INNV-20. RADIOGRAPHIC RESPONSE AND SEIZURE CONTROL IN IDH1 MUTANT GLIOMA PATIENTS USING IVOSIDENIB

Isocitrate dehydrogenase 1 (IDH1) is commonly mutated in grade II-III gliomas, and the mutant enzyme leads to the production of the oncometabolite 2-hydroxyglutarate (2-HG). 2-HG is responsible for the gliomagenesis associated with these tumors and the promotion of seizures via glutamate receptors. Ivosidenib, a small molecule oral mIDH1 inhibitor, has shown promise in clinical trials to treat IDH1 mutant gliomas, and providers can utilize this agent in IDH1 mutant glioma patients. We evaluated our IDH1 mutant glioma patients treated off-label with ivosidenib and described the radiographic response and seizure control in this cohort when ivosidenib was initiated between October 2020 to February 2021. Radiographic response was determined using RANO criteria, and seizure control was determined by comparing seizures per month before and after initiation of ivosidenib. All patients represented received single-agent ivosidenib dosed at 500 mg orally once a day. One patient required a dose reduction to 250 mg orally once a day because of drug-induced diarrhea. In our cohort of six patients, patient age range was 31 to 74 years with four female patients and two male patients. Diagnoses represented were astrocytoma, IDH1 mutant (n=3) oligodendroglioma (WHO), IDH1 mutant, 1p19q co-deleted (n=2), and anaplastic astrocytoma IDH1 mutant (n=1). Three patients experienced a reduction of seizure frequency, two patients did not have seizures before or after therapy, and one patient remained with the same level of seizures (1 seizure/month). Radiographic responses recorded included three patients with stable disease, two patients with minor responses, and one patient with a partial response. Treatment with ivosidenib is ongoing for this cohort of mIDH1 glioma patients. Updated information on prolonged disease control and seizure control in this cohort of IDH1 mutant glioma patients will be presented. Therapeutics, such as ivosidenib, can lead to improved seizure control and radiographic outcomes in IDH1 mutant glioma patients.

294 Evaluation of radiographic response in the intact renal mass (intact-Rmass) to immune checkpoint inhibitor (ICI) combination regimens in patients with metastatic renal cell carcinoma (mRCC)

BackgroundAs most of the patients previously enrolled in trials had nephrectomy before starting systemic treatment (syst-Rx), the response of the intact-Rmass to novel ICI and tyrosine kinase inhibitor (TKI) combination regimens is not well described.MethodsA retrospective review of 227 patients with mRCC who were treated with ICI (single agent or combinations) in the 1st- or 2nd-line was conducted. Following the appropriate regulatory process, collaborators from 6 US sites collected clinical, pathological, and outcome data via chart review. Overall response was investigator-assessed for all patients with at least one post-treatment scan or evidence of clinical progression after treatment initiation. Overall radiographic response (ORR) represents any radiographic response in the metastatic disease per investigator’s assessment. To accurately assess response in intact-Rmass, 3-dimensional measurement of the intact-Rmass was performed and Rmass volume was calculated at baseline and at the time of best overall response for 1st- and 2nd-line therapy. Radiographic response in intact-Rmass is defined as >30% decrease in the Rmass volume.ResultsMedian age at diagnosis was 62 years, 69% were male, 82% had clear cell histology. 15% and 12% had sarcomatoid and rhabdoid features, respectively. Overall, 82 patients (36%) had a measurable intact-Rmass while receiving syst-Rx. 63 (28%) patients never had a nephrectomy, and 10 (4%) patients had delayed nephrectomy after a good overall response to syst-Rx. 108 (48%) received ICI in 1st-line (88/108 received ipilimumab/nivolumab combination). 91 (40%), and 18 (8%) patients received TKI, or ICI+TKI in 1st-line. 161 (71%) and 86 (38%) of the patients received 2nd-line and 3rd-line therapy, respectively. 104 (46%) received ICI in 2nd-line (75/104 treated with single-agent ICI). 48 (21%), and 4 (2%) patients received TKI, or ICI+TKI in 2nd-line. Radiographic response in intact-Rmass for evaluable patients is summarized in table 1. The highest response rates in intact-Rmass were seen with ICI+TKI combinations. Higher rates of radiographic response in intact-Rmass were seen in patients treated with ICI in 1st-line compared to 2nd-line, possibly related to higher usage of ICI combinations (ipilimumab/nivolumab) in 1st-line. Overall metastatic disease response to different regimens in the 1st-line or 2nd-line was not different based on the history of nephrectomy prior to syst-Rx (table 2).Abstract 294 Table 1Radiographic response (≥30% decrease in volume) in the intact renal massAbstract 294 Table 2Overall radiographic response (ORR) per investigator assessmentConclusionsHigher radiographic response rates in the intact-Rmass were seen in patients treated with ICI+TKI and ICI in the 1st-line. There was no significant difference in overall metastatic disease response to 1st- or 2nd-line treatment based on the history of nephrectomy prior to syst-Rx.Ethics ApprovalEach of the 6 participating centers had their IRB approved protocol for retrospective study and data collection. Data Use Agreements were obtained for each center to share limited data set data with University of Wisconsin - Madison (IRB protocol UW17148 # 2018–0213). Final analysis was performed at University of Wisconsin.Consent not applicable to retrospective studies.

