Kathy Boltz, PhD

Findings from a recent phase II study showed the PD-L1 inhibitor durvalumab generated durable responses in bevacizumab-na&iuml;ve patients with recurrent glioblastoma multiforme (GBM). Findings of the study were presented at the 2016 Society for Neuro-Oncology Annual Meeting.

In a 30-patient cohort, the 6-month progression-free survival (PFS) rate was 20.0% (6 patients; 90% CI, 9.7-33.0). The median PFS was 13.9 weeks (95% CI, 8.1-24.0). Of these 6 patients, 3 had wild-type

&ldquo;Among the 6 patients who were progression-free at 6 months, 5 of them remained progression-free for more than 1 year, while 1 patient was ongoing at 48 weeks,&rdquo; said lead author David A. Reardon, MD, Dana-Farber Cancer Institute.

Overall best responses were partial response in 4 patients (13.3%) and stable disease in 14 patients (46.7%) for a disease control rate of 60.0% (18 patients). The median overall survival (OS) was 28.9 weeks (95% CI, 22.9 to not estimated). The 6-month OS rate was 59.0% (90% CI, 42.6-72.2) and the 12-month OS rate was 44.4% (90% CI, 28.9-58.9).

This ongoing phase II, multicenter, open-label study has 3 patient populations: newly diagnosed patients with GBM with unmethylated

promoter (n = 37), recurrent GBM that is bevacizumab-na&iuml;ve, and recurrent GBM that is bevacizumab-refractory (n = 17). The bevacizumab-na&iuml;ve population is divided into 3 groups based on concomitant therapy: no bevacizumab (n = 30), bevacizumab at 10 mg/kg once every 2 weeks (n = 32), and bevacizumab at 3 mg/kg every 2 weeks (n = 32).

This presentation focused on the 30 patients receiving no concomitant bevacizumab. These patients were treated with single-agent durvalumab at 10 mg/kg IV every 2 weeks for up to 12 months. The primary efficacy endpoint for this cohort was PFS at 6 months (PFS-6) and the historical benchmark of PFS-6 of 10% was used, based on historical data from the pre-bevacizumab era. The 30-patient intent-to-treat population included patients who received any dose of durvalumab and had at least 1 baseline and 1 post-baseline tumor assessment.

The first patient was dosed on March 5, 2015, and the data cutoff for this presentation was June 30, 2016. Durvalumab was discontinued by 25 patients (80.6%): 1 for adverse event (3.2%), 2 for physician decision (6.5%), and 22 for progressive disease (71.0%).

The safety analysis set of patients (n = 31) had a median age of 54.0 years (range, 24-77) and was 83.9% male. Measurable lesions at baseline occurred in 24 patients (77.4%). At treatment initiation, 9 patients (29.0%) were on steroids for GBM. The methylation status of

was methylated for 9 patients (29.0%), unmethylated for 15 (48.4%), and unknown for 7 (22.6%). The

gene was mutated in 4 patients (12.9%), wild-type in 22 (71.0%), and unknown in 5 (16.1%). The median time from GBM diagnosis to enrollment was 40.3 weeks (range, 1.9-123.4). Prior to enrollment, 25 patients (80.6%) had 1 relapse and 6 patients (19.4%) had 2 relapses.

The median duration of exposure to durvalumab was 11.1 weeks (range, 0-60), and the median number of doses was 6.0 (range, 1-29).

No grade 4 or 5 treatment-related adverse events (TRAEs) occurred among the 31 patients in this safety analysis set. Additionally, no significant immune-related toxicities or clinically significant laboratory trends were noted. Among non-neurological TRAEs, the only grade 3 event reported was 1 patient with decreased lymphocyte count. Among neurological TRAEs, 1 patient experienced grade 3 headache and 1 patient experienced grade 3 dizziness.

Durvalumab is a human IgG monoclonal antibody that binds to PD-1 and CD80, allowing T cells to recognize and kills tumor cells without the need for cytotoxic activity that is antibody-dependent and cell-mediated. PD-1 is expressed by many lymphocytes that infiltrate GBM, and its ligand, PD-L1, is expressed by 61% to 100% of GBM tumors. The transcription and expression of PD-L1 in GBM is increased when the PTEN suppressor gene is lost, which occurs in 40% to 50% of GBM tumors.

