Humoral response rate and predictors of response to BNT162b2 mRNA COVID19 vaccine in patients with multiple myeloma.

Multiple myeloma (MM) patients are at excess risk for clinically significant COVID19 infection. BNT162b2 mRNA COVID19 (BNT162b2) vaccine provides effective protection against COVID19 for the general population, yet its effect in MM patients may be compromised due to disease and therapy-related factors and was not yet evaluated. This single-centre prospective study included MM patients tested for serological response 14-21 days post second vaccine. Vaccinated healthy volunteers served as controls. In all, 171 MM patients, median age 70 (38-94) were included; 159 active MM and 12 smouldering myeloma (SMM). Seropositive response rate (median titer) was 76% (91 U/ml) in active MM patients vs 98% (992 U/ml) in the 64 controls (P < 0·0001), and 100% (822 U/ml) in SMM patients. Multivariate analysis revealed older age (P = 0·009), exposure to ≥4 novel anti-myeloma drugs (P = 0·02) and hypogammaglobulinaemia (P = 0·002) were associated with lower response rates. None of the novel agents significantly decreased response rate, whereas daratumumab trended towards reduced response (P = 0·08). Adverse events occurred in 53% and 55% of the MM patients and controls, respectively, all transient grade 1-2. In conclusion, BNT162b2 vaccine was safe and provided a high seropositivity rate in MM patients, independent of treatment type. Older, hypogammaglobulinaemic and heavily pretreated patients had lower response rates.

Validation of diffusion MRI as a biomarker for efficacy using randomized phase III trial of bevacizumab with or without VB-111 in recurrent glioblastoma.

BACKGROUND: Evidence from single and multicenter phase II trials have suggested diffusion MRI is a predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF therapy. The current study confirms these findings in a large, randomized phase III clinical trial. METHODS: Patients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus BV in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pretreatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (>1.24 µm2/ms) or low (<1.24 µm2/ms) ADCL, the mean value of the lower peak of the ADC histogram, within the contrast enhancing tumor. RESULTS: Baseline tumor volume (P = .3460) and ADCL (P = .2143) did not differ between treatment arms. Univariate analysis showed patients with high ADCL had a significant survival advantage in all patients (P = .0006), as well as BV (P = .0159) and BV+VB-111 individually (P = .0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume, and ADCL identified continuous measures of tumor volume (P < .0001; HR = 1.0212) and ADCL phenotypes (P = .0012; HR = 0.5574) as independent predictors of OS. CONCLUSION: Baseline diffusion MRI and tumor volume are independent imaging biomarkers of OS in rGBM treated with BV or BV+VB-111.

A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE).

BACKGROUND: Ofranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab. METHODS: This pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS). RESULTS: Enrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91-1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3-5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction. CONCLUSIONS: In this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results. CLINICAL TRIALS REGISTRATION: NCT02511405.

Safety and efficacy of VB-111, an anticancer gene therapy, in patients with recurrent glioblastoma: results of a phase I/II study.

BACKGROUND: VB-111 is a non-replicating adenovirus carrying a Fas-chimera transgene, leading to targeted apoptosis of tumor vascular endothelium and induction of a tumor-specific immune response. This phase I/II study evaluated the safety, tolerability, and efficacy of VB-111 with and without bevacizumab in recurrent glioblastoma (rGBM). METHODS: Patients with rGBM (n = 72) received VB-111 in 4 treatment groups: subtherapeutic (VB-111 dose escalation), limited exposure (LE; VB-111 monotherapy until progression), primed combination (VB-111 monotherapy continued upon progression with combination of bevacizumab), and unprimed combination (upfront combination of VB-111 and bevacizumab). The primary endpoint was median overall survival (OS). Secondary endpoints were safety, overall response rate, and progression-free survival (PFS). RESULTS: VB-111 was well tolerated. The most common adverse event was transient mild-moderate fever. Median OS time was significantly longer in the primed combination group compared with both LE (414 vs 223 days; hazard ratio [HR], 0.48; P = 0.043) and unprimed combination (414 vs 141.5 days; HR, 0.24; P = 0.0056). Patients in the combination phase of the primed combination group had a median PFS time of 90 days compared with 60 in the LE group (HR, 0.36; P = 0.032), and 63 in the unprimed combination group (P = 0.72). Radiographic responders to VB-111 exhibited characteristic, expansive areas of necrosis in the areas of initial enhancing disease. CONCLUSIONS: Patients with rGBM who were primed with VB-111 monotherapy that continued after progression with the addition of bevacizumab showed significant survival and PFS advantage, as well as specific imaging characteristics related to VB-111 mechanism of action. These results warrant further assessment in a randomized controlled study.