DCVax®-L for Glioblastoma

New data presented at ASCO 2019 but no update on pivotal phase III trial.

by Dr. C.H. Weaver M.D. updated 6/2019

Northwest Biotherapeutics, developer of DCVax® personalized immune therapies for solid tumor cancers, initially published interim blinded survival data from its Phase 3 clinical trial of DCVax®-L for newly diagnosed Glioblastoma brain cancer. The data were published with 69 co-authors in the peer reviewed Journal of Translational Medicine (JTM).

Unfortunately new data from this and other trails evaluating SurVax in GBM were not updated at the 2019 American Society of Clinical Oncology meetings in June.

A report evaluating SurVaxM in 63 patients enrolled at five U.S. cancer centers was however released. Patients received one 500 mcg dose of SurVaxM along with 100 mcg sargramostim after resection and chemoradiotherapy, followed by four biweekly doses with adjuvant temozolomide and then maintenance dosing every 12 weeks.

Twelve-month OS from the time of diagnosis was 93.5% in the overall population, 96.9% in the methylated MGMT group and 89.4% in the unmethylated group.

The pivotal phase III trial is ongoing while the data continues to mature, and the Company, the investigators and patients all remain blinded. The interim data set forth in the JTM publication are blinded aggregate data which include patients from both arms of the trial combined: the arm with 2/3 of the patients, who received standard of care plus DCVax-L, and the arm with 1/3 of the patients, who received standard of care plus a placebo. When the patients experienced tumor recurrence, all patients from both arms were allowed to cross over and start receiving DCVax-L, but without being unblinded as to what they had received before tumor recurrence. The patient population enrolled in the trial is similar to that in other recent trials, and more than 75% of the patients were over 50 years old (a factor associated with less favorable outcomes).

Due to the crossover design, nearly 90% of the total 331 patients in the trial have received DCVax-L treatment. For the total 331 patients (both arms of the trial combined) the median survival as of this analysis was 23.1 months from surgery. With the standard of care (SOC) today (surgery, radiation and chemotherapy), median survival for newly diagnosed Glioblastoma is 15-17 months.

For patients with methylated MGMT gene status (131 patients), median survival was 34.7 months from surgery. With standard of care today, median survival for these patients has been reported in the literature as 21.7 months. For patients with unmethylated MGMT gene status (162 patients), the median survival was 19.8 months from surgery. With standard of care today, the median survival for these patients has been reported in the literature as 12.7 months. (MGMT data was not available for 38 patients.)

The top 100 patients (30%) of the total 331 patients in the trial showed particularly extended survival, with median survival of 40.5 months from surgery. This extended survival was not fully explained by known prognostic factors such as age younger than 50 years, methylated MGMT gene status and complete resection (surgical removal) of all of the tumor. Only 8% of these 100 patients had the favorable status on all 3 of these prognostic factors.

With immune therapies, the “long tail” of the survival curve is of particular importance and focus. In this DCVax-L trial, patients who survive past certain time points, have continued onwards to substantially extended survival. The patients are continuing to move through time points based upon when they had their surgery, and only some of the patients had reached certain time points in this trial as of this analysis. For example, 223 patients were ≥30 months past their surgery date as of this analysis; 67 of these (30.0%) have lived ≥30 months and these patients have Kaplan-Meier (KM)-derived median survival estimate of 46.5 months. Also, as of this analysis, 182 patients were ≥36 months past their surgery date; 44 of these (24.2%) have lived ≥36 months and these patients have KM-derived median survival estimate of 88.2 months.

The administration of DCVax-L involves only an intra-dermal injection in the arm, similar to a flu shot, 3 times in the first month of treatment, 3 additional times over the rest of the first year (at months 2, 4 and 8), and twice a year thereafter. It thereby involves only a minimal burden on the patient.

DCVax-L has shown an excellent safety profile in the trial. The DCVax-L product has been administered well over 2,000 times, and only 7 of the 331 patients (2.1%) have experienced a serious adverse event that was deemed at least possibly related to the treatment. The rate of total adverse events (including non-serious events) was comparable to the rate of adverse events with standard of care alone.

The reported data are from the most recent prior full data collection in 2017 The Company is undertaking another full data collection, which is a multi-month process and will be continuing over the coming months.

NW Bio Reports Promising Survival Data In 51 GBM Patients Treated With DCVax®-L

BETHESDA, MD, March 27, 2015 – Northwest Biotherapeutics, Inc. (NASDAQ: NWBO) (“NW Bio”), a biotechnology company developing DCVax® personalized immune therapies for cancer, announced today that Dr. Marnix Bosch, the Company’s Chief Technical Officer, presented encouraging survival data on 51 Glioblastoma multiforme (GBM) brain cancer patients treated with DCVax®-L. The data showed substantially longer than expected survival in patients with apparent early progression (recurrence) of their cancer, including patients with such aggressive cancer that the tumor was already re-growing by the end of 6 weeks of daily radiotherapy and chemotherapy after surgical removal of the original tumor.

As previously announced, Dr. Bosch’s presentation was made at the 2nd Immunotherapy of Cancer (ITOC) Conference in Munich, Germany, yesterday and was webcast. The webcast of the presentation, entitled “Prolonged Survival In Patients With Recurrent GBM Who Are Treated With Tumor Lysate-Pulsed Autologous Dendritic Cells,” can be seen for up to 30 days at The presentation poster can be found on the Company’s website.