In his concluding remarks, Reardon said that pending analyses are evaluating immunocorrelative biomarkers, and that the data he discussed warrant additional studies of durvalumab in GBM.

Reardon DA, Kaley T, Dietrich J, et al. Phase 2 study to evaluate the clinical efficacy and safety of MEDI4736 (durvalumab [DUR]) in patients with glioblastoma (GBM): results for cohort B (CUR monotherapy), bevacizumab (BEV) na&iuml;ve patients with recurrent GBM. Presented at 2016 SNO Annual Meeting; November 17-20, 2016; Scottsdale, Arizona. Abstract ATIM-04.

Articles

Findings from a recent phase II study&nbsp;showed the PD-L1 inhibitor durvalumab generated durable responses in bevacizumab-na&iuml;ve patients with recurrent glioblastoma multiforme (GBM).

Durvalumab Demonstrates Durable Responses in Recurrent GBM

&ldquo;The research question was if treatment with nivolumab to block immune checkpoint pathways could potentiate an antitumor immune response and have synergistic effects with radiotherapy or chemoradiotherapy in patients with newly diagnosed GBM,&rdquo; stated first author by Antonio Omuro, MD, of the Memorial Sloan Kettering Cancer Center.

Cohorts 1c and 1d included patients with newly diagnosed GBM. Patients in cohort 1c (n = 57) were enrolled regardless of

status and those in cohort 1d had unmethylated&nbsp;

All patients were treated with nivolumab at 3 mg/kg every 2 weeks in combination with standard radiotherapy. Those in cohort 1c also received concurrent and adjuvant temozolomide. Those in cohort 1d did not receive temozolomide.

was methylated (n = 11), unmethylated (n = 39), and indeterminate (n = 7). In cohort 1d,&nbsp;

status was indeterminate for 2 patients and unmethylate for 52. The median age of patients was 59 years (range, 25-79) in cohort 1c and 58 years in cohort 1d (range, 28-78). More than 1 measurable lesion was present in 27 patients in cohort 1c (47.4%) and in 24 patients in cohort 1d (45.3%). In cohort 1d, 1 patient received prior radiotherapy and 1 had prior systemic anticancer therapy with anastrozole.

At the data cutoff of September 16, 2016, 51 patients in cohort 1c (89%) and 47 (89%) in cohort 1d continued on the study. Treatment was discontinued in 6 patients in cohort 1c due 3 cases of increased transaminases and 1 case each of asthenia, fatigue, and hypotension. In cohort 1d, 4 patients discontinued treatment due to 1 case each of increased alanine transaminase, increased lipase, herpes simplex virus (HSV) encephalitis, and acute kidney injury.

There were 10 deaths on study (5 in each cohort). The causes of death in cohort 1c were progressive disease (n = 4) and unknown (n = 1). In cohort 1d the causes of death were progressive disease (n = 3), related to HSV encephalitis and clinical decline (n = 1), and unknown (n = 1).

Treatment-related serious adverse events were experienced by 22.8% and 15.1% of patients treated with nivolumab with radiotherapy with temozolomide and without, respectively. There were no new safety signals observed.

The median duration of treatment was 3.25 months (range, 0-14.9) in cohort 1c and 3.71 months (range, 0-11.8) in cohort 1d. Subsequent anticancer therapy was received by 31.6% of the patients in cohort 1c and by 26.4% in cohort 1d, which included systemic therapy, radiotherapy, and surgical resection. ​In 20 evaluable patients across both arms, the 12-month overall survival rate was 80%.

"Results suggest that the combination of nivolumab with radiotherapy with or without temozolomide is feasible and well tolerated, raising no new safety concerns," the authors wrote in their abstract. "These data support continued clinical investigation in this population."

Nivolumab is a fully human IgG4 monoclonal antibody against the PD-1 receptor. It was first FDA approved for advanced melanoma in December 2014, and it has been subsequently approved for advanced lung cancer, renal cell carcinoma, head and neck cancer, Hodgkin lymphoma, and further melanoma indications.

