Prior Antiangiogenic Therapy Research Articles

Real-world experience of second-line axitinib in metastatic renal cell carcinoma: analysis of the Swedish population.

Aim: Assess the time-to-treatment discontinuation (TTD) and overall survival (OS) in a Swedish metastatic renal cell carcinoma (mRCC) nationwide cohort who received second-line axitinib.Methods: Retrospective analysis of 110 patients with mRCC treated with second-line axitinib in Sweden (2012-2019). Patients included in the study received axitinib after mainly first-line sunitinib or pazopanib.Results: The median (95%CI) TTD of patients who received second-line axitinib was 5.2 (3.7-6.1) months with 6 (5.5%) patients still receiving treatment at the time of analysis. Median (95%CI) OS was 12.2 (7.7-14.2) months.Conclusion: The results are consistent with previous findings in mRCC and addto the evidence demonstrating efficacy of second-line axitinib, after failure of a prior anti-angiogenic therapy in a real-world setting.Clinical Trial Registration: NCT04669366 (ClinicalTrials.gov).

Results of a randomised Phase II trial of olaparib, chemotherapy or olaparib and cediranib in patients with platinum-resistant ovarian cancer

BackgroundOCTOVA compared the efficacy of olaparib (O) versus weekly paclitaxel (wP) or olaparib + cediranib (O + C) in recurrent ovarian cancer (OC).AimsThe main aim of the OCTOVA trial was to determine the progression-free survival (PFS) of olaparib (O) versus the oral combination of olaparib plus cediranib (O + C) and weekly paclitaxel (wP) in recurrent ovarian cancer (OC).MethodsIn total, 139 participants who had relapsed within 12 months of platinum therapy were randomised to O (300 mg twice daily), wP (80 mg/m2 d1,8,15, q28) or O + C (300 mg twice daily/20 mg daily, respectively). The primary endpoint was progression-free survival (PFS) of olaparib (O) versus olaparib plus cediranib (O + C) or weekly paclitaxel (wP). The sample size was calculated to observe a PFS hazard ratio (HR) 0.64 in favour of O + C compared to O (20% one-sided type I error, 80% power).ResultsThe majority had platinum-resistant disease (90%), 22% prior PARPi, 34% prior anti-angiogenic therapy, 30% germline BRCA1/2 mutations. The PFS was increased for O + C vs O (O + C 5.4 mo (2.3, 9.6): O 3.7 mo (1.8, 7.6) HR = 0.73; 60% CI: 0.59, 0.89; P = 0.1) and no different between wP and O (wP 3.9 m (1.9, 9.1); O 3.7 mo (1.8, 7.6) HR = 0.89, 60% CI: 0.72, 1.09; P = 0.69). The main treatment-related adverse events included manageable diarrhoea (4% Grade 3) and hypertension (4% Grade 3) in the O + C arm.DiscussionOCTOVA demonstrated the activity of O + C in women with recurrent disease, offering a potential non-chemotherapy option.Trial registrationISRCTN14784018, registered on 19th January 2018 http://www.isrctn.com/ISRCTN14784018.

Tissue Microvessel Density as a Potential Predictive Marker for Vascular Invasion in Colorectal Cancer.

This study aimed to determine whether microvessel density (MVD) in the tumor tissues could be a potential predictive marker for vascular invasion (VI). Surgical specimens of 73 patients with colorectal adenocarcinoma in Phramongkutklao Hospital were analyzed. Tissues of patients receiving preoperative radiation or prior anti-angiogenic therapy were excluded. Tumor MVD was determined using the average number of counted CD34-stained endothelial cells from two selected fields at 200x magnification in each slide. The presence of VI was defined by tumor involvement of endothelial cell-lined spaces. The optimal cut-off value of MVD to predict VI was examined using receiver operating characteristic analysis to assess the area under the curve and accuracy. VI was detected in 17 of 73 specimens (23.3%). Colorectal cancer (CRC) specimens were classified according to MVD as low (61 specimens, 83.6%) and high density (12 specimens, 16.4%). Average MVD was slightly higher in specimens with VI (81.3±9.3) than those without VI (76.3±7.6), but without statistical significance (p = 0.736). The MVD's cut-off value of 60 vessels/200x field provided 88% sensitivity, 40% specificity, and 57.5% accuracy, with the area under the ROC curve of 0.5788. Patients with CRC having MVD of > 60 vessels/200x field were at significantly higher risk of VI than those with CRC having MVD of <60 vessels/200x field (P=0.009, Fisher's exact test). Univariate analysis revealed that MVD, nodal involvement and AJCC tumor stage were associated with the presence of VI (p <0.05). Further multivariate analysis of these three potential variables demonstrated MVD (OR, 11.994; 95% CI, 2.197 to 65.483; p <0.01) and nodal involvement (OR, 10.767; 95% CI, 1.973 to 58.748; p <0.05) as independent prognostic factors associated with VI. Based on our study, MVD immunostaining was an angiogenic marker that potentially be a predictive marker for VI.

