Date: 2014-11-14
Type of information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at the 4th Quadrennial Meeting of the World Federation of Neuro-Oncology
Company: Celldex Therapeutics (USA - NJ)
Product: rindopepimut
Action
mechanism: Rindopepimut (Rintega®) is an investigational immunotherapy that targets the tumor specific oncogene EGFRvIII (v3), a functional and permanently activated variant of the epidermal growth factor receptor (EGFR). Expression of EGFRvIII correlates with increased tumorigenicity in mouse models and poor long term survival in clinical studies of patients with glioblastoma. In addition, EGFRvIII-positive cells are believed to stimulate proliferation of non-EGFRvIII cells through IL-6 cell-to-cell signaling and to release microvesicles containing EGFRvIII, which can merge with neighboring cells, transferring tumor-promoting activity. EGFRvIII expression may also be associated with tumor stem cells that have been identified in glioblastoma. These stem cells contribute to resistance to cytotoxic therapy and tumor recurrence. EGFRvIII is expressed in tumors in about 30% of patients with glioblastoma. It has not been detected at a significant level in normal tissues; therefore, targeting of this tumor-specific molecule is not likely to impact healthy tissues. Rindopepimut has received Fast Track Designation in the United States and Orphan Drug Designation in both the United States and the European Union.
Disease: EGFRvIII-positive glioblastoma
Therapeutic area: Cancer - Oncology - Rare diseases
Country: USA
Trial
details: ReACT is a Phase 2 exploratory study designed to determine if adding rindopepimut to standard of care bevacizumab improves the outcomes for patients with EGFRvIII-positive recurrent glioblastoma across multiple measures. The study includes 3 groups: Group 1 - bevacizumab naive, n=72, patients randomized to receive either rindopepimut or Keyhole Limpet Hemocyanin (KLH) (administered as a control), each along with bevacizumab Group 2 - bevacizumab refractory (defined as having progressed/grown through bevacizumab by RANO criteria within two months of prior bev treatment), n=25, patients receive rindopepimut plus bevacizumab in a single treatment arm Group 2C (C = Confirmatory) - bevacizumab refractory expansion, n=up to 75 (Simon two-stage design; 1st cohort n=28), patients receive rindopepimut plus bevacizumab in a single treatment arm
Latest
news: * On November 14, 2014, Celldex Therapeutics announced an interim update from the Phase 2 ReACT study of rindopepimut in EGFRvIII-positive glioblastoma. The ReACT results demonstrate clear signs of clinical activity in patients with recurrent glioblastoma, including groups both naïve and refractory to bevacizumab (Avastin®). The data were presented in a platform presentation by David A. Reardon, M.D., Clinical Director, Center for Neuro-Oncology, Dana-Farber Cancer Center and Associate Professor of Medicine, Harvard Medical School, and the lead investigator of the ReACT study, at the 4th Quadrennial Meeting of the World Federation of Neuro-Oncology held in conjunction with the 19th Annual Meeting of the Society for Neuro-Oncology (SNO). Presentation Highlights—Interim Data Update Group 1 - Recurrent glioblastoma; bevacizumab (bev) naïve (randomized: rindo + bev vs. control + bev): Primary endpoint of PFS-6 (% alive without progression at 6 months)—rindopepimut 27% vs. control 11%; p=0.048 - Statistically significant overall survival benefit—hazard ratio of 0.47; p=0.0208; rindopepimut median 12.0 months vs. control median 8.8 months - An increase in clinically meaningful tumor shrinkage - Rindopepimut plus bevacizumab was well tolerated; no serious adverse events attributed to rindopepimutEarly anti-EGFRvIII immune response correlates with survival benefit Group 2/2C - Recurrent glioblastoma; bev refractory (single arm: rindo + bev): Rare, but prominent anti-tumor activity did not meet high hurdle for expanded accrual of Group 2C - Noteworthy overall survival compared to historical comparisons - Rindopepimut plus bevacizumab was well tolerated; no serious adverse events attributed to rindopepimut - Early anti-EGFRvIII immune response correlates with survival benefit Across Group 1, Group 2 and Group 2C, rindopepimut plus bevacizumab was very well tolerated (dosing up to 30+ months). There were no unexpected toxicities associated with concomitant bevacizumab administration and there were no serious adverse events attributed to study vaccination. One potentially treatment-related event of Grade 1 intratumoral hemorrhage resulted in discontinuation of rindopepimut treatment. Adverse events were consistent with prior studies of rindopepimut. Detailed Clinical Activity Overview—Interim Data Update Group 1: 72 patients were randomized to receive either rindo + bev (n=35) or control + bev (n=37). 30 patients continue to be followed for survival, including 12 patients who continue to receive treatment. PFS-6: While the data continue to mature, the primary endpoint of the study, progression-free survival at 6 months, is currently positive with 27% of patients treated with rindopepimut still progression free compared to 11% of control patients (p=0.048). Group 2/2C : Results are available for 53 (n=25 patients in Group 2; n=28 in Group 2C) patients enrolled in this arm. Thirteen patients continue to be followed for survival. Survival: The median OS of 5.1 months (95% CI 3.2, 6.5) is noteworthy in these heavily pretreated, refractory EGFRvIII-positive patients. A review of the literature assessing survival in recurrent patients who are bevacizumab-experienced across eight independent studies suggests a weighted-average survival of 3.6 months (range of 2.6 to 5.8 months) in all-comers. 46% of patients in Group 2/2C were alive at 6 months.
Survival: The Overall Survival Kaplan Meyer analysis currently demonstrates a statistically significant benefit (p=0.0208) with a hazard ratio of 0.47 (0.25, 0.91) in favor of the rindopepimut treated patients with early and consistent separation of the curves providing a median difference of 12.0 versus 8.8 months.
Response Rate: 7 out of 29 patients (24%) evaluable for response on the rindopepimut arm experienced a confirmed objective response versus 5 out of 30 patients (17%) evaluable for response on the control arm. Assessments of response were conducted by study investigators according to RANO criteria.
Stable Disease: 74% of patients in the rindopepimut arm had stable disease or better for greater than 2 months versus 57% in the control arm.
Steroid Use: Further emphasizing the level of disease control, 55% of patients on the rindopepimut arm, who were on steroids at the start of treatment, were able to stop steroids during treatment versus 26% on the control arm and 50% of patients on the rindopepimut arm were able to stop steroids for greater than 2 months during treatment versus only 11% on the control arm.
Immune Response: Improved survival was greatest among patients with rapid generation of anti-EGFRvIII humoral response, though even those with slower development of immune responses appear to benefit.
Other: All subgroup analyses, including performance status, steroid use and recent resection, show a hazard ratio in favor of rindopepimut treatment.
Response Rate: As previously reported, two patients experienced complete response (one unconfirmed) and two patients experienced partial response (one unconfirmed). Two of these four patients did not meet the protocol defined definition of refractory in Group 2, the only two such patients enrolled. No additional objective responses were observed in Group 2C and the study did not meet the criteria (defined as two responses per RANO criteria in the first 23 patients enrolled in Group 2C) for continued enrollment. Ten patients with measurable disease experienced objective tumor shrinkage across Group 2/2C.
Stable Disease: 19% of patients had stable disease or better for greater than 2 months (range 2.8 to 16.5 months).
Immune Response: As observed in the bev-naïve patients, early development of high anti-EGFRvIII titer was associated with longer survival and may be predictive for improved outcome in this refractory patient population.
