DCVax-L Improves Survival in Glioblastoma

Autologous tumor lysate-loaded dendritic cell vaccination (DCVax-L) used in combination with standard-of-care treatment extended overall survival (OS) for patients with newly diagnosed glioblastoma (GBM) as well as those with recurrent disease. The phase 3 trial (NCT00045968) met its primary and secondary end points.^1,2

JAMA Oncology published the topline results on November 17, 2022. The median OS for newly diagnosed patients (n = 232) was 19.3 months (95% CI, 17.5-21.3) from randomization with DCVax-L vs 16.5 months (95% CI, 16.0-17.5) in the control group (HR, 0.80; 98% CI, 0.00-0.94; P = .002). The survival rate was 15.7% vs 9.9% at 48 months and 13.0% vs 5.7% at 60 months in favor of the DCVax-L arm.

Investigators concluded that a DCVax-L induced a 20% relative reduction in risk of death at any point in time for patients with newly diagnosed GBM. Furthermore, this relative survival benefit increased over time.

In newly diagnosed patients with methylated MGMT, the median OS was 30.2 months with DCVax-L (n = 90) vs. 21.3 months in controls (n = 199; HR, 0.74; P = .027).

For patients with recurrent GBM (n = 64), the median OS was 13.2 months (95% CI, 9.7-16.8) vs 7.8 months (95% CI, 7.2-8.2) in the control arm (HR, 0.58; 95% CI, 0.00-0.76; P <.001). This translated into a 42% relative reduction in risk of death at any point in time for patients treated with DCVax-L at first recurrence. As in newly diagnosed patients, the survival benefit continued over time.

At 24 months post-recurrence, the OS rate was 20.7% for the DCVax-L arm vs. 9.6% in the control arm. At 30 months, the OS rate was 11.1% vs 5.1% in favor of the experimental arm.

Drugmaker Northwest Biotherapeutics believes these are first phase 3 results of a systemic treatment in nearly 20 years to demonstrate such survival extension in newly diagnosed glioblastoma. Moreover, these data are the first findings from a phase 3 trial of any type of treatment to show such a survival benefit for patients with recurrent glioblastoma in nearly 30 years.

“We are excited to see the meaningful survival extensions in glioblastoma patients treated with DCVax-L in this trial—particularly in the ‘long tail’ of the survival curve, where we see more than double the survival rates as with existing standard of care,” Northwest Biotherapeutics CEO Linda F. Powers said in a news release. “With more than 400 clinical trials for glioblastoma having failed over the past 15 years, it is gratifying to be able to offer new hope to patients who face this devastating disease."

DCVax-L is a fully personalized immune therapy made from a patient’s own dendritic cells and antigens collected from a sample of the patient's own tumor. Technicians then produce a multi-year set of doses from single manufacturing batch. The product is then stored frozen in individual doses and used "off the shelf" throughout the treatment regimen.

Investigators enrolled 331 patients with newly diagnosed GBM from August 2007 to November 2015. The median age was 56 years (range, 19-73) years. Most participants (61.0%) were male and 88.8% were White.

Screening and enrollment were suspended from 2008 through 2011 due to the financial crisis, resumed on a limited basis in 2012. Overall, 91.5% of patients enrolled from 2012 to 2015.

All patients underwent surgical resection, recovery, leukapheresis, and 6 weeks of postoperative standard of care radiochemotherapy prior to enrollment. The median time from surgery to randomization was 3.1 months.

Following initial diagnosis, all patients underwent collection of tumor tissue for manufacturing of DCVax-L. After surgery, investigators diagnosis of glioblastoma was histologically confirmed centrally The MGMT gene promoter methylation status, isocitrate dehydrogenase (IDH) R132 mutation status, and postsurgery minimal (<2 cm2) vs significant (≥2 cm2) residual tumor were determined centrally.

Patients received either DCVax-L or placebo on days 0, 10, and 20, then in months 2, 4, and 8 and months 12, 18, 24, and 30, with monthly temozolomide as standard of care. Each DCVax-L dose comprised 2.5 million DCs injected intradermally in the upper arm.

Investigators compared the treatment groups of the external trials to external control populations to validate the methodology and applied sensitivity analyses to check for biases. They also conducted a matching-adjusted indirect comparison to adjust for imbalances in individual patient characteristics.

The primary end point was OS from randomization to death from any cause in patients with newly diagnosed disease. Investigators measured the secondary end point, OS in patients with recurrent disease, from first recurrence to death from any cause.

Of the 331 enrolled patients, investigators randomly assigned 232 patients to initial DCVax-L treatment and 99 to placebo. Following tumor recurrence, 64 of the 99 patients in the placebo group crossed over to receive DCVax-L.

Eighteen of the 64 patients (28.1%) in the placebo group who crossed over to the DCVax-L arm following progression received beyond the original tumor resection. The median OS was shorter for those who had additional surgery compared with patients who did not (11.8 months; 95% CI, 8.5-14.7 vs 13.4 months; 95% CI, 7.7-19.3).

The median progression-free survival was 6.2 months (95% CI, 5.7-7.4) in the DCVax-L arm and 7.6 months (95% CI, 5.6-10.9) the placebo group. This difference was not statistically significant (P = .47).

Investigators concluded that DCVax-L was well tolerated. Of 2151 total doses administered, only 5 serious adverse events (AEs) were deemed at least possibly related to the investigational treatment. There were 2 cases of grade 3 intracranial edema, 1 case of grade 3 nausea, and 1 case of grade 3 lymph node infection. There was no evidence of any autoimmune reactions or cytokine storm among patients in the experimental arm.

“It is especially encouraging to see these survival extensions with a treatment that has such a benign safety profile,” Powers added. “More than 2100 doses of DCVax-L were administered during the trial, and we found that the adverse event profile was not meaningfully different than with standard of care alone.”

References

1. Liau LM, Ashkan K, Brem S, et al. Association of autologous tumor lysate-loaded dendritic cell vaccination with extension of survival among patients with newly diagnosed and recurrent glioblastoma: a phase 3 prospective externally controlled cohort trial. JAMA Oncol. Published online November 17, 2022. doi:10.1001/jamaoncol.2022.5370
2. Northwest Biotherapeutics reports positive top-line results from phase 3 trial of DCVax-L for glioblastoma. News release. November 17, 2022. https://prn.to/3TKUoZo