REGOMA Trial Research Articles

CTNI-28. IN VITRO GLIOMA STEMLIKE CELL-BASED SCREENING TO PREDICT DRUG SENSITIVITY IN RECURRENTGLIOBLASTOMA: A CLINICAL SERIES AND SYSTEMATIC LITERATURE REVIEW

Abstract INTRODUCTION There is no standard care for recurrent glioblastoma (GBM) after surgery and radiochemotherapy. Lomustine is commonly used in clinical trials, while regorafenib, a multikinase inhibitor, has shown a survival benefit in the randomized multicentric REGOMA trial, becoming the standard treatment in several countries, including Italy. However, due to nonnegligible toxicity, early identification of likely responders is crucial for personalized treatment. Various studies have explored putative molecular predictors of response with conflicting results. Glioma stem-like cells (GSCs), the most treatment-resistant subpopulation, are believed to drive GBM recurrence post-chemoradiotherapy. Thus, GSCs might provide valuable insights into the drug sensitivity of recurrent GBM. MATERIALS AND METHODS Between 2020 and 2022, nine patients enrolled in a prospective study to obtain GSC cultures from tumor tissue obtained at first surgery were treated with regorafenib upon tumor recurrence. Four patients underwent reoperation before starting regorafenib. GSC cultures were exposed to increasing regorafenib doses in vitro to determine sensitivity (IC50). RESULTS The median progression-free survival (PFS) was 3 months, consistent with REGOMA data. Only one patient achieved 6-month PFS (11.1%). GSCs from this patient were the only ones with an IC50 below the plasma range of regorafenib during treatment (IC50 4.6 μM, range 5.2-8.1 μM). Additionally, this patient had not undergone reoperation before starting regorafenib. Systematic literature review showed few but promising studies in which therapy personalization was based on in vitro drug screening. CONCLUSIONS Although preliminary, these findings suggest a potential paradigm shift in personalized treatment for recurrent GBM, utilizing a GSC-based approach rather than molecular profiling. Further evaluation of GSCs from recurrent tumor tissue is necessary to determine their utility.

OS09.7.A GBM AGILE PLATFORM TRIAL FOR NEWLY DIAGNOSED AND RECURRENT GBM: RESULTS OF FIRST EXPERIMENTAL ARM, REGORAFENIB

Abstract BACKGROUND GBM AGILE (NCT03970447;https://www.gcaresearch.org/research/gbm-agile) is a phase 3 Bayesian adaptive platform trial that efficiently tests multiple arms against common control, with 6 arms included to date. Primary endpoint is overall survival (OS). Stage 1 experimental arms are adaptively randomized against other arms. Demonstrated efficacy in stage 1 leads to fixed randomization stage 2. Stages 1 and 2 are combined for registration. Control randomization is fixed. Regorafenib, a multikinase-inhibitor, entered into GBM AGILE as the first arm and therefore was equally randomized against control. Regorafenib showed OS benefit in recurrent disease (RD) in randomized phase 2 REGOMA trial. MATERIAL AND METHODS Patient subtypes in GBM AGILE are newly diagnosed unmethylated (NDU), RD, and—not considered for regorafenib—ND methylated (NDM). Arm indications (signatures) are combinations of subtypes. Control is temozolomide (ND) and lomustine (RD). Efficacy is assessed by OS hazard ratio(HR), arm/control. Efficacy is demonstrated when Bayesian probability of benefit (HR< 1.00) ≥ 98% (roughly analogous P-value: 0.02). Futility occurs at any monthly analysis when Bayesian predictive power (PP) is < 25% for all signatures. Follow-up continues for 12 months after arm’s accrual stops. RESULTS When PP for all 3 pre-defined signatures was < 25%, regorafenib’s accrual was stopped for futility. Regorafenib/control sample sizes were 49/51, 127/128, 176/179 for signatures NDU, RD, and both. Respective PPs: 0.138, 0.030, 0.025—none close to 0.25. Respective mean HRs: 1.26, 1.25, 1.23. Probabilities of benefit (HR< 1.00): 0.35, 0.18, 0.17. At final analysis, mean HRs were 1.07, 1.08, 1.08 with final probabilities of benefit (HR< 1.00) equal to 0.421, 0.312, 0.296—none close to 0.98. CONCLUSION GBM AGILE efficiently and compellingly addressed regorafenib’s role in GBM, in RD and NDU. These findings are germane as they fail to confirm the REGOMA results in RD. GBM AGILE continues to efficiently assess other therapies, including utilizing concurrent and previously accrued controls. This abstract was accepted and previously presented at the 2023 SNO Annual Meeting and published in Neuro-Oncology, Volume 25, Issue Supplement_5, November 2023, Pages v97-v98.