Re-irradiation of recurrent IDH-wildtype glioblastoma in the bevacizumab and immunotherapy era: Target delineation, outcomes and patterns of recurrence

Introduction and backgroundWhile recurrent glioblastoma patients are often treated with re-irradiation, there is limited data on the use of re-irradiation in the setting of bevacizumab (BEV), temozolomide (TMZ) re-challenge, or immune checkpoint inhibition (ICI). We describe target delineation in patients with prior anti-angiogenic therapy, assess safety and efficacy of re-irradiation, and evaluate patterns of recurrence. Materials and methodsPatients with a histologically confirmed diagnosis of glioblastoma treated at a single institution between 2013 and 2021 with re-irradiation were included. Tumor, treatment and clinical data were collected. Logistic and Cox regression analysis were used for statistical analysis. ResultsOne hundred and seventeen recurrent glioblastoma patients were identified, receiving 129 courses of re-irradiation. In 66 % (85/129) of cases, patients had prior BEV. In the 80 patients (62 %) with available re-irradiation plans, 20 (25 %) had all T2/FLAIR abnormality included in the gross tumor volume (GTV). Median overall survival (OS) for the cohort was 7.3 months, and median progression-free survival (PFS) was 3.6 months. Acute CTCAE grade ≥ 3 toxicity occurred in 8 % of cases. Concurrent use of TMZ or ICI was not associated with improved OS nor PFS. On multivariable analysis, higher KPS was significantly associated with longer OS (p < 0.01). On subgroup analysis, patients with prior BEV had significantly more marginal recurrences than those without (26 % vs. 13 %, p < 0.01). ConclusionRe-irradiation can be safely employed in recurrent glioblastoma patients. Marginal recurrence was more frequent in patients with prior BEV, suggesting a need to consider more inclusive treatment volumes incorporating T2/FLAIR abnormality.

Efficacy of anlotinib in Chinese patients with metastatic breast cancer: A retrospective observational study.

Anlotinib, a multitarget tyrosine kinase inhibitor, can inhibit tumour angiogenesis proliferation, metastasis, promote vascular normalization, increase T cell and NK cell activity and infiltration, remodel tumour microenvironment and synergistic immune enhancement. Our study aimes to evaluate the efficacy of anlotinib in the treatment of advanced metastatic breast cancer (MBC) after multiple lines of therapy. Patients included were treated with anlotinib for advanced MBC in the Affiliated Cancer Hospital of Zhengzhou University from 1 January 2019 to 30 June 2023. The objective remission rate, disease-free progression survival and adverse reactions were analysed. We compared and analysed the efficacy of anlotinib in the treatment of advanced metastatic breast cancer, which showed that ORR was 23.6% and DCR was 69.1%. The DCR of monotherapy was 66.7% and that of combination therapy was 69.6% in MBC patients. The combination therapy, combined with chemotherapy had the best effect (79.3%), combined with immunotherapy came second. In addition, the DCR (88.9%) was higher in MBC patients having received prior antiangiogenic therapy. According to the Kaplan-Meier (K-M) survival estimate analysis, the mPFS was 4.17 months (95% CI, 1.758-6.582 months) in Her-2 positive MBC patients, and 7.83 months (95% CI, 2.416-9.104) in Her-2 negative MBC patients. The mPFS was 5.76 months (95% CI, 3.231-8.298 m) in HR positive MBC patients, 7.83 months (95% CI, 3.182-12.478 m) in TNBC patients. Fatigue (20.0%), hypertension (21.8%) and liver dysfunction (18.2%) were common adverse reactions, followed by bone marrow suppression (16.4%), anorexia (14.5%), hypothyroidism (14.5%) and diarrhoea (14.5%). Altogether, Anlotinib monotherapy or combination therapy provides a viable third (or above)-line therapeutic strategy in patients with metastatic breast cancer. The adverse reactions of anlotinib are well tolerated and controllable.

Impact of First Line Antiangiogenic Therapy Duration on Nivolumab Outcome in Metastatic Renal Cell Carcinoma Patients Treated in the GETUG—AFU 26 NIVOREN

BackgroundIn metastatic renal clear cell carcinoma (ccRCC), vascular endothelial growth factor receptor (VEGFR) and immune checkpoint are 2 main therapeutic targets. We investigated the impact of duration exposure to antiangiogenic on immunotherapy clinical outcomes in metastatic ccRCC. MethodsPatients from NIVOREN trial who received nivolumab after only 1 prior antiangiogenic therapy were included. Response rate, clinical benefit, progression free survival (PFS) and overall survival (OS) were prospectively analyzed depending on the duration of the first line (< 6 months, ≥6 months) and exploratory in patients with long first line exposure (≥18 months). The circulating levels of 8 plasma proteins and cytokines at baseline were collected and compared according to first line antiangiogenic duration. ResultsAmong 354 patients, 127 (36%) and 227 (64%) patients had received first line antiangiogenic for < 6months and ≥ 6months respectively. Respective duration of first line therapy was not associated with objective response to nivolumab (20.5% vs. 23.9%, P = .50), or PFS (HR 0.92; P = .421). Median OS was respectively 16.6 and 31.3 months in the <6 and ≥6 months subgroups respectively. Adjusted on international metastatic renal cell carcinoma database consortium risk, age and metastatic site, OS was longer in patients with longer treatment duration in the first line setting (HR 0.73; P = .017). Duration of first line VEGFR TKI was independent from circulating levels of 8 proteins and cytokines at nivolumab baseline. ConclusionNivolumab activity in second line is independent from first-line duration of VEGFR TKI. However, first line VEGFR TKI duration ≥ 6 months is associated with longer OS.

Anlotinib combined with carboplatin/paclitaxel and maintenance anlotinib as front-line treatment for newly diagnosed advanced ovarian cancer: A phase II, single-arm, multicenter study (ALTER-GO-010).

