Abstract
Background
Hypofractionated stereotactic radiotherapy (hFSRT) is a salvage option for recurrent glioblastoma (GB) which may synergize anti-PDL1 treatment. This phase I study evaluated the ...safety and the recommended phase II dose of anti-PDL1 durvalumab combined with hFSRT in patients with recurrent GB.
Methods
Patients were treated with 24 Gy, 8 Gy per fraction on days 1, 3, and 5 combined with the first 1500 mg Durvalumab dose on day 5, followed by infusions q4weeks until progression or for a maximum of 12 months. A standard 3 + 3 Durvalumab dose de-escalation design was used. Longitudinal lymphocytes count, cytokines analyses on plasma samples, and magnetic resonance imaging (MRI) were collected.
Results
Six patients were included. One dose limiting toxicity, an immune-related grade 3 vestibular neuritis related to Durvalumab, was reported. Median progression-free interval (PFI) and overall survival (OS) were 2.3 and 16.7 months, respectively. Multi-modal deep learning-based analysis including MRI, cytokines, and lymphocytes/neutrophil ratio isolated the patients presenting pseudoprogression, the longest PFI and those with the longest OS, but statistical significance cannot be established considering phase I data only.
Conclusion
Combination of hFSRT and Durvalumab in recurrent GB was well tolerated in this phase I study. These encouraging results led to an ongoing randomized phase II. (ClinicalTrials.gov Identifier: NCT02866747).
This phase I study evaluated the safety and recommended phase II dose of anti-PDL1 Durvalumab combined with hypofractionated stereotactic radiotherapy in patients with recurrent glioblastoma.
Background
IDH‐mutant anaplastic astrocytomas (AAs) are chemosensitive tumors for which the best choice of adjuvant chemotherapy between procarbazine, lomustine, and vincristine (PCV) or temozolomide ...(TMZ) after radiotherapy (RT) remains unclear.
Methods
In a large cohort of patients with histologically proven 2016 World Health Organization classification AA with IDH1/2 mutations included in the French national POLA cohort (n = 355), the primary objective was to compare progression‐free survival (PFS) between the two treatment regimens (n = 311). Secondary endpoints were overall survival (OS), progression type, pseudoprogression rate, and toxicity.
Results
The 4‐year PFS in the RT + PCV arm was 70.8% versus 53.5% in the RT + TMZ arm, with a hazard ratio (HR) of 0.58 (95% confidence interval CI, 0.38–0.87; p = .0074) in univariable analysis and 0.63 (95% CI, 0.41–0.97; p = .0348) in multivariable analysis. The 4‐year OS in the RT + PCV arm was 84.3% versus 76.6% in the RT + TMZ arm, with an HR of 0.57 (95% CI, 0.30–1.05; p = .0675) in univariable analysis. Toxicity was significantly higher in the RT + PCV arm with more grade ≥3 toxicity (46.7% vs. 8.6%, p < .0001).
Conclusion
RT + PCV significantly improved PFS compared with RT + TMZ for IDH‐mutant AA. However, RT + TMZ was better tolerated.
Implications for Practice
In the absence of fully conducted randomized trials comparing procarbazine, lomustine, and vincristine (PCV) with temozolomide (TMZ) in adjuvant treatment after radiotherapy (RT) for the management of IDH‐mutant anaplastic astrocytoma (AA) and a similar level of evidence, these two chemotherapies are both equally recommended in international guidelines. This study in a national cohort of IDH‐mutant AA defined according the 2016 World Health Organization (WHO) classification shows for the first time that the RT + PCV regimen significantly improves progression‐free survival in comparison with the RT + TMZ regimen. Even if at the time of analysis the difference in overall survival was not significant, this result provides new evidence for the debate about the chemotherapy regimen to prescribe in adjuvant treatment to RT for WHO 2016 IDH‐mutant AA.
Different subgroups of anaplastic gliomas have been established. This study compared two chemotherapies in combination with radiotherapy to determine best management of IDH‐mutant anaplastic astrocytomas.
Abstract
BACKGROUND
Due to the risk of pseudo-progression, evaluating the response of such combined treatment with anti-PDL1 immunotherapy and hypofractionated stereotactic radiotherapy (hFSRT) in ...patients with recurrent glioblastoma (GBM) is difficult even with iRANO criteria. We aim to analyze multi-modal MRI radiomic features in recurrent GBM patients included in the phase I STERIMGLI (NCT02866747) clinical trial.
MATERIAL AND METHODS
In phase I trial STERIMGLI, six patients received hFSRT 24 Gy in 3 fractions of 8 Gy prescribed to the 80% covering isodose in combination with Durvalumab IV 1500mg the same day following the third fraction of radiation then every 4 weeks for a maximum of 12 months. All patients underwent multi-modal MRI acquisitions. Contrast-enhancement on post-gadolinium T1 MRI (Gd-T1) and hyper-T2 signal on FLAIR MRI were manually segmented as volume-of-interest (VOIs) from baseline at week 0 (W0) and every eight weeks until weeks sixteen (W16). For patient 05, segmentation was performed until progression (W40). First order radiomics were extracted and normalized from these longitudinal VOIs in a total of 42 MRI: volume (in cm3), mean and median intensity, entropy, skewness and kurtosis were computed for each VOI. In total 504 (2 x 42 x 6) features were extracted.
RESULTS
Two patients underwent pseudoprogression (patients 04 and 05).
All patients but one (patient 05) presented an early relapse with an increase of FLAIR and Gd-T1 volumes and respective entropies from the first evaluation without decrease during follow up (until W16).