REGOMA-OSS: a large, Italian, multicenter, prospective, observational study evaluating the efficacy and safety of regorafenib in patients with recurrent glioblastoma

In the randomized phase II REGOMA trial, regorafenib showed promising activity in patients with recurrent glioblastoma. We conducted a large, multicenter, prospective, observational study to confirm the REGOMA data in a real-world setting. The major inclusion criteria were histologically confirmed diagnosis of glioblastoma according to the World Health Organization (WHO) 2016 classification and relapse after radiotherapy with concurrent/adjuvant temozolomide treatment, good performance status [Eastern Cooperative Oncology Group performance status (ECOG PS 0-1)] and good liver function. Regorafenib was administered at the standard dose of 160 mg/day for 3 weeks on/1 week off. Brain magnetic resonance imaging was carried out within 14 days before starting regorafenib and every 8-12 weeks. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate, disease control rate (DCR), safety and health-related quality of life. The Response Assessment in Neuro-Oncology (RANO) criteria were used for response evaluation and Common Terminology Criteria for Adverse Events (CTCAE) version 5 for assessment of adverse events (AEs). From September 2020 to October 2022, 190 patients with recurrent glioblastoma were enrolled from 30 cancer centers in Italy: their median age was 58.5 years [interquartile range (IQR) 53-67 years], 68% were male and 85 (44.7%) were in optimal clinical condition (ECOG PS 0). The number of patients taking steroids at baseline was 113 (60%); the second surgery was carried out in 39 (20.5%). O6-methylguanine-DNA methyltransferase (MGMT) was methylated in 80 patients (50.3%) and 147 (92.4%) of the patients analyzed had isocitrate dehydrogenase (IDH) wild type. The median follow-up period was 20 months (IQR 15.6-25.5 months). The median OS was 7.9 months ([95% confidence interval (CI) 6.5-9.2 months] and the median PFS was 2.6 months (95% CI 2.3-2.9 months). Radiological response was partial response and stable disease in 13 (7.3%) and 26 (14.6%) patients, respectively, with a DCR of 21.9%. The median number of regorafenib cycles per patient was 3 (IQR 2.0-4.0). Grade 3-4 drug-related adverse events were reported in 22.6% of patients. A dose reduction due to AEs was required in 36% of patients. No deaths were considered as treatment-related AEs. This large, real-world observational study showed similar OS with better tolerability of regorafenib in patients with relapsed glioblastoma compared with the REGOMA study.

Exploring Regorafenib Responsiveness and Uncovering Molecular Mechanisms in Recurrent Glioblastoma Tumors through Longitudinal In Vitro Sampling.

Glioblastoma, a deadly brain tumor, shows limited response to standard therapies like temozolomide (TMZ). Recent findings from the REGOMA trial underscore a significant survival improvement offered by Regorafenib (REGO) in recurrent glioblastoma. Our study aimed to propose a 3D ex vivo drug response precision medicine approach to investigate recurrent glioblastoma sensitivity to REGO and elucidate the underlying molecular mechanisms involved in tumor resistance or responsiveness to treatment. Three-dimensional glioblastoma organoids (GB-EXPs) obtained from 18 patients' resected recurrent glioblastoma tumors were treated with TMZ and REGO. Drug responses were evaluated using NAD(P)H FLIM, stratifying tumors as responders (Resp) or non-responders (NRs). Whole-exome sequencing was performed on 16 tissue samples, and whole-transcriptome analysis on 13 GB-EXPs treated and untreated. We found 35% (n = 9) and 77% (n = 20) of tumors responded to TMZ and REGO, respectively, with no instances of TMZ-Resp being REGO-NRs. Exome analysis revealed a unique mutational profile in REGO-Resp tumors compared to NR tumors. Transcriptome analysis identified distinct expression patterns in Resp and NR tumors, impacting Rho GTPase and NOTCH signaling, known to be involved in drug response. In conclusion, recurrent glioblastoma tumors were more responsive to REGO compared to TMZ treatment. Importantly, our approach enables a comprehensive longitudinal exploration of the molecular changes induced by treatment, unveiling promising biomarkers indicative of drug response.

Regorafenib and glioblastoma: a literature review of preclinical studies, molecular mechanisms and clinical effectiveness.

Glioblastoma IDH wild type (GBM) is a very aggressive brain tumour, characterised by an infiltrative growth pattern and by a prominent neoangiogenesis. Its prognosis is unfortunately dismal, and the median overall survival of GBM patients is short (15 months). Clinical management is based on bulk tumour removal and standard chemoradiation with the alkylating drug temozolomide, but the tumour invariably recurs leading to patient's death. Clinical options for GBM patients remained unaltered for almost two decades until the encouraging results obtained by the phase II REGOMA trial allowed the introduction of the multikinase inhibitor regorafenib as a preferred regimen in relapsed GBM treatment by the National Comprehensive Cancer Network (NCCN) 2020 Guideline. Regorafenib, a sorafenib derivative, targets kinases associated with angiogenesis (VEGFR 1-3), as well as oncogenesis (c-KIT, RET, FGFR) and stromal kinases (FGFR, PDGFR-b). It was already approved for metastatic colorectal cancers and hepatocellular carcinomas. The aim of the present review is to focus on both the molecular and clinical knowledge collected in these first three years of regorafenib use in GBM.