5575 Background: Several studies have shown that antiangiogenic drug combined with chemotherapy as first-line treatment, followed by antiangiogenic drug maintenance therapy significantly improve outcomes for patients with ovarian cancer. Anlotinib, a highly effective VEGFRs, FGFRs, PDGFRs and c-kit multi-target tyrosine kinase inhibitor, has been approved for multiple tumor types in China. The aim of this single arm, multicentric, phase II study is to investigate the efficacy and safety of using anlotinib combined with carboplatin/paclitaxel as front-line treatment for advanced ovarian cancer patients. Methods: Eligible patients with FIGO stage III–IV primary epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer and ECOG PS 0-1 undergo primary cytoreductive surgery or interval debulking surgery, will receive 6-8 cycles of chemotherapy (paclitaxel 175 mg/m2 + carboplatin area under the curve [AUC] 5 q3w) and anlotinib (12 mg po qd, days 1-14, 21 days per cycle, anlotinib will be omitted from the first treatment cycle to prevent delayed wound healing). After chemotherapy finished, anlotinib continues as maintenance monotherapy until disease progression, unacceptable toxicity, or death. Patients with prior anti-angiogenic therapy or major surgical procedure within 28 days before starting anlotinib therapy will be excluded. The primary endpoint is progression free survival (PFS). Key secondary endpoints include overall response rate, disease control rate per RECIST1.1, overall survival, safety. Results: From 9 Sep 2021 to 30 Jan 2023, 30 pts were enrolled, including 96.7% (29/30) high-grade serous carcinoma (HGSC) and 3.33% (1/30) endometrioid carcinoma (EC). The median age was 56 years old, with 96.7% (29/30) patients in FIGO stage III and 3.33% (1/30) in stage IV Median follow-up was 5.36 (95% CI: 3.68, - 7.98) months. PFS rates at 6 months and 9 months were both 100%. Twenty-nine patients (96.7%) experienced adverse events (AE) of any level. The most common AEs include white blood cell decreased, neutrophil count decreased, anemia, platelet count decreased, lymphocyte count decreased and hypertension. There was no treatment-related death during the study. Conclusions: Preliminary results of anlotinib combined with carboplatin/paclitaxel have shown favorable efficacy and tolerated safety profile in newly diagnosed advanced ovarian cancer patients. Clinical trial information: NCT04807166 .

ALTER-UC-007: A prospective phase 2 study of anlotinib with gemcitabine and cisplatin or anlotinib with penpulimab as perioperative treatment for patients with muscle-invasive urothelial carcinoma (MIUC).

TPS4612 Background: Radical surgery involving cystectomy and nephroureterectomy is the standard of care for patients with localized muscle-invasive urothelial carcinoma (MIUC). In recent years, neoadjuvant- and adjuvant-containing multimodality therapies have gradually been adopted in attempt to eradicate micrometastatic disease and improve the outcomes achieved with radical surgery alone. This study aims to evaluate the efficacy and safety of anlotinib (a multi-target tyrosine kinase inhibitor of angiogenesis) with gemcitabine and cisplatin or anlotinib with penpulimab (a humanized anti-PD-1 IgG1 monoclonal antibody) as neoadjuvant and adjuvant therapy in patients with MIUC. Methods: In this open-label, prospective, phase 2 study, eligible patients include those with histologically confirmed clinical stage T1-T4N1-3M0, T3-4N0M0 MIUC (tumors of the bladder, renal pelvis, ureter and urethra) fit and planned for radical cystectomy, nephroureterectomy or ureterectomy. Main exclusion criteria are distant metastatic disease; prior chemotherapy, anti-angiogenic therapy, radiation therapy or immunotherapies; active autoimmune disease; uncontrolled hypertension or patients at high bleeding risk. Patients will be enrolled and receive treatment based on PD-L1 status in tumor tissue. The PD-L1 status of eligible patients will be centralized and assessed using an anti-PD-L1 antibody and an immunohistochemical (IHC) assay. PD-L1 positivity was defined as combined positive score (CPS) ≥1 (previously reported as and equivalent to CPS ≥1%). The study treatment is stratified into two cohorts based on PD-L1 expression levels. In cohort 1, the PD-L1 negative patients with MIUC will receive neoadjuvant anlotinib (12 mg orally QD D1-14 every 3 weeks) + gemcitabine (1000 mg/m2, intravenously [IV] on days 1 and 8) + cisplatin (35 mg/m2 IV on days 1 and 8) for a maximum of 4 cycles followed by radical surgery and 2 cycles of adjuvant treatment post-surgery. In cohort 2, PD-L1 positive patients will receive anlotinib (12 mg orally QD D1-14 every 3 weeks) + penpulimab (200 mg IV every 3 weeks) for a maximum of 4 cycles followed by radical surgery and 2 cycles of adjuvant treatment post-surgery. After the completion or discontinuation of the study treatment, safety follow-up and survival follow-up will be performed. Tumor imaging was performed by computed tomography (preferred) or magnetic resonance imaging at baseline, and every 6 weeks during treatment, then every 6 months through year 2. Objective response rate (ORR) is the primary endpoint. Secondary endpoints included pathological complete response rate (pCR), disease-free survival (DFS), overall survival (OS) and safety. Recruitment have begun in October 2022. Currently, the study is active with 1 participant has been enrolled. Clinical trial information: ChiCTR2200063085 .