The interim analysis from the CheckMate-143 study support further clinical evaluation of nivolumab plus radiotherapy with or with temozolomide in patients with newly diagnosed GBM. Two other studies are also investigating nivolumab in combination with radiotherapy: CheckMate-498 for patients with unmethylated

and CheckMate-548 for patients with methylated or indeterminate

Omuro A, Gordana V, Baehring J, et al. Nivolumab combined with radiotherapy with or without temozolomide in patients with newly diagnosed glioblastoma: Results from phase 1 safety cohorts in CheckMate 143.

The PD-1 inhibitor nivolumab was successfully combined with radiotherapy alone or concurrently with temozolomide for patients with newly-diagnosed glioblastoma multiforme in cohorts 1c and 1d from the phase I CheckMate-143 study.&nbsp;

Nivolumab Combinations Feasible for Newly Diagnosed GBM

-mutated glioma across a variety of doses, in a phase I study presented at the 2016 Society for Neuro-Oncology (SNO) Annual Meeting.

Across all efficacy-evaluable patients with

-mutant glioma treated in the open-label study (n = 65), 2 had a minor response (3%; 95% CI, 0.4-10.7), 41 had stable disease (63%), and 20 had progressive disease (31%).

&ldquo;AG-120 is well tolerated and 42% of patients remained on AG-120 as of data cut-off,&rdquo; said presenter Ingo K. Mellinghoff, MD, Vice Chair for Research in the Department of Neurology and Evnin Family Chair in Neuro-Oncology at the Memorial Sloan Kettering Cancer Center in New York, New York. &ldquo;AG-120 has the potential to help a large number of patients with

About 80% of WHO grade II/III gliomas and up to 5% of glioblastomas have mutations in

These mutations result in an altered metabolic state, in which production of 2-hydroxyglutarte (2-HG) is increased. This increased 2-HG production dysregulates genetic and epigenetic processes, leading to oncogenesis. Inhibition of IDH1 reduces 2-HG in preclinical models and tumor growth in the xenograft TS603 glioma model.

In the dose-escalation arm of the phase I study, AG-120 was administered orally once daily over a 28-day cycle at doses ranging from 200 mg to 1200 mg. The dose escalation cohort enrolled 20 patients with

-mutant glioma that had recurred, progressed, or did not respond to standard therapy. A steady-state plasma concentration of AG-120 was achieved in the first cycle of treatment, and plasma exposure above 500 mg daily dosing was not proportional. Based on observed clinical activity, safety, and pharmacokinetic/pharmacodynamic data, 500 mg of AG-120 daily was selected for the expansion.

An additional 46 patients were enrolled into the expansion cohort. In cohort 1 of the expansion arm, patients had non-enhancing

-mutant glioma (n = 24) and had not received tumor resection or radiotherapy within 6 months of enrollment. These patients had 3 or more prior full sets of scan and had progressed within 12 months of enrollment. In cohort 2, labeled a basket cohort, patients had enhancing glioma (n = 22) that was progressive and

-mutant but did not meet other criteria for cohort 1.

The median age across all enrolled patients (N = 66) was 41 years (range, 21-71). Patients had astrocytoma (29%), oligoastrocytoma (18%), glioblastoma (18%), oligodendroglioma (15%). Co-deletion of 1p19q occurred in 17 patients (31% of those tested), and the ATRX mutation was present in 24 patients (92% of those tested). The enrolled patients had received a median of 2 prior systemic therapies (range, 1-6), primarily temozolomide (71%). Prior radiotherapy was received by 49 patients (74%).

In 23 efficacy-evaluable patients with non-enhancing glioma treated at the recommended phase II dose of the AG-120, 2 had minor responses (9%; 95% CI, 1.1-28.0), 19 had stable disease (83%), and 2 had progressive disease (9%). The median duration of treatment was 8.1 months (range, 1.4-17.8). Response data were not yet available for the enhancing cohort. At the time of the analysis, the median duration of treatment was just 1.9 months (range, 0.4-10.4).