Patient 05 presented a Dose Limiting Toxicities and had the longest time to progression after Durvalumab and hFSRT. Contrary to the other patients, his FLAIR radiomics features presented a decrease of volume, intensity and entropy between W0 and W16 then, interestingly an increase between W24 and W40, date of progression. Moreover, patient 05 presented the lowest tumor volume and the lowest Gd-T1entropy. The intensity of the Gd-T1 followed the same trend as the hyper intense signal on the FLAIR in all patients, in particular for patient 05.
CONCLUSION
In our study, entropy and tumor volume for both FLAIR and Gd-T1, and FLAIR intensity seems to be the most interesting parameters to access the response of combined treatment. FLAIR signal may be more specific to the tumor microenvironment.
First order radiomics allowed us to follow tumor heterogeneity and identify the patient with the longest time to progression.
Abstract
BACKGROUND
Glioblastoma (GBM) remains a lethal disease with inevitable local relapse and no standard treatment. Re-irradiation by hypofractionated stereotactic radiotherapy (hFSRT) is an ...option of treatment with tolerable safety, but needs improvement in term of efficacy. Radiotherapy (RT) causes immunogenic tumor cell death but also induces PDL1 and PD1 expression on tumors and immune cells, potentially evoking resistance to RT. Pre-clinical studies combining hFSRT with an anti-PD-1 antibody in GBM have shown increased efficacy of the combination. Clinical studies also show encouraging results when checkpoint inhibitors have been combined with high dose RT. We hypothesized that combining the anti PD-L1 Durvalumab (Durva) with hFSRT will be an effective regimen for patients with recurrent GBM. We designed a phase I/II clinical trial studying the combination of hFSRT with Durva for recurrent GBM≤35 mm diameter. Results of the phase I are presented.
MATERIAL AND METHODS
Patients were included from February 2017 to October 2017.
A standard 3 + 3 de-escalation design was used. Patients were treated by hFSRT 24 Gy, 8 Gy/fraction at 80% isodose, every other day, combined with Durva infusion 1500mg first dose (Level 1) or 750 mg (Level -1) delivered on the last hFSRT day followed by 1500 mg Durva infusion every four weeks until relapse. The schema was defined as safe if one patient or less among 6 presents a dose limiting toxicity (DLT). Brain MRI was performed before RT and then every 8 weeks until relapse. Tumor assessment was performed according to RANO criteria.
RESULTS
Among the 6 patients (3 methylated MGMT, 3 unmethylated MGMT; all wild type IDH) included at the level 1, all completed the hFSRT course, only one had a DLT which was an immune related grade 3 vestibular neuritis. At the time of analysis (24/01/19), all the patients had a local tumor progression, 4 were still alive. Local progression free interval (LPFI) ranges from 2.1 to 8.1 months. Interestingly the 2 patients who presented a pseudo-progression had a prolonged LPFI (5.7 and 8.1 months) compared to the other patients. All the patients except these 2 patients had a lymphopenia at inclusion. PDL-1 expression varied from 0 to 70% in the primary tumor.
CONCLUSION
Combining three 8 Gy fractions of hFSRT with 1500 mg Durvalumab on the 3rd fraction hFSRT and every 4 weeks for recurrent GBM is well tolerated justifying exploration of its efficacy in the phase II which is currently in interim analysis
Abstract
Background
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Survival data in GBM are correlated with systematic local relapse, whose management is not ...standardized. Several treatments can be discussed in recurrent GBM, including re-irradiation. Hypofractionated Stereotactic Radiation Therapy (hFSRT) has shown efficacy and safety in recurrent GBM (PFS from 3.4 to 5 months), but needs improvement. Pre-clinical studies have assessed the combination of hFSRT with anti-PD-1 antibody in newly diagnosed GBM with significant efficacy. We hypothesized that the combination of a checkpoint inhibitor with high-dose RT can improve survival for patients with recurrent GBM. Thus, we performed a national, multicenter, open-label phase I/II trial to assess the combination of hFSRT with anti-PD-L1 Durvalumab (Durva) for unifocal recurrent GBM (size ≤ 35 mm). We present the results of the bi-centric phase I.
Material and Methods
A standard 3 + 3 dose-escalation design was performed. Patients were treated by hFSRT in 3 fractions (8 Gy per fraction at 80% isodose, for a total dose of 24 Gy) on Day 1, 3 and 5. Durva infusion 1500 mg first dose (Level 1) or 750 mg (Level -1) started on the last day of hFSRT (Day 5). Then, 1500 mg Durva were delivered every 4 weeks until relapse (for a maximum of 12 months). The combination was defined as safe if 1 patient or less among 6 present a dose-limiting toxicity (DLT) within the first 4 weeks after RT. Secondary objectives included intracranial PFS and OS. Brain MRI, Quality of Life and Neuro-Cognition Tests were performed before RT and then every 8 weeks until relapse.
Results
All of the 6 patients included at the Level 1 completed the hFSRT course. Four patients presented adverse effects (any grade). Only 1 presented a DLT (immune related grade 3 vestibular neuritis), with a distant response observed (Durva efficacy or abscopal effect). No DLT related to hSFRT or combination of Durva and hFSRT was reported. Neither serious adverse event nor immune-related adverse event of special interest was reported during DLT period. Complete results (intracranial PFS, OS) are currently being analysed.
Conclusion
The combination of hFSRT (24 Gy, 3x8 Gy on Day 1, 3, and 5) with Durvalumab (1500 mg) on the third fraction of hFSRT (Day 5) and then every 4 weeks for recurrent GBM is well tolerated. Complete phase I results will be presented. Multicentric phase II study is ongoing.
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