Advanced RCC Research Articles

Patient perspectives on the impact of immune therapy on comorbid conditions in kidney cancer.

640 Background: Immune based regimen has rapidly become the mainstay of frontline therapy in advanced RCC. The median survival is in the range of 48-55 months and long term remissions are feasible. The impact of the therapy on other health conditions has not been studied. The immune therapy toxicities can potentially be long lasting and life changing. With the conversion of advanced RCC to a chronic disease, awareness and management of these conditions is important. With the use of immune checkpoint therapy in the adjuvant setting has made this information even more critical. Methods: The survey was developed by the Kidney Cancer Research Alliance (KCCure), with multidisciplinary representation from urologic surgeons, medical oncologists and patient advocates. The survey was broadcast between 07/2022 and 09/2022 to patients via website, mailing lists and social media platforms. Multiple responses from the same patient were prohibited via anonymized IP address tracking. The comorbid conditions were collected and patient perspective on changes to any medical conditions was evaluated in the survey questionnaire. Results: Patients with metastatic disease being treated with systemic therapy were included in this survey. A total of 1062 patients responded to the survey of which 399 patients self identified as being metastatic and 289 reported to be treated with immune based systemic therapy. The table includes patient characteristics. 85% respondents were from the United States. The most common condition that developed after starting immune based therapy was thyroid dysfunction as seen in 81 patients, followed by hypertension (Htn) in 50 pts, chronic kidney disease in 23 pts, heart disease in 10 patients and diabetes mellitus (DM) in 13 pts. Immune disorders developed in 26 (10%) patients. Conclusions: There is a noteworthy incidence of medical conditions emerging as a result of immune checkpoint inhibitor therapies in RCC. This information would be a starting point for studying the long term effects of immune therapy and would lead towards development of survivorship programs for renal cancer. [Table: see text]

Phase 1b/2 study of combination 177Lu girentuximab plus cabozantinib and nivolumab in treatment naïve patients with advanced clear cell RCC.

TPS749 Background: Complete response (CR) is still a rare event in patients with advanced clear cell renal cell carcinoma (ccRCC). The combination of nivolumab plus cabozantinib was recently approved for the first-line treatment of ccRCC based on the CheckMate 9ER phase 3 study demonstrating improved progression-free survival (PFS) and objective response rate (ORR) in comparison to sunitinib. However, the CR rate was only 9%. Since the anti-tumor effects of immune checkpoint inhibitors are dependent on the presence of activated tumor-infiltrating T cells, drugs that could synergize with T cells’ anti-tumor activity can allow us to improve CR rates. Activation of the cGAS-STING pathway which is induced by radiation-induced DNA damage, is one promising mechanism that has been investigated. Many studies have shown that radiation treatment augments immune checkpoint inhibition. However, it is not always possible to radiate all metastatic lesions. Therefore, targeted peptide receptor radionuclide therapies, have been developed by conjugating radioisotopes to receptor binding analogs targeting specific cancer cell surface proteins, thereby delivering targeted radiation to cancer cells in the body with minimal damage to surrounding healthy cells. 177Lu girentuximab is the first antibody-radioisotope designed for ccRCC, targeting carbonic anhydrase 9-expressing cells, which includes >90% of ccRCC. It has been tested in metastatic ccRCC as a single agent and shown to be safe and effective in stabilizing disease in 57% of pts. In this study, we hypothesize that 177Lu girentuximab-induced DNA damage will potentiate the STING pathway, and this activation will synergize with nivolumab and cabozantinib to promote trafficking and infiltration of activated T cells to tumors and achieve higher CR rates. Methods: Up to 100 patients with treatment naïve, biopsy-proven ccRCC with adequate organ/marrow function with ≥1 evaluable lesion by RECIST 1.1 will be enrolled. A 5-patient safety lead-in will evaluate myelosuppression. Ongoing safety, and futility monitoring will employ a Bayesian approach. The sample size was chosen for reasonable operating characteristics to distinguish a CR rate (primary endpoint) of 18% as better than 9% using a beta(0.09, 0.91) prior. Secondary endpoints are ORR, PFS by RECIST 1.1, and overall survival. 177Lu-girentuximab 1480 MBq/m2 (61% of single agent MTD) will be administered every 12 weeks for up to 3 cycles. Starting with the second cycle, nivolumab and cabozantinib will be added at standard dose. To explore the effects of the treatment on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with [18F]F-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics and proteomics studies. This investigator initiated trial is supported by Telix Pharmaceuticals and DOD grant W81XWH-22-1-0456.