CTNI-85. GBM AGILE PLATFORM TRIAL FOR NEWLY DIAGNOSED AND RECURRENT GBM: RESULTS OF FIRST EXPERIMENTAL ARM, REGORAFENIB

Abstract GBM AGILE (NCT03970447;https://www.gcaresearch.org/research/gbm-agile) is a phase 3 Bayesian adaptive platform trial that efficiently tests multiple arms against common control, with 6 arms included to date. Primary endpoint is overall survival (OS). Stage 1 experimental arms are adaptively randomized against other arms. Demonstrated efficacy in stage 1 leads to fixed randomization stage 2. Stages 1 and 2 are combined for registration. Control randomization is fixed. Regorafenib, a multikinase-inhibitor, entered into GBM AGILE as the first arm and therefore was equally randomized against control. Regorafenib showed OS benefit in recurrent disease (RD) in randomized phase 2 REGOMA trial. METHODS: Patient subtypes in GBM AGILE are newly diagnosed unmethylated (NDU), RD, and—not considered for regorafenib—ND methylated (NDM). Arm indications (signatures) are combinations of subtypes. Control is temozolomide (ND) and lomustine (RD). Efficacy is assessed by OS hazard ratio(HR), arm/control. Efficacy is demonstrated when Bayesian probability of benefit (HR< 1.00) ≥ 98% (roughly analogous P-value: 0.02). Futility occurs at any monthly analysis when Bayesian predictive power (PP) is < 25% for all signatures. Follow-up continues for 12 months after arm’s accrual stops. RESULTS: for regorafenib: When PP for all 3 pre-defined signatures was < 25%, regorafenib’s accrual was stopped for futility. Regorafenib/control sample sizes were 49/51, 126/128, 175/179 for signatures NDU, RD, and both. Respective PPs: 0.138, 0.030, 0.025—none close to 0.25. Respective mean HRs: 1.26, 1.25, 1.23. Probabilities of benefit (HR< 1.00): 0.35, 0.18, 0.17. At final analysis, mean HRs were 1.07, 1.12, 1.10 with final probabilities of benefit (HR< 1.00) equal to 0.43, 0.24, 0.24—none close to 0.98. CONCLUSION: GBM AGILE efficiently and compellingly addressed regorafenib’s role in GBM, in RD and NDU. These findings are germane as they fail to confirm the REGOMA results in RD. GBM AGILE continues to efficiently assess other therapies, including utilizing concurrent and previously accrued controls.

CTNI-39. REGOMA-OS: A LARGE ITALIAN MULTICENTER, PROSPECTIVE, OBSERVATIONAL STUDY ANALYZING REGORAFENIB EFFICACY AND SAFETY IN RECURRENT GLIOBLASTOMA PATIENTS

Abstract BACKGROUND in the randomized phase 2 REGOMA trial, regorafenib (REG) showed promising activity in recurrent glioblastoma (GBM) patients (PTS); subsequently, in Italy the National Health System has permitted the reimbursement of the REG as second-line therapy. We performed a large multicenter, prospective and observational study to confirm REGOMA data in a real-world setting. Materials and METHODS major inclusion criteria were: histologically confirmed diagnosis of GBM according to WHO 2016 and relapse after Stupp treatment, good performance status (ECOG PS 0-1), good liver function. REG was administered at standard dose of 160mg/die for 3 weeks on/1 week off. Brain MRI was performed within 14 days before starting REG and every 8-12 weeks, subsequently. Primary endpoint was overall survival. RANO criteria were used for response evaluation, CTACAE v. 5 for adverse events. RESULTS from Sept 2020 to Oct 2022, 192 recurrent GBM PTS were enrolled from 29 Cancer Centres in Italy: median age was 58ys (IQR 52.8-67.0), 68% male, ECOG PS was 0 in 85 (44%), 115 PTS (60%) undertook steroids at baseline. MGMT was methylated in 43%, IDHwt in 92%. Median follow-up was 16.6 months (IQR 12.6-19.6). Median OS was 8.2ms (95% CI 6.5-9.6), 12ms-OS 34.7% (95%CI 27.2-42.4); median PFS was 2.6ms (95%CI 2.3-2.9), 6ms-PFS 14.3%. Radiological response was PR and SD in 12 (8%) and 25 (16%) PTS. 77 (44%) PTS received third-line therapy. The median of REG cycles per patient was 3 (IQR 2.0-4.0). Grade 3-4 adverse events (AE) were reported in 53 (28%) PTS; reduction/delay and permanent discontinuation due to AE in 36% and 8% of PTS. No death was considered as treatment-related AE. CONCLUSIONS compared to the REGOMA trial, this large Italian multicenter, prospective and observational trial confirmed the results in terms of overall survival with a good toxicity profile of REG in recurrent GBM PTS.

BIOM-13. ASSOCIATION OF HAND-FOOT SKIN REACTIONS WITH SURVIVAL IN RECURRENT GLIOBLASTOMA PATIENTS TREATED WITH REGORAFENIB