Tissue based biomarkers in non-clear cell RCC: Correlative analysis from the ASPEN clinical trial

Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC), particularly papillary renal cell carcinoma, in order to inform on initial treatment selection and identify potentially novel targets for therapy. We enrolled 108 patients in ASPEN, an international randomized open-label phase 2 trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC treated with the mTOR inhibitor everolimus (n=57) or the vascular endothelial growth factor (VEGF) receptor inhibitor sunitinib (n=51), stratified by MSKCC risk and histology. The primary endpoint was overall survival (OS) and secondary efficacy endpoints for this exploratory biomarker analysis were radiographic progression-free survival (rPFS) defined by intention-to-treat using the RECIST 1.1 criteria and radiographic response rates. Tissue biomarkers (n=78) of mTOR pathway activation (phospho-S6 and -Akt, c-kit) and VEGF pathway activation (HIF-1α, c-MET) were prospectively explored in tumor tissue by immunohistochemistry prior to treatment and associated with clinical outcomes. We found that S6 activation was more common in poor-risk NC-RCC tumors and S6/Akt activation was associated with worse PFS and OS outcomes with both everolimus and sunitinib, while c-kit was commonly expressed in chromophobe tumors and associated with improved outcomes with both agents. C-MET was commonly expressed in papillary tumors and was associated with lower rates of radiographic response but did not predict PFS for either agent. In multivariable analysis, both pAkt and c-kit were statistically significant prognostic biomarkers of OS. No predictive biomarkers of treatment response were identified for clinical outcomes. Most biomarker subgroups had improved outcomes with sunitinib as compared to everolimus.

mTOR and VEGF Tissue Biomarkers and Sunitinib/Everolimus Outcomes in Non-Clear Cell Renal Cancer

Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC), particularly papillary renal cell carcinoma, in order to inform on initial treatment selection and identify potentially novel targets for therapy. We enrolled 108 patients in ASPEN, an international randomized open-label phase 2 trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC treated with the mTOR inhibitor everolimus (n=57) or the vascular endothelial growth factor (VEGF) receptor inhibitor sunitinib (n=51), stratified by MSKCC risk and histology. The primary endpoint was overall survival (OS) and secondary efficacy endpoints for this exploratory biomarker analysis were radiographic progression-free survival (rPFS) defined by intention-to-treat using the RECIST 1.1 criteria and radiographic response rates. Tissue biomarkers (n=78) of mTOR pathway activation (phospho-S6 and -Akt, c-kit) and VEGF pathway activation (HIF-1α, c-MET) were prospectively explored in tumor tissue by immunohistochemistry prior to treatment and associated with clinical outcomes. We found that S6 activation was more common in poor risk NC-RCC tumors and S6/Akt activation was associated with worse PFS and OS outcomes with both everolimus and sunitinib, while c-kit was commonly expressed in chromophobe tumors and associated with improved outcomes with both agents. C-MET was commonly expressed in papillary tumors and was associated with lower rates of radiographic response but did not predict PFS for either agent. In multivariable analysis, both pAkt and c-kit were statistically significant prognostic biomarkers of OS. No predictive biomarkers of treatment response were identified for clinical outcomes. Most biomarker subgroups had improved outcomes with sunitinib as compared to everolimus.

Clinical outcomes in patients with metastatic renal cell carcinoma and brain metastasis treated with ipilimumab and nivolumab

The combination of ipilimumab plus nivolumab (I+N) has greatly improved outcomes in patients with intermediate or poor-risk untreated metastatic renal cell carcinoma (mRCC). However, little is known about the outcomes of patients with brain metastasis (BrM) treated with I+N. A search was performed to retrospectively identify all patients with mRCC treated with I+N in the Duke Cancer Institute and the Cleveland Clinic Taussig Cancer Center, followed by a chart review. Patients were included if they had BrM at the time of I+N initiation. Cohort characteristics are summarized with descriptive statistics. Kaplan-Meier method was used to estimate overall survival (OS) and global, intracranial, and extracranial progression-free survival (PFS) for the cohort and log rank test was used to compare OS and PFS between patient groups. Radiographic response was categorized by RECIST. Fisher’s exact test was used to correlate patient factors with radiographic response. From October 2017 to December 2020, 19 patients with BrM received I+N for mRCC with a median follow-up time of 27.1 months (range 15.0–35.6). By International Metastatic RCC Database Consortium (IMDC) risk criteria, 16% had favorable, 58% had intermediate, and 26% had poor-risk disease. 68% were systemic therapy naïve, and 77% of patients had clear cell histology. 95% had received local CNS directed therapy with surgery, radiotherapy, or both. The objective response rate was 44% (0% complete response) with three of six patients treated in the second line or greater setting experiencing a partial response. The median PFS was 7.6 months (95% CI 5.6 to 14.9). The median extracranial PFS was 8.5 months (95% CI 5.6 to 19.7), and median intracranial PFS was 14.7 months (95% CI 7.2 to not reached). No variables assessed were significantly associated with radiographic response (gender, IMDC risk, presence of bone metastasis, line of therapy, or presence of immune related adverse events). In our retrospective cohort of patients with mRCC with BrM, I+N, in combination with CNS-directed local therapy, appears to have clinical efficacy as previously described with responses seen beyond the first-line setting. Further investigation is warranted in this population given exclusion from prior clinical trials.

