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Breast Cancer Confirmatory Studies Arrive Amid End Point Controversy The controversy is complicated by the seemingly unclear or even contradictory stance by the FDA about what it considers a “gold standard” study end point for FDA approval; however, the role of conditional or provisional accelerated ap proval, as opposed to full approval, must be put in perspective. Introduced in 1992, the accelerated approval process was originated so the FDA could grant marketing authorization, or provisional approval based on surrogate end points such as PFS, conditional on additional studies to further define clinical benefit, for agents that fulfill unmet medical needs, such as for HIV/AIDS and cancer. This process provides for more rapid access of these medications to populations with few treatment options, but does not guarantee a conversion to full approval after further studies are complete. An agent that was available, therefore, could be later taken off the market when its approval is rescinded, such as the case with the antileukemia agent gemtuzumab ozogamicin.4 For bevacizumab, not only was full approval not granted, but also withdrawal of approval was determined. This decision was based on 2 factors: an unclear clinical benefit when evaluating the end point of PFS compared with OS; and concern about the benefit-to-risk ratio. These evaluations were based on the release of 2 manufacturersponsored confirmatory trials: Avastin and Docetaxel (AVADO) and Regimens in Bevacizumab for Breast Oncology (RIBBON)-1. The randomized, double-blind, phase 3 AVADO study evaluated the use of bevacizumab in patients with HER2negative breast cancer who were treatment-naïve for metastatic disease.5 A total of 736 patients were enrolled into 1 of 3 treatment arms: docetaxel (100 mg/m2 every 3 weeks) plus placebo every 3 weeks; docetaxel plus 7.5 mg/kg bevacizumab every 3 weeks; or docetaxel plus 15 mg/kg bevacizumab every 3 weeks. Entry criteria were similar to the E2100 trial. Unlike the E2100 trial, however, patients whose disease progressed were given the option to receive bevacizumab in combination with second-line chemotherapy; approximately 34% of the docetaxel-alone group received bevacizumab after progression. There was significant improvement in PFS in the docetaxel plus bevacizumab 15-mg/kg arm (8.1 months vs 10.1 months; HR, 0.77; P = .006), although the PFS was nonsignificant in the docetaxel plus bevacizumab 7.5-mg/kg arm (9.0 months vs 8.1 months; HR, 0.86, P = .12). OS was not statistically different among treatment groups: 31.9 months in the docetaxel plus placebo group; 30.8 months in the docetaxel
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plus bevacizumab 7.5-mg/kg group; and 30.2 months in the docetaxel plus bevacizumab 15-mg/kg group. Similar to the E2100 trial, more patients in the bevacizumab arms experienced grade 3 and 4 toxicity, especially neutropenia, febrile neutropenia, and hypertension (Table 2).
The controversy is complicated by the seemingly unclear or even contradictory stance by the FDA about what it considers a “gold standard” study end point for FDA approval.