Abstract INTRODUCTION The phase 2 REGOMA trial suggested a survival benefit of the multikinase inhibitor regorafenib for treating patients with glioblastoma at first recurrence. Hand-foot skin reactions (HFSR) following multikinase inhibitor therapy have been reported to predict prolonged overall survival (OS) in patients with solid tumors. The predictive value of HFSR in patients with recurrent glioblastoma undergoing regorafenib therapy remains to be investigated. METHODS Fifty-seven patients (age range, 35-77 years) with recurrent IDH-wildtype glioblastomas were retrospectively identified from five centers in Germany and Switzerland. Regorafenib was administered at 160 mg/d for the first three weeks of each 4-week cycle, with individual dose adjustments according to toxicity. Patients were stratified into two groups based on the occurrence of HFSR following regorafenib. Group differences were investigated using the Mann-Whitney rank-sum and Fisher's exact tests. Kaplan-Meier analysis was used for univariate analyses, and the Cox proportional hazards regression model for multivariate analyses. RESULTS Patients received a median of two regorafenib cycles (range, 1-14 cycles). Median follow-up after recurrence was 7.0 months (range, 0.6-35.9 months). The median number of previous treatment lines was 2 (range, 1-6 lines). At the time of data analysis, 47 patients (82%) had died. HFSR were observed in 14 out of 57 patients (25%) and associated with a significantly longer OS (10.6 vs. 6.0 months; P = 0.040). No significant group differences (HFSR compared to no HFSR) were observed regarding age, the extent of resection, MGMT promoter methylation, Karnofsky performance status, or the number of completed regorafenib cycles (all P > 0.05). Cox proportional hazards regression analysis confirmed that HFSR were associated with longer OS (P = 0.039; HR, 0.438), independent of age, Karnofsky performance status, and the number of previous treatment lines (all P > 0.05). CONCLUSION Our data suggest that the occurrence of HFSR following regorafenib is associated with longer OS in recurrent glioblastoma patients.

NIMG-20. ASSESSMENT OF RESPONSE TO REGORAFENIB IN RECURRENT GLIOMA PATIENTS USING FET PET AND MRI INCLUDING ADC VALUES

Abstract INTRODUCTION Currently, data on O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET and MRI parameters for the evaluation of response to regorafenib in glioma patients remain scarce. METHODS Twenty patients (age range, 30-72 years) with recurrent CNS WHO grade 3 or 4 gliomas (glioblastoma, 85%) were treated according to the REGOMA trial. FET PET and MRI were performed at baseline and follow-up after the second cycle. Static FET PET parameters comprised tumor-to-brain ratios (TBR) and metabolic tumor volumes (MTV). Parameters derived from dynamic FET PET acquisition were time-to-peak and slope. MRI response assessment was based on RANO criteria. Additionally, various apparent diffusion coefficients (ADC) parameters were obtained from diffusion-weighted MRI. Thresholds derived from FET PET and ADC parameters were defined using ROC analyses to predict an overall survival (OS) of ≥6 months. The predictive values of FET PET parameters, ADC values, and RANO criteria were subsequently evaluated using univariate and multivariate survival estimates. RESULTS Patients received a median of three regorafenib cycles (range, 2-10 cycles). After treatment initiation, the median follow-up was 8.6 months (range, 3.2-27.3 months). After two cycles of regorafenib, a reduction of mean TBR values by ≥10% predicted significantly longer OS (9.9 vs. 5.3 months; P=0.023). Additionally, absolute mean TBR values ≤2.0 at follow-up were prognostic and associated with a significantly longer OS (10.6 vs. 4.5 months; P=0.007). In contrast, MTV, dynamic PET parameters, RANO criteria, and ADC values were not predictive for response or were prognostic (all P >0.05). Multivariate survival analyses revealed that relative mean TBR changes were most potent in predicting response to regorafenib (P=0.038; HR, 0.246) and absolute mean TBR values for prognostication (P< 0.001; HR, 0.005). CONCLUSION In contrast to MRI metrics, FET PET parameters are clinically valuable for identifying responders to regorafenib early after treatment initiation and helpful for prognostication.

JS09.6.A ASSESSMENT OF RESPONSE TO REGORAFENIB IN RECURRENT GLIOMA PATIENTS USING FET PET AND MRI INCLUDING ADC VALUES

Abstract BACKGROUND The phase 2 REGOMA trial suggested that glioblastoma patients treated with the multikinase inhibitor regorafenib at first progression have significantly longer overall survival than patients treated with lomustine. Here, we evaluated the value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET and MRI for the evaluation of response to regorafenib in recurrent glioma patients. MATERIAL AND METHODS Twenty patients (age range, 30-72 years) with CNS WHO grade 3 or 4 gliomas (glioblastoma, 85%) at recurrence were treated according to the REGOMA trial with regorafenib at 160 mg/d for the first three weeks of each 4-week cycle, with individual dose adjustment according to toxicity. FET PET and MRI were performed at baseline and follow-up after the second cycle. Static FET PET parameters comprised tumor-to-brain ratios (TBR) and metabolic tumor volumes (MTV). Parameters derived from dynamic FET PET acquisition were time-to-peak and slope. MRI response assessment was based on RANO criteria. Additionally, mean and minimum apparent diffusion coefficients (ADC) were obtained from diffusion-weighted MRI. FET PET parameters and ADC thresholds were defined using ROC analyses to predict an overall survival of ≥ 6 months. The predictive values of FET PET parameters, ADC values, and RANO criteria were subsequently evaluated using univariate and multivariate survival estimates. RESULTS Patients received a median of three regorafenib cycles (range, 2-10 cycles). After treatment initiation, the median follow-up was 8.6 months (range, 3.2-27.3 months). The median number of previous treatment lines was two (range, 1-4 lines). At the time of data analysis, 17 patients (85%) had died. After two cycles of regorafenib, a regorafenib-induced reduction of mean TBR values by ≥ 10% predicted a longer overall survival (9.9 vs. 5.3 months; P=0.023). Interestingly, absolute mean TBR values ≤ 2.0 at follow-up were prognostic and associated with longer OS (10.6 vs. 4.5 months; P=0.007). In contrast, MTV, dynamic PET parameters, RANO criteria, and ADC values were not predictive for response or prognostic (all P>0.05). Multivariate survival analyses revealed that relative mean TBR changes were most potent in predicting response to regorafenib (P=0.038; HR, 0.246) and absolute mean TBR values for prognostication (P<0.001; HR, 0.005). CONCLUSION Data suggest that FET PET parameters are clinically valuable for identifying responders to regorafenib early after treatment initiation and helpful for prognostication. MRI parameters, including ADC values, do not appear to add valuable information in this context.