Volumetric study reveals the relationship between outcome and early radiographic response during bevacizumab-containing chemoradiotherapy for unresectable glioblastoma

Purpose Although we have shown the clinical benefit of bevacizumab (BEV) in the treatment of unresectable newly diagnosed glioblastomas (nd-GBM), the relationship between early radiographic response and survival outcome remains unclear. We performed a volumetric study of early radiographic responses in nd-GBM treated with BEV. Methods Twenty-two patients with unresectable nd-GBM treated with BEV during concurrent temozolomide radiotherapy were analyzed. An experienced neuroradiologist interpreted early responses on fluid-attenuated inversion recovery (FLAIR) and gadolinium-enhanced T1-weighted images (GdT1WI). Volumetric changes were evaluated using diffusion-weighted imaging (DWI) and GdT1WI according to the Response Assessment in Neuro-Oncology (RANO) criteria. The results were categorized into improved (complete response [CR] or partial response [PR]) or non-improved (stable disease [SD] or progressive disease [PD]) groups; outcomes were compared using Kaplan–Meier analysis. Results The volumetric GdT1WI improvement was a significant predictive factor for overall survival (OS) prolongation (p = 0.0093, median OS: 24.7 vs. 13.6 months); however, FLAIR and DWI images were not predictive. The threshold for the neuroradiologist’s interpretation of improvement in GdT1WI was nearly 20% of volume reduction, which was lesser than 50%, the definition of PR applied in the RANO criteria. However, even less stringent neuroradiologist interpretation could successfully predict OS prolongation (improved vs. non-improved: p = 0.0067, median OS: 17.6 vs. 8.3 months). Significant impact of OS on the early response in volumetric GdT1WI was observed within the cut-off range of 20–50% (20%, p = 0.0315; 30%, p = 0.087; 40%, p = 0.0456). Conclusions Early response during BEV-containing chemoradiation can be a predictive indicator of patient outcome in unresectable nd-GBM.

Volumetric Study Reveals the Relationship Between Outcome and Early Radiographic Response During Bevacizumab-Containing Chemoradiotherapy for Unresectable Glioblastoma

Purpose: Although we have shown the clinical benefit of bevacizumab (BEV) in the treatment of unresectable newly diagnosed glioblastomas (nd-GBMs), the relationship between early radiographic response and survival outcome remains unclear. We performed a volumetric study of the early radiographic responses in nd-GBMs treated with BEV.Methods: Twenty-two patients with unresectable nd-GBM treated with BEV during concurrent temozolomide radiotherapy were analyzed. Early responses in fluid-attenuated inversion-recovery (FLAIR) and gadolinium-enhanced T1-weighted images (GdT1WI) were interpreted by an experienced neuroradiologist. Volumetric changes were evaluated using diffusion-weighted imaging (DWI) and GdT1WI according to the Response assessment in neuro-oncology (RANO) criteria. The results were categorized into improved (complete response [CR] or partial response [PR]) or non-improved (stable disease [SD] or progressive disease [PD]) groups; outcomes were compared using Kaplan-Meier analysis.Results: The volumetric GdT1WI improvement was a significant predictive factor for overall survival (OS) prolongation (p=0.0093, median OS: 24.7 vs. 13.6 months); however, FLAIR and DWI images were not predictive. The threshold for the neuroradiologist-interpretation of improvement in GdT1WI was nearly 20% of volume reduction, which was lesser than 50%, the definition of PR applied in RANO criteria; however, even less stringent neuroradiologist-interpretation could successfully predict OS prolongation (improved vs. non-improved: p=0.0067, median OS: 17.6 vs. 8.3 months). Significant impact of OS on the early response in volumetric GdT1WI was observed within the cut-off range of 20 to 50% (20%, p=0.0315; 30%, p=0.087; 40%, p=0.0456).Conclusions: Early response during BEV-containing chemoradiation can be a predictive indicator for patient outcome in unresectable nd-GBMs.