Outcomes by IMDC risk in the COSMIC-313 phase 3 trial evaluating cabozantinib (C) plus nivolumab (N) and ipilimumab (I) in first-line advanced RCC (aRCC) of IMDC intermediate or poor risk.

605 Background: In COSMIC-313 (NCT03937219), C+N+I significantly improved progression-free survival (PFS) compared with N+I in first-line aRCC of IMDC intermediate or poor risk (Choueiri ESMO 2022). Here, outcomes are analyzed by IMDC risk group. Methods: A total of 855 patients (pts) with clear cell aRCC of IMDC intermediate or poor risk were randomized to receive C 40 mg QD or matched placebo (P), stratified by region and IMDC risk. Both treatment groups received N (3 mg/kg IV Q3W) + I (1 mg/kg IV Q3W) for 4 cycles followed by N (480 mg IV Q4W); N was administered for up to 2 years. The primary endpoint was PFS by blinded independent radiology review (BIRC) per RECIST 1.1 in the first 550 randomized pts (PITT population). The secondary endpoint was overall survival (OS) in all randomized pts; objective response rate (ORR) and safety were additional endpoints. Results: Overall, 75% of pts were IMDC intermediate and 25% were poor risk. Meaningful differences in baseline characteristics for intermediate vs poor risk in the PITT population were observed for KPS ≥90 (67% vs 47%), prior nephrectomy (71% vs 44%), and ≥2 target/non-target lesions per BIRC (68% vs 83%); characteristics were balanced across treatment arms for intermediate risk but some imbalances were seen for poor risk (42% for C+N+I vs 52% for P+N+I had KPS ≥90 and 37% vs 50% had prior nephrectomy). In intermediate risk pts, PFS was improved with C+N+I (HR 0.63, 95% CI 0.47–0.85), and ORR and DCR (PITT population) were numerically higher (Table). For poor risk pts, no difference in PFS and ORR was apparent, but DCR was numerically higher with C+N+I. PD as best response was lower with C+N+I vs P+N+I in both risk groups. Duration of response was not reached (NR) in each treatment group. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 74% with C+N+I vs 42% with P+N+I for intermediate risk and 67% vs 38% for poor risk. TRAEs led to discontinuation of all treatment components in 14% vs 5% for intermediate risk and 5% vs 4% for poor risk. Additional analyses relevant to IMDC risk group will be presented. Conclusions: In COSMIC-313, C+N+I improved PFS vs P+N+I in first-line aRCC of IMDC intermediate or poor risk; subgroup analysis suggested that the benefit was primarily in intermediate risk pts. Follow-up for OS is ongoing. Clinical trial information: NCT03937219 . [Table: see text]

Antibody-Based Therapeutics for the Treatment of Renal Cell Carcinoma: Challenges and Opportunities.

Renal cell carcinoma (RCC) is among the top 10 most common cancers in both men and women with an estimated 75 000 cases each year in the US. Over the last decade, the therapeutic landscape for patients with metastatic RCC has significantly evolved, with immunotherapy emerging as the new front-line therapy. Despite significant improvement in toxicity profile and survival outcomes, key concerns such as patient selection, treatment sequencing, and intrinsic and acquired resistance remain unresolved. Emerging options such as antibody-based therapeutics (eg, anti-CD70, anti-CA9, and anti-ENPP3) are being explored in clinical trials for patients with cancer resistant or refractory to current immunotherapies. Despite positive results for hematological cancers, breast cancer, and more recently bladder cancer, most antibody-based therapies failed to improve the outcomes in patients with advanced RCC. This underscores the need to understand the underlying causes of failed responses to this treatment class, which will ultimately support the rational design of more effective and tolerable treatments. In this review, we summarize the evolving landscape of RCC therapeutics and describe recent clinical trials with emerging antibody-based therapeutics. We also describe the challenges that need to be overcome for the successful creation of therapeutic antibodies for treating RCC.

First-line therapy for elderly patients with advanced renal cell carcinoma in the immuno-oncology era: a network meta-analysis.