P10.29.A FUNCTIONALLY INSTRUCTED COMBINATION-TREATMENTS INVOLVING REGORAFENIB IN EXPERIMENTAL GLIOMA

Abstract BACKGROUND Glioblastoma are incurable primary tumors of the central nervous system. The standard of care for newly diagnosed glioblastoma outside clinical trials includes a combination of radiation therapy, alkylating chemotherapy and tumor-treating fields. Yet, for progressive glioblastoma, only lomustine is registered in Europe. The REGOMA trial (Lombardi et al., Lancet Oncol 2019) had investigated regorafenib versus lomustine in a phase 2-trial. Furthermore, the use of regorafenib in a compassionate-use-program was recently reported (Tzaridis et al., Neuro Oncol 2019) Yet, the regorafenib arm in the Glioblastoma Adaptive Global Innovative Learning Environment (GBM Agile) master protocol was stopped after an interim analysis that showed a low probability of improvement of overall survival compared with control (press release 21 September 2022). We investigated here a functional genomics-based approach to discover and validate potential modulators of response to regorafenib treatment in experimental glioma in vitro, in vivo and ex vivo. MATERIAL AND METHODS We performed CRISPR/Cas9 activation (Calabrese P65-HSF activation library) and knockout (genome-wide knockout library Brunello) screens during treatment with regorafenib, sequenced and analyzed the genomic DNA of the remaining cells. RESULTS We discovered functionally-instructed molecular hits, designed a drug library for further validation by functional assays in vitro and combination treatments in murine glioma models in vivo. CONCLUSION Taken together, we discovered and validated functionally-instructed combination treatment options involving regorafenib. Our finalized results will be presented.

P17.07.A REGORAFENIB IN RECURRENT GLIOBLASTOMA PATIENTS: AN ITALIAN OBSERVATIONAL, MULTICENTRIC AND PROSPECTIVE TRIAL (REGOMA-OSS)

Abstract BACKGROUND In the randomized phase 2 REGOMA trial, regorafenib has shown promising activity in recurrent glioblastoma patients with a significantly longer survival compared to the standard lomustine therapy. Subsequently, in Italy regorafenib was approved as second-line therapy by the Italian Medicines Agency. We performed a large multicenter, prospective and observational study to confirm REGOMA data in the real-world setting. METHODS Based on the REGOMA results, at least 150 patients had to be enrolled to estimate a 1-year survival rate with a precision of 7.8% and a confidence interval of 95%. Major inclusion criteria were: histologically confirmed diagnosis of glioblastoma according to WHO 2016, radiologically documented first relapse/progression after Stupp treatment, good performance status (ECOG PS 0-1), adequate hepatic and hematological function, stable or decreasing corticosteroid use within 7 days before starting regorafenib.Regorafenib has been administered at the standard dose of 160 mg/die for 3 weeks on/1 week off, until disease progression or unacceptable toxicity. Brain MRI has been performed within 14 days before starting regorafenib and then every 8-12 weeks. Primary endpoint is overall survival. Secondary endpoints include: progression-free survival, objective response rate, toxicity and quality of life. RANO criteria is used for response evaluation, CTCAE v. 5.0 for adverse events, EORTC QLQ-C30 and brain module BN20 for quality of life. Recruitment started in September 2020 and finished in October 2022. 191 recurrent glioblastoma patients were prospectively enrolled from 29 cancer centers in Italy: median age was 59 years (IQR 52.6-66.9), 68% male and 32% female, ECOG PS was 0 in 84 (44%), 115 pts (60%) undertook steroids at baseline. MGMT was methylated in 43% and IDH1/2 was wild-type in 92% of patients. The results from this large multicenter Italian study are expected in the second half of 2023.

OS09.2.A REGORAFENIB IN COMBINATION WITH TEMOZOLOMIDE WITH OR WITHOUT RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED MGMT-METHYLATED, IDH WILDTYPE GLIOBLASTOMA: A PHASE I DOSE-FINDING STUDY (REGOMA-2, EUDRA CT N° 2021-001604-15)