CTIM-25. NEOADJUVANT ANTI-PD1 IMMUNOTHERAPY FOR SURGICALLY ACCESSIBLE RECURRENT GLIOBLASTOMA: CLINICAL AND MOLECULAR OUTCOMES OF A STAGE 2 SINGLE-ARM EXPANSION COHORT

Abstract Glioblastoma is immunologically “cold”, with little clinical response to single-agent immune-checkpoint inhibitors (ICI). Our previous randomized study of neoadjuvant and adjuvant pembrolizumab versus adjuvant pembrolizumab in recurrent glioblastoma identified a molecular signature for ICI and suggested that neoadjuvant pembrolizumab improved survival (PMID30742122). We extended these original findings with a single-arm expansion cohort of glioblastoma patients at first or second relapse undergoing surgical resection for recurrent disease. Eligibility was identical to the original study. Patients receiving &amp;gt; 4mg dexamethasone, or with prior immunotherapy or anti-angiogenic therapy were excluded. The primary objective was to determine the effect of neoadjuvant pembrolizumab on cell cycle/cancer proliferation genes. Secondary objectives were PFS-6 and OS. Twenty-five patients received neoadjuvant pembrolizumab followed by tumor resection and adjuvant pembrolizumab until progression or unacceptable toxicity. The median age of participants was 60 years and median KPS was 90. Ninety-six percent of tumors were IDH wild-type and 48% were MGMT promoter methylated. Neoadjuvant pembrolizumab continued to induce alterations in the tumor microenvironment (T-cell/IFN upregulation, cell cycle downregulation; molecular responders (MR)), but the proportion of MR in this trial was 36% compared with 70% in the original treatment cohort. Median OS was 6.8 months. There were no CTCAE grade 4-5 AEs attributable to pembrolizumab. Further analysis of prognostic differences between stage 1 and 2 subjects is underway, as are additional immune and genotypic correlates to further define molecular changes induced by pembrolizumab. Anti-PD1 monotherapy triggers an intra-tumoral genetic signature associated with interferon-γ response and suppression of cell cycle/cancer proliferation in recurrent glioblastoma, though does not extend OS. This surgical window-of-opportunity paradigm allows for attribution of molecular effects to single agents. Future work will evaluate the differences in patient population, tumor characteristics, and address additional immune checkpoints and/or signaling pathways that can be targeted to augment the effectiveness of anti-PD1 in glioblastoma.

141P Real-world study of cabozantinib treatment of advanced renal cell carcinoma in Taiwan

This study describes the real-world prescribing patterns, effectiveness, and tolerability of cabozantinib in patients in Taiwan with advanced renal cell carcinoma (aRCC) that progressed despite prior antiangiogenic therapy.

Efficacy and Safety of Telaglenastat Plus Cabozantinib vs Placebo Plus Cabozantinib in Patients With Advanced Renal Cell Carcinoma

Dysregulated metabolism is a hallmark of renal cell carcinoma (RCC). Glutaminase is a key enzyme that fuels tumor growth by converting glutamine to glutamate. Telaglenastat is an investigational, first-in-class, selective, oral glutaminase inhibitor that blocks glutamine utilization and downstream pathways. Preclinically, telaglenastat synergized with cabozantinib, a VEGFR2/MET/AXL inhibitor, in RCC models. To compare the efficacy and safety of telaglenastat plus cabozantinib (Tela + Cabo) vs placebo plus cabozantinib (Pbo + Cabo). CANTATA was a randomized, placebo-controlled, double-blind, pivotal trial conducted at sites in the US, Europe, Australia, and New Zealand. Eligible patients had metastatic clear-cell RCC following progression on 1 to 2 prior lines of therapy, including 1 or more antiangiogenic therapies or nivolumab plus ipilimumab. The data cutoff date was August 31, 2020. Data analysis was performed from December 2020 to February 2021. Patients were randomized 1:1 to receive oral cabozantinib (60 mg daily) with either telaglenastat (800 mg twice daily) or placebo until disease progression or unacceptable toxicity. The primary end point was progression-free survival (Response Evaluation Criteria in Solid Tumors version 1.1) assessed by blinded independent radiology review. A total of 444 patients were randomized: 221 to Tela + Cabo (median [range] age, 61 [21-81] years; 47 [21%] women and 174 [79%] men) and 223 to Pbo + Cabo (median [range] age, 62 [29-83] years; 68 [30%] women and 155 [70%] men). A total of 276 (62%) patients had received prior immune checkpoint inhibitors, including 128 with prior nivolumab plus ipilimumab, 93 of whom had not received prior antiangiogenic therapy. Median progression-free survival was 9.2 months for Tela + Cabo vs 9.3 months for Pbo + Cabo (HR, 0.94; 95% CI, 0.74-1.21; P = .65). Overall response rates were 31% (69 of 221) with Tela + Cabo vs 28% (62 of 223) with Pbo + Cabo. Treatment-emergent adverse event (TEAE) rates were similar between arms. Grade 3 to 4 TEAEs occurred in 160 patients (71%) with Tela + Cabo and 172 patients (79%) with Pbo + Cabo and included hypertension (38 patients [17%] vs 40 patients [18%]) and diarrhea (34 patients [15%] vs 29 patients [13%]). Cabozantinib was discontinued due to AEs in 23 patients (10%) receiving Tela + Cabo and 33 patients (15%) receiving Pbo + Cabo. In this randomized clinical trial, telaglenastat did not improve the efficacy of cabozantinib in metastatic RCC. Tela + Cabo was well tolerated with AEs consistent with the known risks of both agents. ClinicalTrials.gov Identifier: NCT03428217.