Across the full study, baseline plasma levels of 2-HG were not elevated above those of healthy volunteers. After treatment with AG-120, levels of 2-HG were decreased by 95% in 2 patients at day 15 of cycle 1 (

<.01 vs baseline) and 25 patients had this reduction after day 1 of cycle 2 (

Exploratory imaging to measure the effects of AG-120 on tumor growth rates was explored in the non-enhancing glioma expansion cohort. A total of 174 MRI scans were examined, including 63 historical scans (2 of the 24 patients lacked historical scans) and 111 MRIs done on protocol. Tumor slope was determined to be stable or decreased by volumetric analysis in 14 of 22 patients (64%) and by bidimensional analysis in 12 of 22 (55%). Mellinghoff commented that volumetric analysis requires further development as a response evaluation tool.

&ldquo;The SNO presentation is the first look at data for AG-120 in a defined cohort of glioma patients, where we evaluated the potential for volumetric analyses to improve our understanding of the response patterns beyond the conventional bi-dimensional methods,&rdquo; Mellinghoff said. &ldquo;This methodology could be instrumental in developing more effective, targeted therapies for patients with this disease.&rdquo;

As of August 1, 2016, 28 of 66 patients (42%) remained on treatment. The reasons for the 38 discontinuations were progressive disease (n = 34), physician decision (n = 3), and adverse events (n = 1). No dose-limiting toxicities were observed and no on-treatment deaths occurred.

The maximum tolerated dose was not reached. At least 1 serious treatment-emergent adverse event was experienced by 11 of the 66 patients (17%), and all were deemed unrelated to treatment. Adverse events of any grade were experienced by 62 patients (94%), and grade 3 or higher adverse events were experienced by 14 patients (21%).

Further evaluation of inhibitors of IDH in glioma is warranted, based on these results. Mellinghoff stated that the brain-penetrant pan-IDH inhibitor AG-881 is under phase I investigation in patients with gliomas or other solid tumors with mutated

. The primary endpoint of this study is focused on safety and tolerability (NCT02481154).

Mellinghoff IK, Tauat M, Maher E, et al. AG120, a first-in-class mutant IDH1 inhibitor in patients with recurrent or progressive IDH1 mutant glioma: results from the phase 1 glioma expansion cohorts.

The IDH1 inhibitor AG-120 showed promising stable disease rates along with a few minor responses for patients with non-enhancing&nbsp;<em>IDH1</em>-mutated glioma across a variety of doses.&nbsp;

IDH1 Inhibition Emerging as Viable Option for Glioma

Median OS was 20.8 months in the Optune arm (95% CI, 19.0-22.6) and 16.0 months in the temozolomide-alone arm (95% CI, 13.9-18.2). The hazard ratio of 0.65 (95% CI, 0.54-0.79;

= .0006) favored the Optune arm. Median progression-free survival (PFS) was 6.7 months in the Optune arm (95% CI, 6.1-8.1) and 4.0 months in the temozolomide arm (95% CI, 3.8-4.3). The hazard ratio for PFS of 0.63 (95% CI, 0.52-0.76;

&ldquo;[Optune] should be considered the new standard of care,&rdquo; lead study author Roger Stupp, MD, of the University of Zurich Switzerland, said when presenting the findings. &ldquo;The magnitude of benefit is similar to what we saw when we added temozolomide as standard of care.&rdquo;

Optune is a portable, noninvasive, battery-operated device that attaches directly to the patient&rsquo;s head to deliver tumor-treating fields to the brain. The device is thought to slow or reverse tumor growth by inhibiting mitosis during metaphase, anaphase, and telophase. The updated findings confirmed the survival benefit observed at the study&rsquo;s interim analysis, which led to the October 2015 FDA approval of the Optune combination for use in patients with newly diagnosed GBM following surgery, chemotherapy, and radiation therapy.

The phase III EF-14 study randomized 695 patients after they had already received standard temozolomide and radiation therapy (about 4 months after initial diagnosis). A total of 466 patients were randomized to receive Optune and temozolomide and 229 received temozolomide alone.