Abstract BACKGROUND Glioblastoma (GBM) is associated with the activation of multiple signaling pathways, including the receptor tyrosine kinases, VEGFR, FGFR and PDGFR. The potential response to anti-angiogenic agents makes GBM an attractive target for regorafenib (REG). Antitumor activity of REG in recurrent GBM patients was shown in the phase II REGOMA trial. Interestingly, in “in vivo” studies, beneficial effects were observed with the combination of REG and temozolomide (TMZ) in subcutaneous xenografts. MATERIAL AND METHODS This phase I open-label multicentric study in progress is evaluating the addition of REG to standard of care treatment with TMZ as adjuvant therapy (cohort A), and in combination with TMZ + radiotherapy (RT) as concomitant therapy (cohort B), in newly diagnosed MGMT-methylated, IDH wildtype GBM patients. Primary objectives are: to determine the safety and tolerability of REG and to establish the maximum tolerated dose (MTD) of REG in these two cohorts. Secondary objectives are: the assessment of pharmacokinetics of REG, TMZ, and possible pharmacokinetic interactions between TMZ and REG in cohort A; the assessment of preliminary antitumor activity; the evaluation of quality of life during the treatment. The dose escalation is being explored according to a “3 + 3” design, starting from cohort A and following 3 dose levels of REG [80 mg, 120 mg and 160 mg]. After finding the MTD in cohort A, the cohort B dose escalation will start, exploring escalating oral doses of REG in combination with concomitant TMZ + RT (60 Gy/30 fractions). In the adjuvant phase of cohort B, REG will be given with TMZ at MTD shown in the prior adjuvant phase dose escalation.The DLT (dose-limiting toxicity) evaluation period will be two cycles from the start of cycle 1 of adjuvant phase (in cohort A) and from day 1 to the last day of the concomitant phase (in cohort B). Recruitment started in May 2022; Level 1 in cohort A (3 patients) has been completed without DLT. Approximately 36 subjects will be enrolled.

Clinical activity of regorafenib in elderly patients with recurrent glioblastoma.

Glioblastoma multiforme is one of the most frequent and aggressive primary tumors in the central nervous system, representing >60% of all brain tumors in adults. Despite treatment, prognosis remains poor with most if not all patients experiencing disease recurrence and a 2-year survival rate of 27%. At present, no confirmed standard treatment exists for recurrent glioblastoma. Regorafenib is one of the few options available, based on results from the REGOMA trial. In the present study, a real-life retrospective investigation on the role of regorafenib in patients with recurrent glioblastoma (>60 years old) from two main Oncological Units in South Italy (Azienda Ospedaliera Universitaria Luigi Vanvitelli, Naples, Italy and Ospedale Civile San Giovanni di Dio, Frattamaggiore, Naples, Italy), was performed. The primary endpoint was overall survival (OS), whereas progression-free survival (PFS), objective response rate and disease control were secondary endpoints. Survival was then analyzed according to age, isocitrate dehydrogenase (IDH) and methylated methylguanine-DNA-methyltransferase (MGMT) status. A total of 56 patients met the eligibility criteria. The intention to treat population median PFS (mPFS) was 4.1 months and median OS (mOS) was 6.8 months. Age did not appear to have a significant influence on mPFS. mOS in MGMT-methylated patients was improved compared with that of the unmethylated group (7.7 months vs. 5.6 months). Both mOS and mPFS were longer in IDH-mutant patients. The present study was one of the first real life analyses of regorafenib in recurrent glioblastoma. The results were in line with the REGOMA trial. Age did not appear to be a prognostic factor, thus suggesting that treatment choice should not be different in elderly. MGMT methylation appeared to influence OS. To the best of our knowledge, this was the first report of regorafenib activity in older patients and, while the results were statistically significant, these should be confirmed in further studies.

CTNI-25. REGORAFENIB IN RECURRENT GLIOBLASTOMA PATIENTS: A MULTICENTRIC REAL-LIFE STUDY

Abstract BACKGROUND In the phase 2 REGOMA trial, regorafenib improved overall survival, as compared to lomustine, for glioblastoma (GBM) patients at first progression after chemoradiation. Here, we present the results of a real-life multicentre study that analysed response to treatments, tolerability, and outcome of GBM patients treated with regorafenib at first tumour progression. PATIENTS AND METHODS Regorafenib was given following an escalation dose protocol (1st cycle: 80 mg/day for 2 weeks, then 120 mg/day for one week; 2nd cycle: 120 mg/day for 2 weeks, then 160 mg/day for one week; 160 mg/day from the 3rd cycle). Progression-free survival (PFS) and overall survival (OS) were defined as time from regorafenib initiation and disease progression or death. RESULTS From January 2020 to January 2022, 66 GBM patients were included. Median age was 60.0 years. MGMTp methylation was found in 30 patients (45.5%). Median dose was 120 mg/day 21q28 day, which was lower than that used in REGOMA trial (149 mg). Median PFS (mPFS) was 2.7 months and median OS (mOS) 7.1 months. RANO response to regorafenib was partial response (PR) in 10 (15.1%), stable disease in 14 (21.2%), and progressive disease in 42 (63.7%) patients. Forty-six (69.7%) patients presented adverse events of any grade, and 21 (31.8%) grade III-IV toxicity. Two patients only (3.0%) interrupted regorafenib due to toxicity. In a multivariable analysis, factors associated with disease progression were higher age (p = 0.035) and absence of MGMTp methylation (p = 0.024). CONCLUSION In our study, mPFS and mOS were similar to those of the 59 patients enrolled in the regorafenib arm of REGOMA trial (2.7 vs 2.0 months; 7.1 vs 7.4 months, respectively). However, we observed a higher rate of PRs (15% versus 3.0%). Moreover, we had a lower incidence of discontinuations due to toxicity, maybe because of the lower dose intensity.