Response to apatinib and camrelizumab combined treatment in a radioiodine refractory differentiated thyroid cancer patient resistant to prior anti-angiogenic therapy: A case report and literature review

BackgroundPatients with radioactive iodine refractory progressive (RAIR) differentiated thyroid cancer (DTC) often developed resistance after first-line therapy. Apatinib plus camrelizumab is a therapy with promising efficacy in patients with other malignant cancers. Herein, we presented a case of progressive RAIR DTC treated with apatinib plus camrelizumab.Case presentationWe reported a 43-year-old man diagnosed as DTC with metastases in the lungs, the 7th cervical vertebra, and malignant lymph nodes mainly in the mediastinum. While initially showing disease stabilization after giving the first-line multitargeted kinase inhibitor (MKI) therapy, the patient developed progressive disease and was enrolled into a combined therapy with both apatinib and camrelizumab on November 10, 2020. Upon the first 6 months, the combination therapy showed disease control in terms of both stable structural lesions and biochemical thyroglobulin (Tg) level. Six months later, a decrease over the targeted lesions was observed and a partial response (PR) according to RECIST 1.1 criteria was finally achieved upon 12 months’ assessment, followed by the decline in serum Tg level. The main adverse event was occasional diarrhea without treatment interruption.ConclusionWe reported a case with RAIR DTC that benefited from combination immunotherapy, apatinib plus camrelizumab, after resistance from donafenib. We observed a gradually getting better efficacy and a mild and long duration of this combination therapy and hoped to provide a therapeutic choice for these patients.

Pivotal study of ofra-vec (VB-111) combined with paclitaxel versus paclitaxel for treatment of platinum-resistant ovarian cancer (OVAL, VB-111-701/GOG-3018).

TPS5606 Background: Ofranergene obadenovec (Ofra-vec, VB-111) is an anti-cancer gene based immune activator and targeted vascular disruptor. The dual mechanism of action triggers a broad antiangiogenic effect and induces of a tumor directed immune response. A phase II trial in patients with platinum resistant ovarian cancer (PROC) demonstrated that ofra-vec in combination with weekly paclitaxel was well tolerated and associated with a CA-125 Objective Response Rate (ORR) of 58%, a trend for improved survival and induction of an immunotherapeutic effect of tumor infiltration with CD-8 T cells. Based on these observations, a pivotal phase III study was initiated in collaboration with the GOG Foundation, Inc. Methods: Study NCT03398655 is an international, randomized, double-blind, placebo-controlled, phase III study. Eligible patients have recurrent PROC and may have been previously treated with up to 5 prior lines of therapy (but not &gt;2 for PROC). Patient are randomized 1:1 to receive ofra-vec (1x1013 Viral Particles) with weekly paclitaxel (80mg/m2), or weekly paclitaxel with placebo. Randomization is stratified by number of prior treatment lines, prior antiangiogenic therapy and platinum refractory disease status. The dual primary endpoints are OS and PFS. A pre-planned interim analysis of CA-125 response (GCIG) performed by the DSMC met the pre-defined criteria showing that CA-125 ORR in the treatment arm was at least 10% higher than in the control arm. Study is enrolling in the US, EU, Japan and Israel, with 90% enrollment to date. Completion of accrual is anticipated in Q1 2022. Clinical trial information: NCT03398655.

Frontline therapy of anlotinib combined with carboplatin/paclitaxel and maintenance anlotinib in patients with newly diagnosed advanced ovarian cancer: A phase II, single-arm, multicenter study.

TPS5607 Background: It has been reported that antiangiogenic drug combined with chemotherapy as first-line treatment, and subsequent antiangiogenic drug as maintenance therapy for ovarian cancer can achieve better clinical benefits. Anlotinib is a highly effective VEGFRs, FGFRs, PDGFRs and c-kit multi-target tyrosine kinase inhibitor which has been approved for the treatment of several solid tumors in China. This single arm, multicentric, phase II study is expected to investigate the efficacy and safety of anlotinib combined with carboplatin/paclitaxel as front-line treatment in patients with advanced ovarian cancer. Methods: Eligible patients with FIGO stage III–IV primary epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer and ECOG PS 0-1 undergo primary debulking surgery or interval debulking surgery, will receive 6-8 cycles of chemotherapy (paclitaxel 175 mg/m2 + carboplatin area under the curve [AUC] 5 q3w) and anlotinib (12 mg po qd, days 1-14, 21 days per cycle, anlotinib will be omitted from the first treatment cycle to prevent delayed wound healing). Anlotinib as maintenance monotherapy will be continue until disease progression, unacceptable toxicity, or death. Patients with prior anti-angiogenic therapy and major surgical procedure within 28 days before the first date of anlotinib therapy will be excluded. This study will recruit approximately 56 patients. The primary endpoint is progression free survival. Key secondary endpoints include overall response rate, disease control rate per RECIST1.1, overall survival, safety. The study began enrolling patients in August 2021 and is ongoing. Clinical trial information: NCT04807166.

