Celldex’s lead program RINTEGA demonstrates overall survival benefit in patients with recurrent glioblastoma

Celldex Therapeutics, Inc. (NASDAQ: CLDX) today presented positive results from the Company’s randomized, double‐blind Phase 2 study of RINTEGA^® (rindopepimut) in patients with EGFRvIII‐positive, recurrent glioblastoma at the 2015 American Society of Clinical Oncology (ASCO) in Chicago. The primary endpoint of the study, progression‐free survival at six months (PFS6) was met, and a clear advantage was demonstrated across multiple, clinically important endpoints including overall survival (OS), long‐term progression‐free survival, objective response rate (ORR) and need for steroids. The data were presented in an oral presentation by David A. Reardon, M.D., Clinical Director, Center for Neuro‐Oncology, Dana‐Farber Cancer Institute; Associate Professor of Medicine, Harvard Medical School; and President of the Society for Neuro‐Oncology, as well as the lead investigator of the ReACT study. A webcast/conference call will be held Monday, June 1, 2015 at 8:00 a.m. ET to discuss the results; details are provided below.

RINTEGA is an investigational EGFRvIII specific therapeutic vaccine. Patients with glioblastoma that express the EGFRvIII mutation typically have a worse prognosis than the overall glioblastoma population, including poor long‐term survival.

“The results of the ReACT study are striking because we are observing an extremely rare overall survival advantage that is now translating into long‐term survival for a number of patients—something not seen in highly aggressive, EGFRvIII‐positive glioblastoma,” said David A. Reardon, M.D. “Importantly, patients on the RINTEGA arm are not only surviving longer, they are experiencing a notable decrease in the need for steroids and the numerous side effects associated with their use. We are in dire need of better treatment options, and I believe RINTEGA could become a critical therapy for patients with EGFRvIII‐ positive glioblastoma. Above all, I think these results offer much needed hope to patients, their families and the physicians who treat them that progress is being made in treating this devastating disease.”

“The ReACT study tells a compelling story across multiple, clinically relevant endpoints where the data consistently favor RINTEGA,” said Thomas Davis, M.D., Executive Vice President and Chief Medical Officer of Celldex. “This is one of the most challenging disease settings, and we were extremely pleased to see that even in patients with bulky, growing tumors, RINTEGA generated remarkably frequent and robust anti‐EGFRvIII immune responses, which strongly correlated with meaningful clinical activity. These results mirror what we have seen in earlier RINTEGA studies conducted in newly‐diagnosed patients, supporting our belief that RINTEGA will be an important treatment option for all patients with EGFRvIII‐positive glioblastoma.”

As previously guided, if updated data remained consistent with previously reported results, the Company intended to discuss the potential significance of the ReACT study with regulatory bodies. Given the consistency of the results, this process is ongoing, and the Company will communicate the outcome of these discussions when they are completed.

Presentation Highlights

ReACT is a randomized, controlled Phase 2 exploratory study designed to determine if adding RINTEGA to standard of care bevacizumab (BV; Avastin^®) improves outcomes for patients with EGFRvIII‐positive, recurrent glioblastoma across multiple measures. Patients [n=73 intent to treat (ITT); n=67 per protocol (PP)] were bevacizumab‐naïve at study entry. Investigator‐reported interim data including study results through October 2014 were presented in late 2014. Data presented at ASCO were adjudicated by an independent review committee (IRC) blinded to treatment group assignment and included study results through March 2015 for both ITT and PP populations; tumor responses were evaluated in accordance with RANO criteria. The IRC analyses are statistically equivalent with and confirm the previously reported results.

PFS6: The primary endpoint of PFS6 was met. Given the exploratory nature and size of the trial, the ReACT study required a PFS6 1‐sided p‐value of 0.2 (powered at 80%) for positivity.

SURVIVAL: RINTEGA+BV demonstrated a statistically significant, clinically meaningful overall survival benefit compared to BV alone. Consistent with previous studies of RINTEGA and the published data observed for immune‐mediated therapeutics, this survival benefit includes an emerging “tail” on the RINTEGA survival curve with multiple patients exceeding what is customary survival for EGFRvIII‐ positive glioblastoma. Nine patients (ITT) on the RINTEGA arm continue to be followed for survival, including six without disease progression receiving ongoing treatment. Six patients on the control arm continue to be followed for survival, including two without disease progression receiving ongoing treatment. At 12 months, 45% of RINTEGA patients (ITT) were alive versus 31% of control patients. While these data are early and continue to mature, at 18 months, 30% of RINTEGA patients (ITT) were alive versus 15% of control patients. The Company will continue to follow patients for long‐term survival and will update these numbers at an appropriate scientific conference.

OBJECTIVE RESPONSE RATE (ORR): Nine out of 30 evaluable ITT patients (30%) on the RINTEGA arm experienced a confirmed objective response versus six out of 34 evaluable patients (18%) on the control arm. Nine out of 29 evaluable PP patients (31%) on the RINTEGA arm experienced a confirmed objective response versus five out of 32 evaluable patients (16%) on the control arm. Five patients on the RINTEGA arm experienced durable responses greater than six months, and three of these patients experienced durable responses greater than one year (range of 14.8+ to 18.4+months). In contrast only one patient on the control arm experienced a durable response greater than six months, and none experienced a response greater than one year.

STEROID USE: Further emphasizing the level of disease control, 56% of patients on the RINTEGA arm who were on steroids at the start of treatment were able to stop steroids during treatment versus 42% on the control arm, and 44% of patients on the RINTEGA arm were able to stop steroids for at least two months during treatment versus only 21% on the control arm. Six patients on the RINTEGA arm were able to stop steroids for more than six months, and of these three were able to stop for more than one year versus none on the control arm for either time point.

• IMMUNE RESPONSE: Prolonged survival was associated with high anti‐EGFRvIII humoral responses that were predominantly of the cell killing IgG1 isotype, and recent in vivo experiments have shown those immune responses had tumor killing function through antibody dependent cellular cytotoxicity (ADCC) of EGFRvIII‐expressing tumor cells. This biologic effector function is rarely proven for immune therapies. Importantly, rapid generation of anti‐EGFRvIII humoral response correlated with longer survival, though even those with slower development of immune responses benefitted. No patient in the control arm had detectable EGFRvIII specific antibody response. This effect is consistent with RINTEGA’s proposed mechanism of action as a targeted immunotherapeutic vaccine.
• OTHER: Subgroup analyses, including performance status, steroid use and recent resection, favor RINTEGA treatment.
• SAFETY: RINTEGA was very well tolerated without additive toxicity to bevacizumab