乌鸦传媒

The combination of oncolytic DNX-2401 virotherapy with pembrolizumab (Keytruda) failed to meet a phase I/II study's primary endpoint of objective response rate (ORR) in patients with recurrent glioblastoma, but did demonstrate a "notable survival benefit" in select patients.

Among 49 patients who received DNX-2401 followed by pembrolizumab, the ORR was 10.4% (90% CI 4.2-20.7), which was numerically greater than the prespecified historical rate of 5% but did not meet the statistical endpoint, reported Gelareh Zadeh, MD, PhD, of the University of Toronto, and colleagues.

However, the 12-month overall survival (OS) rate was 52.7% (95% CI 40.1-69.2), which was statistically greater than the prespecified control rate of 20%, they noted in .

Moreover, Zadeh and colleagues said that objective responses led to longer survival (HR 0.20, 95% CI 0.05-0.87), and that three patients completed treatment with durable responses, and remained alive at 45, 48, and 60 months.

"While the primary endpoint of objective response was not met, the secondary endpoint of 12-month survival, which is more clinically meaningful and reliable than response rate, was met and the survival of objective responders are encouraging, suggesting that tumor control led to improved survival," the authors wrote. "These results are promising and particularly relevant in this population of patients who did not receive repeat resection of tumor and for whom efficacious and nontoxic treatments are entirely lacking."

The median OS was 12.5 months, Zadeh and team reported, and median time to response was 3.0 months, while median duration of response was 9.4 months in patients who showed an objective response. An additional 22 patients in the intent-to-treat population had stable disease lasting longer than 28 days, which resulted in a clinical benefit rate of 56.2% (95% CI 41.1-70.5).

The authors also looked at possible biomarkers for cancer immunotherapy in glioblastoma, and using gene expression data, found that objective responses occurred exclusively in patients with tumors that had moderate PD-1 expression and inflammation before treatment, and that these patients also had longer survival times.

In discussing the rationale behind combining DNX-2401 with an immune checkpoint inhibitor, Zadeh and colleagues noted that after treatment with standard of care -- surgical resection followed by concomitant chemoradiotherapy and adjuvant temozolomide -- glioblastoma patients ultimately experience disease recurrence at an average of 7 months after diagnosis. And while immune checkpoint blockade has improved outcomes in a variety of cancers, they noted that its efficacy has been limited in recurrent glioblastoma, "where the tumor microenvironment is innately immunosuppressive."

"Our previous trial demonstrated that not only does the virus act by killing cancer cells directly, it also effectively activates the innate immune system to convert these immunologically cold tumors into hot tumors," said co-author Frederick Lang, MD, of the University of Texas MD Anderson Cancer Center in Houston, in a . "This led us to evaluate a combination with checkpoint inhibitors, which we now see can improve survival outcomes in a subset of patients."

Clinical trials of intratumoral oncolytic virotherapy in adult and pediatric patients with supratentorial high-grade gliomas have shown apparent responses and improved survival outcomes in some patients as compared with historical controls.

In a phase I study of 12 pediatric patients with diffuse intrinsic pontine glioma (DIPG), an infusion of DNX-2401 followed by radiotherapy in all but one patient resulted in a median OS of 17.8 months, whereas studies involving patients with DIPG treated with radiotherapy alone demonstrated a median OS of 8 to 12 months, with little additional benefit observed with the addition of various drugs.

In a accompanying the new study, Adela Wu, MD, and Michael Lim, MD, both of Stanford University School of Medicine in California, said the next step following this study should be a randomized trial evaluating the combination of DNX-2401 and pembrolizumab versus a control treatment.

"The cancer immunology field requires further in-depth understanding of the [glioblastoma] microenvironment and creative solutions for generating effective therapies against 'cold' tumors," they wrote. "Combination immunotherapy involving checkpoint blockade in conjunction with an oncolytic virus is an exciting possibility, and we look forward to seeing follow-up efficacy and biomarker studies."

The enrolled 49 patients at 13 participating institutions in North America from September 2016 to January 2019. The median age of patients was 53 years, and 41% were women. The majority of patients (80%) presented after their first recurrence, and all patients had a histopathological diagnosis of glioblastoma, with the exception of one patient with gliosarcoma.

Patients were treated with one dose of DNX-2401, followed by intravenous pembrolizumab starting 7 days later. There were no dose-limiting toxicities observed, and the median duration of exposure to treatment with DNX-2401 and pembrolizumab was 153 days, with three patients completing the full 2-year course of pembrolizumab.

Most adverse events (AEs) considered to be treatment-related were grade 1 or 2 events, the most common being brain edema (37%), headache (31%), and fatigue (29%). Treatment-related serious AEs observed in more than one patient included brain edema (16%), dysphasia (6%), and hemiparesis (6%). Serious cerebral edema was managed with either short-course dexamethasone (89%) and/or other concomitant supportive medications, and no patients needed to undergo surgery for serious cerebral edema.

Zadeh and colleagues noted that previous trials showed a 12-month OS rate of 32% in patients treated with DNX-2401 alone, while median OS was 9.3 months and 9.8 months with DNX-2401 or PD-1 blockade alone, respectively.

"Although this trial was not designed to distinguish the effects of DNX-2401 versus pembrolizumab versus combination therapy, the notable survival data point to the potential of improved efficacy in combining oncolytic virus with checkpoint inhibition," they wrote.

Comment