Assessing the Safety and Efficacy of Two Starting Doses of Lenvatinib Plus Everolimus in Patients with Renal Cell Carcinoma: A Randomized Phase 2 Trial

BackgroundLenvatinib (18 mg) plus everolimus (5 mg) is approved for patients with advanced renal cell carcinoma (RCC) after one or more prior antiangiogenic therapies. ObjectiveTo assess whether a lower starting dose of lenvatinib has comparable efficacy with improved tolerability for patients with advanced RCC treated with lenvatinib plus everolimus. Design, setting, and participantsA randomized, open-label, phase 2 global trial was conducted in patients with advanced clear cell RCC and disease progression after one prior vascular endothelial growth factor–targeted therapy (prior anti–programmed death-1/programmed death ligand-1 therapy permitted). InterventionPatients were randomly assigned 1:1 to the 14- or 18-mg lenvatinib starting dose, both in combination with everolimus 5 mg/d. Patients in the 14-mg arm were to be uptitrated to lenvatinib 18 mg at cycle 2, day 1, barring intolerable grade 2 or any grade ≥3 treatment-emergent adverse events (TEAEs) requiring dose reduction occurring in the first 28-d cycle. Outcome measurements and statistical analysisThe primary efficacy endpoint was investigator-assessed objective response rate (ORR) as of week 24 (ORRwk24); the noninferiority threshold of the 14- versus 18-mg arm was p ≤ 0.045. The primary safety endpoint was the proportion of patients with intolerable grade 2 or any grade ≥3 TEAEs within 24 wk of randomization. Results and limitationsThe ORRwk24 for the 14-mg arm (32% [95% confidence interval {CI} 25–39]) was not noninferior to the ORRwk24 in the 18-mg arm (35% [95% CI 27–42]; odds ratio: 0.88; 90% CI 0.59–1.32; p = 0.3). The proportion of intolerable grade 2 or any grade ≥3 TEAEs was similar between the two arms (14 mg, 83% vs 18 mg, 80%; p = 0.5). The secondary endpoints of overall ORR, progression-free survival, and overall survival numerically favored the 18-mg arm. A limitation of this study was that the study design did not allow for a full comparison of progression-free survival between treatment arms. ConclusionsThe study findings support the approved dosing regimen of lenvatinib 18 mg plus everolimus 5 mg daily for patients with advanced RCC. Patient summaryIn this report, we examined two doses of lenvatinib (the approved 18-mg dose and a lower dose of 14 mg) in people with advanced renal cell carcinoma to determine whether the lower dose (which was increased to the approved 18-mg dose after the first treatment cycle) could improve safety without affecting efficacy. The results showed that the efficacy of the lower lenvatinib dose (14 mg) was not the same as that of the approved (18 mg) dose, although safety results were similar, so the approved lenvatinib 18-mg dose should still be used.

Ezabenlimab (BI 754091), an anti-PD-1 antibody, in combination with BI 836880, a VEGF/Ang2-blocking nanobody, in patients (pts) with advanced colorectal cancer (CRC).

98 Background: Anti-PD-1 antibodies may have synergistic effects with other immunomodulatory or targeted agents. This open-label, Phase II platform trial is investigating ezabenlimab, an anti-PD-1 antibody, combined with other agents. Module C of the platform is assessing ezabenlimab plus BI 836880, a humanized bispecific nanobody targeting VEGF/Ang2. Pts are being enrolled into 5 advanced solid tumor cohorts: gastric/gastroesophageal adenocarcinoma; solid tumors (except non-squamous NSCLC or melanoma) with secondary resistance to anti-PD-(L)1 treatment (progression after at least SD for ≥4 months); solid tumors with primary resistance to anti-PD-(L)1 treatment; microsatellite stable (MSS) CRC; mismatch repair-proficient/MSS endometrial carcinoma. Here, we report data from the CRC cohort which has completed recruitment. Methods: Pts with locally advanced, unresectable or metastatic, MSS CRC were enrolled. Patients had received ≥1 line of prior systemic therapy for metastatic disease but were anti-PD-(L)-1 therapy-naïve. Prior anti-angiogenic therapy was permitted. Pts received BI 836880 720 mg plus ezabenlimab 240 mg iv q3w for 1 year or until disease progression, consent withdrawal or undue toxicity. Primary endpoint: investigator-assessed OR (CR or PR per RECIST v1.1). Secondary endpoints: duration of response, disease control, and PFS; safety is also being assessed. Results: 30 pts have been treated: 57% male; median age 61.5 years. All pts had received prior chemotherapy; most pts (23 [77%]) had received prior bevacizumab. At data cut-off (Sep 2021), median duration (range) of treatment was 115.5 (28–295) days; 6 pts remain on treatment. 1 (3%) pt (who had not received prior bevacizumab) achieved a confirmed PR; 16 (53%) pts had SD. Median duration (range) of SD was 128.5 (42–242) days. 29/17/2 (97/57/7%) pts had an AE (any/G3/G4). The most frequent AEs (any/G3) were nausea (40/10%), fatigue (30/3%), peripheral edema (30/0%), vomiting (27/7%), and hypertension (27/17%). There were two G4 AEs (hypertension; platelet count decreased) and no G5 AEs. 24/10/2 (80/33/7%) pts had a drug-related AE (any/G3/G4); most commonly (any/G3) nausea (33/7%), fatigue (27/3%) and hypertension (27/17%). 3 (10%) pts had an infusion-related reaction (G1, n = 1; G2, n = 2). 2 (7%) pts had an AE leading to discontinuation (G3 bile duct stone and G2 peripheral edema). Immune-related AEs were reported in 6 (20%) pts and serious AEs occurred in 13 (43%) pts. Conclusions: BI 836880 plus ezabenlimab had a manageable safety profile in pts with advanced MSS CRC; however, anti-tumor activity was limited in these pts, the majority of whom had received prior bevacizumab. Clinical trial information: NCT03697304.