The 2 treatment arms were well balanced. Among patients with available tissue, over 80% had the

The patients in the Optune arm received a median of 8.2 cycles of treatment, where a cycle was 1 month, and a median of 6 cycles of temozolomide. Adherence to Optune was 75%. The patients in the temozolomide-alone arm received a median of 5 cycles.

The 2-year OS was 42.5% in the Optune arm (95% CI, 38.0-47.4) and 30% in the temozolomide arm (95% CI, 24.4-37.0). From diagnosis, patient survival was 24.5 months in the Optune arm (95% CI, 22.8-26.3) and 19.8 months in the temozolomide arm (95% CI, 17.6-22.1). From diagnosis, median PFS was 11.2 months (95% CI, 10.0-11.8) in the Optune arm and 7.8 months (95% CI, 7.3-8.2) in the temozolomide arm.

&ldquo;The 2-year annual survival rate is meaningful, and [Optune] resulted in a 30% absolute increase in survival. We are getting to something that is at least meaningful to patients and their families in terms of longer time to be together,&rdquo; said Stupp. Further, survival benefit in terms of annual survival rates occurred at 1 year (72.6% in Optune arm vs 65.3% in temozolomide arm;

Cox proportional hazard ratios for OS found

status was the strongest predictor for benefit (HR = 0.512;

<.001). Hazard ratios favored TTF across treatment, gender,

status, age, Karnofsky performance status (KPS), and tumor location. Likewise, subgroup analyses indicated benefits for all subgroups. The subgroups analyzed included

methylated vs unmethylated; resection by biopsy, partial, or gross total; age under 50 years or 50 years or older; KPS 90-100 or 80 or below; and gender.

In both study arms, 9% of patients experienced grade 3 blood and lymphatic system disorders, while grade 4 disorders were experienced by 4% in the Optune arm and by 2% in the temozolomide alone arm. Convulsions of grade 3 affected 3% of patients in both arms, with 1% of the patients in the Optune arm affected by grade 4 convulsions. In the Optune arm, about half the patients experienced some skin reaction from the treatment device.

Stupp R, Idbaih A, Steinberg DM, et al. Prospective, multi-center phase III trial of tumor treating fields together with temozolomide compared to temozolomide alone in patients with newly diagnosed glioblastoma. Presented at 2016 SNO Annual Meeting; November 17-20, 2016; Scottsdale, Arizona. Abstract LTBK-01.

&ldquo;The long-term analysis further supports our data showing that Optune together with temozolomide is a better treatment option for newly diagnosed GBM patients compared to temozolomide alone,&rdquo; Asaf Danziger, CEO of Novocure, the developer of Optune, said in a statement. &ldquo;We believe these results will give healthcare providers further confidence in our therapy and transform the standard of care in newly diagnosed GBM. Our priority is to improve the lives of GBM patients, and we believe these results will help us to accomplish our mission.&rdquo;

Treatment with the combination of Optune and temozolomide improved overall survival by 4.8 months compared with temozolomide alone in patients with newly diagnosed glioblastoma multiforme.

Optune/Temozolomide New Standard of Care for GBM

Treatment with the PD-1 inhibitor pembrolizumab elicited a durable clinical benefit rate of 28% along with a manageable safety profile for patients with recurrent glioblastoma multiforme (GBM) that expressed PD-L1 on &ge;1% of cells, according to data from a small phase Ib trial presented at the 2016 Society for Neuro-Oncology Annual Meeting.

&ldquo;The durability of benefit was the most striking indicator of the efficacy of pembrolizumab for these patients. Some of these patients are up over 80 weeks and maintaining progression-free survival, which is remarkable,&rdquo; said Reardon, from the Dana-Farber Cancer Institute.

The study, labeled KEYNOTE-028, enrolled 26 patients who were positive for PD-L1 on &ge;1% of cells in tumor nests or positive bands in stroma. To determine PD-L1 status, tumor samples, which could be archival or newly obtained from nonirradiated lesion, were assessed through immunohistochemistry using a prototype assay and the 22C3 antibody clone.

