maintenance therapy in ovarian cancer has now been present for several years, it has not yet been adopted uniformly into practice. According to data from Kantar Health’s CancerMPact® Treatment Architecture, 20137, approximately 75% of patients in the United States and Western Europe who receive Avastin-based induction regimens as first-line therapy (which is approximately 20% of patients) also receive maintenance therapy; the high use of maintenance Avastin in these patients is supported by data from the GOG-0218 trial that showed no PFS or OS benefit if Avastin was given as part of induction only5. In contrast, in patients who receive a non-Avastin-containing induction regimen as first-line therapy (approximately 80% of patients), maintenance therapy is less common, with only 45-55% of those patients currently receiving any maintenance therapy. This leaves a great deal of room in the market for new, efficacious agents in the maintenance setting.
In addition to Avastin, a number of other anti-angiogenic agents have entered development for ovarian cancer, and Votrient ® (pazopanib, GlaxoSmithKline) has entered the ring specifically in the maintenance setting. Votrient is a broad spectrum tyrosine kinase inhibitor that is currently approved in the U.S. and the European Union for use in renal cell carcinoma and soft tissue sarcoma. Like Avastin, it has activity against VEGF receptors, and it also has activity against PDGF receptors and c-kit. In 2009, the Phase III international Intergroup AGO-OVAR16 trial (NCT00866697, also known as the POIZE trial) was initiated to evaluate Votrient as maintenance therapy in patients with advanced ovarian cancer. A total of 940 patients who had not progressed after at least 5 cycles of chemotherapy with a platinum-taxane combination were randomized 1:1 to receive either placebo or maintenance therapy with single agent Votrient (800 mg QD) for up to two years. The primary endpoint of the trial was PFS, and secondary endpoints included OS, 3-year PFS, quality of life measurements, and safety/tolerability.
Results of the trial were presented on June 1at the 2013 American Society of Clinical Oncology (ASCO) annual meeting1, and the trial met its primary endpoint, with Votrient maintenance significantly extending median PFS by 5.6 months compared to placebo (mPFS: 17.9 months versus 12.3 months, HR: 0.766, p<0.0021, see Table 1). However, although mature OS results are not yet available, an interim analysis (with events from only 20.1% of patients available) did not find any survival benefit of the Votrient arm compared to the placebo arm (medians not yet reached in either arm, HR: 0.994). With the current immature OS data, the Kaplan-Meier survival curves appear to be completely overlapping.
Adverse events observed in the Votrient arm were in line with the known safety profile of Votrient from other tumors; the most frequently reported Grade 3/4 adverse events were hypertension, neutropenia, liver-related toxicity and diarrhea (see Table 1). As would be expected, there was a higher incidence of adverse events in the Votrient arm compared to placebo, and patients in the Votrient arm had a higher rate of dose reduction (58% versus 14%). In addition, patients had a shorter mean exposure to Votrient compared to placebo (8.9 months versus 11.7 months).
If the mature OS data from the AVO-OVAR16 trial continue to be non-significant, Votrient is likely to experience the same regulatory fate in ovarian cancer as Avastin. As mentioned earlier, the Phase III trials evaluating Avastin as first-line induction and maintenance therapy found a significant PFS benefit, but not an OS benefit. Based on these results, Avastin was approved by the European Medicines Agency (EMA) in late 2011 for use in first-line induction and maintenance therapy for advanced ovarian cancer. However, without an OS benefit, Roche has not filed for approval in the U.S., strongly suggesting that the FDA has provided guidance that PFS without OS is not approvable. Similarly, if mature OS data for the AVO-OVAR16 trial continue to show no OS benefit for Votrient, it is unlikely to be approved as maintenance therapy by the FDA, even with the significant PFS benefit. However, as with Avastin, it is likely that this PFS benefit alone will support approval of Votrient by the EMA. Even if it does not receive an FDA approval, however, Votrient (again, like Avastin) is approved in other indications in the United States, and it could still see off-label U.S. utilization, especially if it receives an NCCN recommendation. Notably, however, the NCCN has given Avastin a Category 3 recommendation for use in first-line, which suggests substantial disagreement among panel members as to the clinical benefit provided by Avastin. With similar level of benefit for Votrient (discussed below), Votrient is likely to receive a similar low-level recommendation.
Aside from the question of regulatory approval, there is also the question of potential adoption of Votrient in the maintenance setting. Due to different Phase III trial designs, any use of maintenance Votrient is most likely to be restricted to a separate patient population from maintenance Avastin, which is largely limited to patients who receive Avastin-based induction regimens7. In contrast, patients in the AVO-OVAR16 trial who received maintenance Votrient received non-Avastin-containing induction regimens (a platinum-taxane combination), and Votrient is most likely to be used in (and any regulatory approval would be limited to) this patient population. With the majority of patients in the U.S. and Europe currently receiving non-Avastin first-line regimens, this leaves a great deal of room in the market for Votrient to establish itself as a standard choice for maintenance therapy in this patient population.
As can be seen in Table 2, cross trial comparisons suggest that the PFS benefit of maintenance Votrient is roughly comparable to both Avastin induction/maintenance as well as 12-months paclitaxel maintenance; although the magnitude of PFS benefit at the median is greater with Votrient compared to that achieved with Avastin in its two studies (5.6 months compared with 2.4-2.9 months), the Hazard Ratio is similar in across these three studies. Without stand-out efficacy results, Votrient will need to differentiate itself in other ways. As anti-angiogenic agents, both Avastin and Votrient have overlapping toxicity profiles, but there are some distinctions; in ovarian cancer trials, Votrient has shown a higher incidence of hypertension, while Avastin has shown a higher rate of gastrointestinal perforations (see Table 3). Both Avastin and Votrient also have a different toxicity profile from paclitaxel, which can cause sensory neuropathy in patients. Other factors are also likely to affect adoption rates. Quality of life data has yet to be reported for the AVO-OVAR16 trial, but could be a significant factor in willingness to prescribe. Convenience of administration may also play a role ― Votrient is an oral agent while Avastin and standard chemotherapy are administered intravenously, and the prolonged administration of maintenance therapy could favor an oral. Cost will also be a significant factor ― one year of low-dose Avastin maintenance costs approximately $40,000 whereas two years of Votrient maintenance will cost approximately $171,000. This high price tag is sure to hinder use in both the U.S. and the more cost-sensitive European market.
- duBois et al., ASCO 2013, Abstract LBA5503.
- Markman et al., JCO, 21(13): 2460-2465, 2003.
- Markman, ASCO 2006, Abstract 5005.
- Pecorelli et al., JCO 27(28): 4642-4648, 2009.
- Burger et al., NEJM, 2011.
- Perren et al., NEJM, 2011.
- Kantar Health, CancerMPact® Treatment Architecture U.S. and Western Europe, accessed June 1, 2013.