Tyrosine kinase inhibitors (TKI) or immune checkpoint blockade (ICB), either alone or in combination, confers a significant overall survival (OS) benefit for metastatic RCC in the first-line setting. However, guidance for optimal treatment selection in elderly patients remains limited. A database search was performed to identify eligible randomized controlled trials (RCTs) evaluating first-line regimens for patients with advanced RCC older than 65years old. The primary outcomes were progression-free survival (PFS) and OS. Indirect comparisons of available regimens were estimated using a random-effects network meta-analysis. A total of 14 and five RCTs were eligible for PFS and OS analyses. Compared with sunitinib, pembrolizumab plus axitinib (HR 0.68, 95% CI 0.48-0.97) and pembrolizumab plus lenvatinib (HR 0.61, 95% CI 0.4-0.94) were associated with improved OS. Pembrolizumab plus lenvatinib, nivolumab plus cabozantinib, pembrolizumab plus axitinib, and cabozantinib alone each showed improved PFS over sunitinib. Among these, pembrolizumab plus lenvatinib showed better PFS than pembrolizumab plus axitinib (HR 0.58, 95% CI 0.37-0.91), but no PFS difference compared to nivolumab plus cabozantinib (HR 0.63, 95% CI 0.39-1.03) and cabozantinib alone (HR 0.84, 95% CI 0.40-1.77). Network ranking showed pembrolizumab plus lenvatinib provided the favored OS and PFS benefit for elderly patients. The combination of ICB with TKI such as pembrolizumab plus lenvatinib needs to be considered over monotherapy in the elderly population, but further validation using real-world data or prospective trials is necessary to confirm the efficacy and safety of first-line regimens for the geriatric population with advanced RCC.

Lenvatinib and Pembrolizumab (Lenvima and Keytruda)


 CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.
 The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.
 This review assesses Lenvima (lenvatinib) 20 mg (two 10 mg capsules) orally once daily in combination with Keytruda (pembrolizumab) administered as an IV infusion over 30 minutes every 3 weeks.
 Indication: In combination with pembrolizumab, for the treatment of adult patients with advanced (not amenable to curative surgery or radiation) or metastatic RCC with no prior systemic therapy for metastatic RCC.

Molecular analysis and favorable clinical outcomes in real-world patients with metastatic renal cell carcinoma

Background Prior biomarker studies have mainly been restricted to advanced RCC patients treated in clinical trials or have had limited integration of immunotherapy features such as programmed death ligand (PD-L)-1 with gene expression signatures intended to capture other canonical pathways to confirm their prognostic value. Material and methods PD-L1 and PD-L2 by immunohistochemistry (IHC), PD-L2 messenger RNA (mRNA), and 10 gene expression profile (GEP) signatures targeting immune, angiogenesis and canonical pathways were analyzed in nephrectomy specimens from 227 advanced clear cell RCC (ccRCC) and 42 non-clear cell RCC (nccRCC) patients treated with targeted therapies including VEGF and mTOR inhibitors. Biomarker association with best overall response (BOR), progression-free survival (PFS), and overall survival (OS) were evaluated using multivariable modeling. Except for PD-L1 IHC and angiogenesis, tested with a nominal p-value of .05, multiplicity control was applied with a 0.1 significance level given limited experience in this setting. Results The strongest biomarker correlations were observed for hypoxia inducible factor (HIF)-2a and angiogenesis signatures (rho = 0.860 [ccRCC], 0.819 [nccRCC]); hypoxia and glycolysis signatures (rho = 0.943 [ccRCC], 0.973 [nccRCC]); PD-L2 mRNA and T-cell-inflamed GEP signatures (rho = 0.764 [ccRCC], 0.897 [nccRCC]); and PD-L2 mRNA and monocytic myeloid-derived suppressor cell signature (rho = 0.787 [ccRCC], 0.815 [nccRCC]). For ccRCC, higher angiogenesis expression was associated with improved BOR (OR:2.85 [95%CI:1.37, 5.93]), longer PFS (HR:0.61 [95%CI:0.45, 0.82]) and OS (HR:0.74 [95%CI:0.54, 1.00]); higher PD-L1 expression with shorter OS (HR:1.44 [95%CI:1.01, 2.07]). For nccRCC, there was more than a two-fold increased risk with longer OS associated with lower angiogenesis (HR:2.43 [95%CI:1.04, 5.68]), glycolysis (HR:7.03 [95%CI:1.51, 32.76]) and hypoxia (HR:8.83 [95%CI:1.69, 46.05]) gene signature expression. Conclusion Data pointed at PD-L1 IHC and angiogenesis expression in ccRCC and hypoxia, glycolysis, and angiogenesis expression in nccRCC as potential prognostic factors. These findings may have implications for the design and interpretation of advanced RCC trials and to identify potential targets for combination therapy strategies.

Economic evaluation of first-line nivolumab plus cabozantinib for advanced renal cell carcinoma in China.