PD40-11 CLINICAL ACTIVITY OF NIVOLUMAB IN ADVANCED HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER (HLRCC)-ASSOCIATED KIDNEY CANCER

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) II (PD40)1 Sep 2021PD40-11 CLINICAL ACTIVITY OF NIVOLUMAB IN ADVANCED HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER (HLRCC)-ASSOCIATED KIDNEY CANCER Alexis Rompre-Brodeur, Julia Friend, Daniel Girardi, Sandeep Gurram, Paul D. Leger, Munjid Al-Harthy, Ashkan Malayeri, Beatriz Walter Rodriguez, Rabindra Gautam, Jeanny B. Aragon-Ching, Jaime R. Merchan, Arash Rezazadeh Kalebasty, Maria J Merino, W Marston Linehan, and Ramaprasad Srinivasan Alexis Rompre-BrodeurAlexis Rompre-Brodeur More articles by this author , Julia FriendJulia Friend More articles by this author , Daniel GirardiDaniel Girardi More articles by this author , Sandeep GurramSandeep Gurram More articles by this author , Paul D. LegerPaul D. Leger More articles by this author , Munjid Al-HarthyMunjid Al-Harthy More articles by this author , Ashkan MalayeriAshkan Malayeri More articles by this author , Beatriz Walter RodriguezBeatriz Walter Rodriguez More articles by this author , Rabindra GautamRabindra Gautam More articles by this author , Jeanny B. Aragon-ChingJeanny B. Aragon-Ching More articles by this author , Jaime R. MerchanJaime R. Merchan More articles by this author , Arash Rezazadeh KalebastyArash Rezazadeh Kalebasty More articles by this author , Maria J MerinoMaria J Merino More articles by this author , W Marston LinehanW Marston Linehan More articles by this author , and Ramaprasad SrinivasanRamaprasad Srinivasan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002050.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) is a hereditary condition characterized by an increased risk for a clinically aggressive papillary renal cell cancer variant. We aimed to evaluate the clinical activity of nivolumab (anti-PD1 antibody) in patients with advanced HLRCC-associated kidney cancer as salvage therapy following treatment with antiangiogenic targeted therapy. METHODS: Patients with advanced HLRCC-associated kidney cancer who were followed at our institution and had received nivolumab between 2016 and 2020 were reviewed. Objective response rate, progression-free survival (PFS), and duration of response (DOR) per RECIST 1.1 were evaluated. RESULTS: Twenty patients with advanced HLRCC-associated kidney cancer (median age 48.9 years; 16 males/4 females) were identified for inclusion in this analysis. All had received prior antiangiogenic therapy (bevacizumab in combination with erlotinib in 18/20 [90%]). 13/20 (65%) had received one prior line of treatment and 7/20 (35%) had received two or three lines of treatment. The most common sites of metastasis were retroperitoneal (50%), mediastinal lymph nodes (30%), bones (30%), and liver (30%). Seven patients (35%) achieved an objective response including four (20%) with a complete response and three (15%) with a partial response. Median follow up was 22.7 months, and the median PFS was 4.2 months (95% CI 3.4-NR). In patients with an objective response, the median DOR was of 25.7 months (95% CI 18.9-NR). Thirteen patients (65%) were alive at the time of data cutoff and the median OS was not reached (95% CI 21.7-NR). Therapy was generally well tolerated, but two patients (10%) discontinued therapy for immune-related adverse events. CONCLUSIONS: Nivolumab demonstrated antitumor activity with acceptable toxicity in patients with advanced HLRCC-associated kidney cancer treated with prior antiangiogenic therapy. To our knowledge, this report represents the first systematic evaluation of the efficacy of an immune checkpoint inhibitor in this patient population. Source of Funding: NA © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e678-e678 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alexis Rompre-Brodeur More articles by this author Julia Friend More articles by this author Daniel Girardi More articles by this author Sandeep Gurram More articles by this author Paul D. Leger More articles by this author Munjid Al-Harthy More articles by this author Ashkan Malayeri More articles by this author Beatriz Walter Rodriguez More articles by this author Rabindra Gautam More articles by this author Jeanny B. Aragon-Ching More articles by this author Jaime R. Merchan More articles by this author Arash Rezazadeh Kalebasty More articles by this author Maria J Merino More articles by this author W Marston Linehan More articles by this author Ramaprasad Srinivasan More articles by this author Expand All Advertisement Loading ...

Current status and future perspectives of immunotherapy against urothelial and kidney cancer.

Much attention has been paid to immune checkpoint inhibitors to various cancer treatments. In urothelial cancer, pembrolizumab was initially approved for patients who either recurred or progressed following platinum-based chemotherapy. For the platinum-fit population, although the standard first-line treatment is still platinum-based systemic chemotherapy, avelumab has been recently approved as a maintenance therapy for patients who have not had disease progression with four to sixcycles of first-line chemotherapy. In addition, adjuvant nivolumab has just prolonged disease-free survival (DFS) by ~10months, compared with placebo in patients with muscle-invasive bladder urothelial cancer or upper tract urothelial cancer at high-risk of recurrence after radical surgical resection. On the other hand, in kidney cancer, nivolumab was initially approved for advanced renal cell carcinoma patients after one or two prior anti-angiogenic therapies. Next, combinations of two immune checkpoint inhibitors (nivolumab + ipilimumab) and immune checkpoint inhibitor+tyrosine kinase inhibitors (pembrolizumab + axitinib and avelumab + axitinib) were approved for the first-line treatment for patients with advanced renal cell carcinoma. Recently, new generation tyrosine kinase inhibitors, such as cabozantinib and lenvatinib have been combined with immune checkpoint inhibitors. Both nivolumab + cabozantinib and pembrolizumab + lenvatinib have demonstrated superior progression-free survival and objective response rate, compared with sunitinib. So far, no prospective trials have demonstrated the duration of immune checkpoint inhibitor treatments. We are now doing the Japan Clinical Oncology Group 1905 trial, where patients with advanced renal cell carcinoma who have received an immune checkpoint inhibitor for 24weeks are divided into two groups: those who continue immune checkpoint inhibitor treatment and those who discontinue immune checkpoint inhibitor treatment.