The 51 GBM patients were treated in an Information Arm outside the Company’s Phase III clinical trial because they were not eligible for the trial, due to evidence of early tumor re-growth following 6 weeks of daily radiotherapy and chemotherapy which are standard of care. Overall Survival data is available for all 51 patients; however, MRI images are only available for 46 of the 51 patients. These 46 patients were classified by an independent medical imaging company into 3 groups, as follows. The other 5 patients remained unclassified, due to lack of available images.

  • 20 Rapid-Progressor Patients: Patients with a new lesion ? 1 cm. in size, or tumor growth of ?25% both at a Baseline Visit and at Month 2 thereafter;
  • 25 Indeterminate Patients: Patients with evidence of progression at the Baseline Visit (rendering them ineligible for the trial), followed by stable disease, modest progression and/or modest regression (or unclear tumor measurements), neither of which is enough to classify them as either a Rapid-Progressor or a Pseudo-Progressor;
  • 1 Pseudo-Progressor: A patient whose Month 2 image showed resolution of most of the prior appearance of tumor growth that had been seen at the Baseline Visit.

The prognosis for Rapid Progressor patients is especially poor: their median Overall Survival is only about 8 to 10 months, according to published scientific literature, and they generally are not expected to respond much to any treatments. There is no established benchmark for Overall Survival of the Indeterminate Patients, however, they can be compared to the general population of GBM patients, for whom median Overall Survival is 14.6 months.

The survival to date, for each of these groups of Information Arm patients treated with DCVax-L, is as follows:

  • Overall: The median OS of the group of 51 Information Arm patients as a whole is 18.3 months. About 30% of the patients (15 of the 51) lived beyond 2 years, and most of these patients (12 of the 15) remain alive.
  • 20 Rapid-Progressors: The median OS among these 20 DCVax-L treated patients is 15.3 months (with patients surviving as long as 37.1 months), compared to expected median OS of 8.3 – 10.8 months with existing treatments, based on published literature on comparable patient populations — a 50% improvement over the expected survival time. Further, one-third of these patients (7 of the 20) lived beyond 18 months – a doubling of the expected survival time with existing treatments.
  • 25 Indeterminate Patients: The median OS among these DCVax-L treated patients is 21.5 months (with patients surviving as long as 40.7 months), compared to median OS in the general population of newly diagnosed GBM patients of 14.6 months – a 50% improvement over the expected survival time. Further, 9 of these 25 patients remain alive today at more than 24 months, 6 of these 9 patients have exceeded 30 months, and 4 of these 9 patients have reached 35-40+ months.
  • 1 Pseudo-Progressor: This patient is still alive, with OS of 30.1 months to date.
  • 5 Unclassified Patients: The median OS is 9.2 months (with patients surviving as long as 30.1 months).

As reflected in these data, both Rapid-Progressor Patients and Indeterminate Patients (as well as the Pseudo-Progressor Patient) treated with DCVax-L in the Company’s Information Arm are surviving substantially longer than would be expected based on clinical experience reported in the literature.

DCVax-L also continues to show an excellent safety profile, with no serious adverse events observed in these Information Arm patients.

“We are quite encouraged to see survival times in our DCVax-L treated Information Arm patients that exceed the expected survival times with existing treatments by 50% or more” commented Linda Powers, CEO of NW Bio. “This survival data, which has been collected by the independent CRO managing our Phase III trial, provides an encouraging insight into the potential results of the DCVax-L treatments for newly diagnosed patients in the Phase III trial. The survival data also reinforce the results we have seen with extended survival in our prior Phase I/II trials, and reinforce NW Bio’s position as a leader in immune therapies for cancer.”

Background

The Company treated a total of 55 patients in an “Information Arm” outside of the Company’s ongoing Phase III clinical trial of DCVax-L for newly diagnosed GBM: 51 of these 55 patients were not eligible for the trial because they had evidence of early progression (tumor growth) at a Baseline Visit at the end of 6 weeks of daily radiotherapy and chemotherapy after surgical resection of their brain tumor; 4 of the patients were not eligible for the trial for other reasons (e.g., insufficient doses of DCVax-L).

These Information Arm patients received the same DCVax-L product, on the same treatment schedule, in the same medical centers, in the same time period as the Phase III clinical trial, and the data have been collected and maintained by the same contract research organization (CRO) managing the Phase III trial.

As Dr. Bosch described in his conference presentation, as part of the eligibility assessment for the Phase III clinical trial, patients underwent MRI imaging at a Baseline Visit at the end of the 6 weeks of daily radiotherapy and chemotherapy which is standard of care following the surgical removal of the original tumor. Patients who already have disease progression (tumor re-growth) so quickly, and in the midst of such daily treatments, are generally considered to be “Rapid Progressors.” Such patients are usually excluded or segregated in studies and analyses because their disease is so accelerated that it is not comparable to regular GBM patients.

The patients in NW Bio’s Information Arm were evaluated through MRI imaging at the Baseline Visit and at Month 2 thereafter. All images were reviewed and analyzed by an independent specialized medical imaging company. Each image was reviewed separately by two independent reviewers, and any material differences were resolved by a third independent reviewer. Reviews were conducted using both RANO and McDonald criteria.

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