CTNI-15. REGORAFENIB IN COMBINATION WITH TEMOZOLOMIDE WITH OR WITHOUT RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED MGMT-METHYLATED, IDH WILDTYPE GLIOBLASTOMA: A PHASE I DOSE-FINDING STUDY (REGOMA-2)

Abstract Glioblastoma (GBM) has activation of multiple signaling pathways in the tumor microenvironment, including the receptor tyrosine kinases, VEGFR, FGFR and PDGFR. The potential response to anti-angiogenic agents makes GBM an attractive target for regorafenib (REG). Antitumor activity of REG in recurrent GBM patients was shown in the REGOMA trial. Interestingly, in “in vivo” studies, beneficial effects were observed with the combination of REG and temozolomide (TMZ) in subcutaneously xenografts. This phase I open-label multicentric study will evaluate the addition of REG to standard of care treatment with TMZ as adjuvant therapy (cohort A), and in combination with TMZ+RT as concomitant therapy (cohort B), in newly diagnosed MGMT-methylated, IDH wildtype GBM patients. Primary objectives are: to determine the safety and tolerability of REG and to establish the maximum tolerated dose (MTD) of REG in those two cohorts. Secondary objectives are: assessment of pharmacokinetics of REG, TMZ and possible pharmacokinetic interactions between TMZ and REG (cohort A); assessment of preliminary antitumor activity; evaluation of quality of life during the treatment. The dose escalation will be explored according to a “3 + 3” design, starting from cohort A and following 3 dose levels of REG [80 mg, 120 mg and 160 mg; level -1 40 mg will be evaluated in case of Dose-Limiting Toxicity (DLT) during REG 80 mg]. After finding the MTD in cohort A, the cohort B dose escalation will start, exploring escalating oral doses of REG in combination with concomitant TMZ+RT (60 Gy/30 fractions); in the adjuvant phase of cohort B, REG will be given (in association to TMZ) at MTD shown in the prior adjuvant phase dose escalation.The DLT evaluation period will be two cycles from the start of cycle 1 of adjuvant or from day 1 to last day of the concomitant phase. Approximately 36 subjects will be enrolled.

OS07.4.A Regorafenib in recurrent glioblastoma patients: a multicentric real-life study

Abstract Background Few options are still available for recurrent glioblastoma (GBM). In the Italian phase 2 REGOMA trial, regorafenib improved overall survival, as compared to lomustine, for GBM patients at first progression after chemoradiation. Here, we present the results of a real-life multicentre study that analysed clinical and radiological features, response to treatments, tolerability, and outcome of a cohort of GBM patients treated with regorafenib at first tumour progression. Patients and Methods We enrolled GBM patients at first tumour progression in three Italian Institutions (Turin, Treviso, Bari). Regorafenib was administered following an escalation dose protocol (1st cycle: 80 mg/day for 2 weeks, then 120 mg/day for one week; 2nd cycle: 120 mg/day for 2 weeks, then 160 mg/day for one week; 160 mg/day from the 3rd cycle). MRI scans were obtained at baseline and every 3 months. Progression-free survival (PFS) and overall survival (OS) were defined as time from regorafenib initiation and disease progression or death. Results From January 2020 to January 2022, 66 GBM patients were included. Median age was 60.0 years. MGMTp methylation was found in 30 patients (45.5%). First-line treatment consisted in chemoradiation in 61 (92.4%), in upfront TMZ (3, 4.5%) or RT alone followed by TMZ (2, 3.0%). Median dose was 120 mg/day 21q28 day, which was lower than that used in REGOMA trial (149 mg). Median PFS (mPFS) was 2.7 months (2.4 - 3.0 95% CI) and median OS (mOS) 7.1 months (5.4 - 8.9 95% CI). Best RANO response to regorafenib was partial response (PR) in 10 (15.1%), stable disease in 14 (21.2%), and progressive disease in 42 (63.7%) patients. All PRs were observed within the first three months of treatment. Patients who completed treatment up the 6th, 9th, and 12th cycles were 20, 3 and 2, respectively. Forty-six (69.7%) patients presented adverse events of any grade, and 21 (31.8%) grade III-IV toxicity. The most frequent adverse events were fatigue (33.3%), hand-foot syndrome (27.3%), and liver enzymes increase (15.2%). Two patients only (3.0%) interrupted regorafenib due to toxicity.In a multivariable analysis, factors significantly associated with disease progression were higher age (p = 0.035) and absence of MGMTp methylation (p = 0.024). Conclusion In this real-life study on 66 patients, mPFS and mOS were similar to those of the 59 patients enrolled in the regorafenib arm of REGOMA trial (2.7 vs 2.0 months; 7.1 vs 7.4 months, respectively). However, we observed a higher rate of PRs as compared to REGOMA (15% versus 3.0%). Type and severity of adverse events were similar between the two studies. Moreover, we had a lower incidence of discontinuations of regorafenib due to toxicity, maybe attributable to the lower dose intensity.We are further analysing the data of MRI-perfusion, with the aim to explore whether it can predict an early response or progression in comparison to standard MRI.