Quality-adjusted Time Without Symptoms or Toxicity (Q-TWiST) for Lenvatinib plus Everolimus Versus Everolimus Monotherapy in Patients with Advanced Renal Cell Carcinoma

BackgroundThe lenvatinib (LEN) plus everolimus (EVE) combination demonstrated improved progression-free survival over everolimus alone in a phase 2 trial (Study-205). ObjectiveTo compare quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) between LEN + EVE and EVE alone among patients with advanced renal cell carcinoma (RCC) following one prior antiangiogenic therapy. Design, setting, and participantsThis was a post hoc analysis of Study-205. Outcome measurements and statistical analysisSurvival time was partitioned into three mutually exclusive health states: time with grade 3/4 toxicity (TOX); time before disease progression and without grade 3/4 toxicity (TWiST); and time after disease progression (REL). The mean time in each state was weighted by utility measures and summed to calculate Q-TWiST. Nonparametric bootstrapping generated 95% confidence intervals (CIs). In the base case, utility for TWiST, TOX, and REL was assigned as 1.0, 0.5, and 0.5, respectively. Sensitivity analyses applied alternative utility values for REL, TOX, and TWiST. A relative gain in Q-TWiST of ≥10% and ≥15% has been established as clinically important and clearly clinically important, respectively. Results and limitationsPatients receiving LEN + EVE (n = 51) had a significant mean Q-TWiST gain of 3.7 mo (14.7 vs 11.0 mo; 95% CI for difference 1.3–6.3), with a relative gain of 24% compared to EVE alone. In a sensitivity analysis using alternative utility values for TWiST (varied from 0.55 to 0.9) with utility set to 0.5 for both TOX and REL, the relative Q-TWiST gain was maintained (ranging from 11.0% to 21.2%; all significant) across varying utility values. Limitations include the sample size, the absence of utility estimates, and the length of adverse events from the trial. ConclusionsLEN + EVE showed a significant and clearly clinically important improvement in quality-adjusted survival time versus EVE alone. Patient summaryPatients with advanced kidney cancer who had received other previous treatments experienced a clearly clinically important improvement in quality survival time when treated with lenvatinib plus everolimus compared to everolimus alone.

Anlotinib plus pemetrexed as a further treatment for patients with platinum-resistant ovarian cancer: A single-arm, open-label, phase II study.

5533 Background: Non-platinum chemotherapy is widely used in platinum-resistant recurrent ovarian cancer treatment but with limited efficacy. Combing chemotherapy with angiogenic inhibitors is a new therapeutic choice. Anlotinib is a novel tyrosine kinase inhibitor targeting multiple receptors involved in tumor proliferation, vasculature, and tumor microenvironment. The study aimed to further assess the efficacy and safety of anlotinib combined with pemetrexed in platinum-resistant ovarian cancer. Methods: Patients who had received at least two different chemotherapy regimens (including the first line platinum-based regimen), with histologically proven recurrent platinum-resistant or platinum-refractory epithelial ovarian cancer (including salpingocarcinoma and peritoneal carcinoma), ECOG 0-2, were considered eligible for enrollment to receive six 21-days cycles of anlotinib (12 mg QD from day 1 to 14; 21 days per cycle) orally plus pemetrexed intravenously (0.5 g/m2 on day 1; 21 days per cycle). Subsequent maintenance treatment was anlotinib monotherapy (12 mg QD from day 1 to 14; 21 days per cycle) till disease progression or intolerant toxicity. The primary endpoint was objective response rate (ORR), and the secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and safety. Results: As of Jan 2021, 27 patients were enrolled. The median number of chemotherapy was 4 (range, 2-10) and 51.9% (14/27) of patients had ever received antiangiogenic therapy. The ORR was 36.4% (partial response (PR) in 8 patients; 95% CI, 17.2-59.3). The DCR was 100.0% (PR in 8 patients and stable disease (SD) in 14 patients; 95% CI, 73.5-100). The median time of the first response was 1.6 months (range, 1.3-4.4). The median PFS was 9.3 months (95% CI, NE-NE). Furthermore, the ORR of patients with and without prior antiangiogenic therapy was 16.7% (95%CI, 2.1-48.4) and 60.0% (95%CI, 26.2-87.8) respectively (P = 0.074). Any grades of adverse events (AEs) were observed in 92.6% (25/27) of patients, containing allergic eruption (33.3%), hand-foot syndrome (29.6%), hypertension (25.9%), and fatigue (25.9%). The grade 3-4 adverse events were only observed in 5 patients, including 1 with grade 3 proteinuria, 1 with grade 3 ascites, 1 with grade 3 fatigue, 1 with grade 3 edema limbs and 1 with grade 4 anemia. Conclusions: The treatment of anlotinib plus pemetrexed showed a promising antitumor activity with tolerable toxicity for patients in platinum-resistant and refractory ovarian cancer. Clinical trial information: ChiCTR2000029654.