The median age of patients was 55.5 years (range, 33-76) and the ECOG performance status was 0 for 11 patients (42%), 1 for 14 (54%), and missing for 1 (4%). Prior to enrollment, all patients had received standard of care therapies, and 31% had experienced 2 or more recurrences. The median time from original diagnosis to study enrollment was 20.0 months (range, 7.6-81.6).

After patients progressed on the study, 6 had surgery (23%), 1 had radiation (4%), and 10 had oncologic drugs and biologics (39%). Reardon explained that immunotherapies, such as pembrolizumab, may help subsequent treatments because of the effects on the immune system. So, this study is tracking subsequent treatments after patients progress.

One patient experienced a partial response (4%). Stable disease was achieved in 12 patients (48%). The disease control rate, which was 28%, was defined as the rate of complete response plus partial response plus stable disease for &ge;6 months. Progressive disease occurred in 10 patients (40%).

Reardon shared images of target lesions in a patient with a confirmed partial response as assessed by RECIST v1.1 by the investigator. The lesion was visible at baseline and then no longer apparent at 40 weeks. A waterfall plot of best change from baseline in tumor size by RECIST v1.1 investigator review illustrated that 46% of the patients had experienced a decrease in target lesions, with 4 patients having a decrease of 30% or more.

The median time to response was 36.3 weeks (range, 7.7-37.6 weeks). The median response duration was 12.1 weeks (range, 8.3-12.1 weeks). The median duration of stable disease was 39.4 weeks (range, 7.1+ to 85.9+ weeks).

Median progression-free survival (PFS) was 3 months (95% CI, 2-9). The 6-month PFS rate was 44% and the 12-month PFS rate was 16%. The median overall survival (OS) was 14 months (95% CI, 10 to not reached), the 6-month OS rate was 85%, and the 12-month OS rate was 74%. Lead investigator, David A. Reardon, MD, noted that the Kaplan-Meier curves showed that a small tail of patients have durable benefit.

Overall, 15% of patients experienced a grade 3/4 adverse events (AE), a low enough rate for Reardon to label it as &ldquo;Fairly reassuring.&rdquo; Less than 10% of the patients experienced immune-related AEs, which included colitis in 2 patients (8%), hypothyroidism in 2 (8%), hyperthyroidism in 2 (8%), and drug eruption in 1 (4%). The median follow-up was 60.9 weeks (range, 11.7-94.0). No grade 4 cerebral edema occurred. No treatment-related deaths or discontinuations occurred.

&ldquo;This agent was quite well tolerated for the glioblastoma population. There were really no unusual or unexpected side effects that occurred, which is always reassuring,&rdquo; said Reardon.

Reardon stated that further investigation of anti-PD-1 therapy in this patient population is warranted. Immunocorrelative analyses are ongoing, including work to correlate the level of PD-L1 expression in a tumor with outcomes.

Reardon DA, Kim T-M, Frenel J-S, et al. Results of the phase Ib KEYNOTE-28 multi-cohort trial of pembrolizumab monotherapy in patients with recurrent PD-L1-positive glioblastoma multiforme (GBM).

Treatment with the PD-1 inhibitor elicited a durable clinical benefit rate of 28% along with a manageable safety profile for patients with recurrent glioblastoma multiforme that expressed PD-L1 on &ge;1% of cells.

Pembrolizumab Active, Tolerable for Recurrent Glioblastoma

Toca 511 is a retroviral replicating vector and it is being combined with oral Toca FC, which is extended-release 5-fluorocytosine (5-FC). Toca 511 (vocimagene amiretrorepvec) encodes a cytosine deaminase (CD) that is yeast-derived, codon-optimized, and heat-stabilized. Toca 511 converts 5-FC to the anticancer drug 5-fluorouracil (5-FU) in infected tumors. This phase I study is seeking to determine the highest tolerated doses and the viral pharmacokinetics of these agents in patients who have recurrent high-grade glioma.

&ldquo;Toca 511 delivers the prodrug activator gene cytosine deaminase. CD converts 5-FC to 5-FU. Though 5-FU has a very short half-life, it affects direct cell killing and impacts the cancer microenvironment in a localized manner,&rdquo; said lead author Timothy Cloughesy, MD, director of the Neuro-Oncology Program at the University of California Los Angeles. 5-FU kills the tumor and also activates the immune system against the cancer.