The second trial, RIBBON-1, was an international, phase 3, multicenter, placebo-controlled study in treatmentnaïve patients.6 Before enrollment, the investigators selected the chemotherapy regimen of either capecitabine, or taxane/anthracycline. Patients then were randomized 2:1 to bevacizumab or placebo. The bevacizumab dose was 15 mg/kg every 3 weeks. Patients in this trial were permitted to receive open-label bevacizumab 5 mg/kg per week as secondline therapy after progressive disease. The RIBBON-1 trial used the same primary and secondary end points as the E2100, along with similar schedules and criteria to assess patients. RIBBON-1 enrolled a total of 1237 patients, 615 in the capecitabine arm and 622 in the taxane/anthracycline arm. The PFS was 5.7 months in the capecitabine plus placebo arm and 8.6 months in the capecitabine plus bevacizumab arm (HR, 0.69; P <.001). In the taxane/anthracycline plus placebo arm, median PFS was 8 months compared with 9.2 months in the bevacizumab group (HR, 0.64; P <.001). When evaluating a planned subset of taxane versus taxane plus bevacizumab, the PFS was 8.2 months compared with 9.2 months, respectively; the PFS of anthracycline versus anthracycline plus bevacizumab was also significant, 7.9 months compared with 9.2, respectively (HR, 0.55; P <.001). Again, the OS was not statistically significant among groups. In the capecitabine group, the HR for OS was 0.85 (P = .27), whereas in the taxane/ anthracycline cohort, the HR for OS was 1.03 (P = .83). Of note, after progression, 54.4% of the capecitabinealone patients and 50.7% of the taxane/anthracycline patients received open-label bevacizumab. Similar to AVADO and E2100, grade
3 and 4 adverse events in the RIBBON1 trial were significantly higher in the bevacizumab arms. Hypertension and proteinuria were increased with bevacizumab. There were more treatment discontinuations resulting from adverse effects in the bevacizumab arm. Deaths related to treatment were similar among groups. Both RIBBON-1 and AVADO did not appear to confirm the impressive 5.5-month median PFS increase seen in E2100 and confirmed a lack of OS benefit. In July 2010, therefore, ODAC met to consider these 2 trial results to recommend to the FDA either the conversion to full approval or withdrawal of approval. The committee voted 12:1 to recommend that the FDA remove the indication for metastatic breast cancer from the label, citing that the data demonstrated that PFS did not appear to act as a surrogate for OS and, therefore, a lack of favorable risk-to-benefit profile. Approval Review Following an extended review period by the FDA, which heightened expectations and resulted in emotionally charged media coverage of the impending decision, the FDA announced its plan to withdraw approval in December 2010. However, the manufacturer soon appealed by filing an opposition petition to request an administrative hearing open to the public. The focus of the appeal was mainly contingent upon the increase in PFS shown in the E2100 trial, although that trial had been criticized for being open label, making quality-of-life data less meaningful.7 Also, they argued E2100, RIBBON-1, and AVADO used PFS as the primary end point based on the assumption that the
FDA accepted this end point for approval and, therefore, the trials may have been underpowered to address OS. Furthermore, PFS may be considered an important end point for patients, because it may delay symptoms and improve quality of life. In addition, in metastatic colorectal cancer, PFS is considered a valid end point for drug approval. Additional points outlined in the appeal were that the large difference observed in PFS in the E2100 trial was not replicated in subsequent trials because of the lower dose intensity of docetaxel compared with the E2100 paclitaxel trial, which resulted from increased toxicity of docetaxel, and that there is a potentially synergistic effect between paclitaxel and bevacizumab that may not occur with other combinations. There are no data to substantiate these claims, however. The confusion by the public over the seeming back and forth on bevacizumab’s efficacy is certainly understandable when many experts, organizations, and agencies—not just the FDA and ODAC—remain divided on many issues. Other agents for metastatic cancers have been FDA-approved on the basis of a median PFS increase alone. Indeed, bevacizumab remains approved for breast cancer in several European countries and remains on the list of preferred regimens (with paclitaxel) for HER2-negative breast cancer by the National Comprehensive Cancer Network (NCCN) 2011 breast cancer guidelines, albeit with a statement that it does not increase OS.8 Additional debate also concerns whether OS is measurable in future metastatic breast cancer trials. This is especially challenging, because patients
Table 2 Serious Adverse Events (Grade 3-5) with Bevacizumab Total Control Group, %
Total Bevacizumab Group, %
Number of patients
980
1681
Fatal adverse events
1.5
1.1
Hypertension
0.7
8.8
Thrombosis Sensory neuropathy
3 7.8
3.4 7.1
Neutropenia
5.3
7.9
Proteinuria
0
3.4
Left ventricular dysfunction
0.7
1.8
Bleeding events Febrile neutropenia Gastrointestinal perforation
0.3 3.4 0.3
1.2 6.3 0.5
Total serious adverse events
27.6
43.8
Data compiled from: Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666-2676; Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2negative metastatic breast cancer. J Clin Oncol. 2010;28:3239-3247; Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29:1252-1260.
OCTOber 2011 I VOL 4, NO 7
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