P11.53.B Efficacy and tolerability of regorafenib in pretreated patients with progressive CNS grade 3 or 4 gliomas

Abstract Background The phase 2 REGOMA trial suggested an encouraging overall survival benefit in glioblastoma patients at first relapse treated with the multikinase inhibitor regorafenib. Here, we evaluated the efficacy and side effects of regorafenib in a real-life setting. Material and Methods From 2018-2021, 30 patients with progressive WHO CNS grade 3 or 4 gliomas treated with regorafenib (160 mg/d; first 3 weeks of each 4-week cycle) with individual dose adjustment depending on toxicity were retrospectively identified. Side effects were evaluated according to the Common Terminology Criteria for Adverse Events (version 5.0). MRI was obtained at baseline and after every second cycle. Tumor progression was assessed according to RANO criteria. After regorafenib initiation, the median progression-free survival (PFS) and overall survival (OS) were calculated. Results The median number of treatment lines before regorafenib was 2 (range, 1-4). The majority of patients (73%) had two or more pretreatment lines. At first relapse, 27% of patients received regorafenib. A total of 94 regorafenib cycles were administered (median number of cycles, 2; range, 1-9 cycles). Grade 3 and 4 side effects were observed in 47% and 7% of patients, respectively, and were not significantly increased in patients with two or more pretreatments (P>0.05). The most frequent grade 3 or 4 side effects were laboratory abnormalities (62%). PFS was 2.6 months (range, 0.8-8.2 months), and the OS was 6.2 months (range, 0.9-24 months). Conclusion In patients with progressive WHO grade 3 or 4 gliomas, predominantly with two pretreatment lines or more, regorafenib seems to be effective despite considerable grade 3 or 4 side effects.

Efficacy and tolerability of regorafenib in pretreated patients with progressive CNS grade 3 or 4 gliomas

BackgroundThe phase 2 REGOMA trial suggested an encouraging overall survival benefit in glioblastoma patients at first relapse treated with the multikinase inhibitor regorafenib. Here, we evaluated the efficacy and side effects of regorafenib in a real-life setting.MethodsFrom 2018 to 2021, 30 patients with progressive WHO CNS grade 3 or 4 gliomas treated with regorafenib (160 mg/day; first 3 weeks of each 4-week cycle) with individual dose adjustment depending on toxicity were retrospectively identified. Side effects were evaluated according to the Common Terminology Criteria for Adverse Events (version 5.0). MRI was obtained at baseline and after every second cycle. Tumor progression was assessed according to RANO criteria. After regorafenib initiation, the median PFS and OS were calculated.ResultsThe median number of treatment lines before regorafenib was 2 (range 1–4). Most patients (73%) had two or more pretreatment lines. At first relapse, 27% of patients received regorafenib. A total of 94 regorafenib cycles were administered (median 2 cycles; range 1–9 cycles). Grade 3 and 4 side effects were observed in 47% and 7% of patients, respectively, and were not significantly increased in patients with two or more pretreatments (P > 0.05). The most frequent grade 3 or 4 side effects were laboratory abnormalities (62%). PFS was 2.6 months (range 0.8–8.2 months), and the OS was 6.2 months (range 0.9–24 months).ConclusionsIn patients with progressive WHO grade 3 or 4 gliomas, predominantly with two pretreatment lines or more, regorafenib seems to be effective despite considerable grade 3 or 4 side effects.

CTNI-50. REGORAFENIB IN RECURRENT GLIOBLASTOMA PATIENTS: A LARGE REAL-LIFE EXPERIENCE

Abstract INTRODUCTION Regorafenib (REG), an oral multikinase inhibitor, showed benefit in recurrent GBM (recGBM) patients in the REGOMA trial. We investigated the clinical outcome and safety of REG in a real-life population of recGBM patients treated at Veneto Institute of Oncology as off-label use. MATERIAL AND METHODS Patients receiving REG were entered prospectively on a clinical database. Data were retrospectively analyzed. The primary endpoints were overall survival (OS) and safety. The major inclusion criteria were: histologically confirmed diagnosis of GBM, disease progression by RANO criteria after Stupp protocol, ECOG PS ≤ 2. Patients received REG 160 mg per day for the first 3 weeks in a 4-week cycle. Kaplan-Meier method was used to estimate the survival, RANO criteria for radiological assessment, CTCAE v5.0 for drug related adverse events. RESULTS 54 patients were enrolled: median age was 56, ECOG PS 0-1 in 91%, MGMTmet in 53%, second surgery at the time of relapse in 30%. Median follow-up was 11.1ms, 30 PTS (56%) had died and 50 PTS (93%) had progressed. MedianOS was 10.2 ms (95%CI, 6.4-13.9), 12m-OS was 43%; medianPFS was 2.3 ms (95%CI, 1.3-3.3) and 6m-PFS was 18%. Disease control rate (DCR) was 46.3%; stable disease was reported in 38.8% and partial response in 7.4%. Age, MGMT and corticosteroid use at baseline were not statistically significant on multivariate analysis for OS. Grade 3 drug-related adverse events (AEs) occurred in 10 patients (18%) and the most frequent were hand-foot skin reaction, asthenia and increased lipase and transaminases; 1 PT(2%) reported a grade 4 AE (rash maculo-papular). AEs led to REG dose reductions in 37% of patients and, it was permanently discontinued in 5%. CONCLUSIONS We reported a “real-world” experience of REG in recGBM patients. Results are close to those reported in REGOMA trial; we showed a longer OS. Toxicity was manageable. Encouraging clinical benefits of REG in recGBM population were confirmed.