In this open-label phase I study, Toca 511 was administered intravenously over 1, 3, or 5 days in 17 patients. Subsequently, tumors were resected and then Toca 511 was injected into the resection cavity walls. Then, 6 weeks later, Toca FC was administered for 7 days every 6 weeks.

Eligible patients had to have a resection of at least 80% planned, be aged 18 to 80 years old, and have a Karnofsky performance score of at least 70. The 17 enrolled patients had a median age of 52 years (range, 28-77) and 8 (47.1%) were male. Baseline Karnofsky performance scores were 70 to 80 in 3 patients (17.7%) and 90 to 100 in 14 patients (82.4%).

The initial tumor histologies of the enrolled patients were glioblastoma multiforme in 14 (82.4%), anaplastic astrocytoma in 1 (5.9%), and anaplastic oligoastrocytoma in 2 (11.8%). Their number of recurrences, including their current recurrence, was 1 recurrence in 8 patients (47.1%), 2 in 3 patients (17.6%), and 3 or more in 6 patients (35.3%).

The combination of intravenous and intracranial Toca 511 was generally well tolerated. Vasogenic edema of at least grade 3 occurred in 1 patient in the 3-day IV cohort; it was consistent with intracranial inflammation or rapid tumor progression. The patient experienced a related grade 3 cerebral cyst.

Additionally, 2 patients (11.8%) experienced grade 1/2 pyrexia, 2 patients (11.8%) experienced grade 1/2 malaise, and 1 patient (5.9%) experienced grade 1/2 vasogenic edema. No treatment-related deaths were reported.

The only dose-limiting toxicity was the grade 3 vasogenic edema, but, notably, it occurred 33 days after the surgery and intracranial Toca 511 injection and prior to the Toca FC treatment.

When the resected tumor samples were examined, viral DNA was found in 13 of 17 (76%). The amount of viral DNA was dose-dependent, as it was detected in 3 of 5 (60%) subjects who received the 1-day delivery, in 7 of 9 (78%) subjects who received the 3-day delivery, and in all 3 (100%) patients who received the 5-day delivery. Quantifiable DNA was found in 8 of 17 (47%) subjects overall, which included 1 of 5 (20%) in the 1-day, 5 of 9 (56%) in the 3-day, and 2 of 3 (67%) in the 5-day cohorts.

Transgene expression was detected by IHC, which indicated that approximately 50% of dividing cells were transduced by Toca 511. At 5 weeks after the Toca 511 injection, viral RNA could not be detected in the blood at levels above the lower quantification limit.

Independent radiology reviews of 11 subjects found 1 radiological complete response (with an unrelated stroke) and 2 patients with stable disease. Cloughesy shared scans of a patient with glioblastoma multiforme who had a complete response after 12 cycles and has remained alive for more than 2 years.

The median OS was 13.6 months (95% CI, 5.8-20.6). This compares favorably with historic data, noted Cloughesy.

&ldquo;Overall survival preliminarily looks interesting when compared with historical benchmarks,&rdquo; stated Cloughesy. &ldquo;Preliminary overall survival data is encouraging.&rdquo;

A phase Ib trial has been initiated to investigate IV Toca 511 in solid tumors (NCT02576665). This study will include brain metastases from breast cancer and NSCLC, colorectal cancer with liver metastases, metastatic renal cell carcinoma, locally advanced or recurrent melanoma, and locally advanced or metastatic pancreatic or breast cancer.

Cloughesy C, Walbert T, Bota D, et al. Successful cancer-selective gene delivery following intravenous Toca 511 delivery in patients with recurrent high grade glioma (HGG). Presented at 2016 SNO Annual Meeting; November 17-20, 2016; Scottsdale, Arizona. Abstract 4.

Treatment with the novel regimen of Toca 511 and Toca FC demonstrated a median overall survival of 13.6 months for patients with high-grade gliomas, representing a marked improvement over historical median survivals of 7.2 to 9.2 months.<br />
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