BackgroundIn the Checkmate9ER trial, first-line treatment with nivolumab combined with cabozantinib (NI + CA) has shown efficacy for advanced renal cell carcinoma. This study aims to evaluate the impact of the health and economic outcomes of NI + CA in China.MethodsClinical efficacy data were derived from pivotal phase III CheckMate 9ER trial. A three-state partitioned survival model was established based on disease progression. Progression-free survival and overall survival of NI + CA vs. sunitinib were fitted with log-logistic and log-normal distributions, respectively. Mixture cure, non-mixture cure, and Royston/Parmar spline models were used to evaluate model robustness. The results derived the computational cost from the Chinese healthcare system perspective. The primary outcomes were quality-adjusted life-years (QALYs), total cost in US dollars, as well as incremental cost-effectiveness ratios (ICERs) at the willingness-to-pay threshold in China. One-way and probabilistic sensitivity analysis were also used to assess the robustness of the model.ResultsIn the base-case analysis result, 0.86 additional QALYs could be obtained in the NI+CA (3.84 QALYs) versus the sunitinib strategy (2.97 QALYs). The ICER of NI+CA compared with the sunitinib strategy was US$292,945 per QALY. The ICER value in the NI+CA strategy was higher than the Chinese willingness-to-pay threshold of US$38,024 per QALY. Although NI+CA can improve long-term patient survival significantly over sunitinib in the treatment of advanced renal cell carcinoma, it is unlikely to be cost-effective due to high cost. The results of the one-way sensitivity analysis showed that drug cost, health utility value at the stage of disease progression, and subsequent treatment proportion had a greater impact on the stability of ICER values.ConclusionsNivolumab combined with cabozantinib can prolong the life of patients with advanced renal cell carcinoma and improve their quality of life, but there is a corresponding increase in medical cost. The NI + CA strategy is unlikely to be considered cost-effective in the treatment of advanced RCC from the perspective of Chinese healthcare system.

1468P IO-synthesise RCC: Real-world outcomes of nivolumab in patients (pts) with previously treated advanced non-clear cell renal cell carcinoma (nccRCC) – A pooled analysis from France and Germany

Nivolumab (nivo) is the first immune checkpoint inhibitor approved for previously treated advanced RCC, based on the efficacy demonstrated in the CheckMate 025 trial. Efficacy data of nivo in pts with advanced nccRCC are limited, especially in real-world setting, although there is a high unmet medical need. This analysis focuses on advanced nccRCC pts enrolled in two observational studies.

1454P Optimizing ipilimumab in RCC: Results from SAKK 07/17 (CM-980) nivolumab (N) + ipilimumab (Ipi) in mRCC

N + Ipi is approved for 1st line treatment in advanced RCC patients (pts) with an intermediate or poor risk score (IMDC). The CheckMate 214 study (CM-214) with 4 cycles of Ipi (1mg/kg/q3w ) and N (3mg/kg/q2w) showed superior outcomes for N+Ipi compared to Sunitinib. SAKK 07/17 (CM-980) is a prospective single-stage single-arm multicenter phase II trial with 10 swiss centres and a total of 74 pts examining the treatment-related adverse events (TRAEs) by individualizing Ipi applications while preserving overall efficacy and outcome.

Combination of sunitinib and 177Lu-labeled antibody cG250 targeted radioimmunotherapy: A promising new therapeutic strategy for patients with advanced renal cell cancer

Sunitinib is an effective treatment for patients with metastatic Renal Cell Carcinoma (mRCC) but ultimately resistance occurs. The aim of this study was to investigate sunitinib resistance in RCCs and to develop therapeutic combination strategies with targeted radioimmunotherapy (RIT).We studied two RCC models, analyzed Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) and AXL/MET expression and performed therapy studies in Balb/cnu/nu mice combining sunitinib and [177Lu]Lu-cG250 RIT (6.5 MBq/10 μg), specifically targeting RCC cells.pAXL and pMET were expressed in sunitinib-resistant SK-RC-52 and absent in sunitinib-sensitive NU12. NGS evaluation showed that expression of VEGFA, VEGFB, VEGFD, PGF and VEGFR1,2,3 was higher and expression of VEGFC and PDGFA was lower in NU12 than in SK-RC-52.Therapy studies combining sunitinib with [177Lu]Lu-cG250 RIT showed that the best response in mice with “resistant” SK-RC-52 tumors was observed with two cycles of Sunitinib and [177Lu]Lu-cG250 RIT, probably due to increased vascular permeability by sunitinib treatment. In the “sensitive” NU12 model, two cycles of [177Lu]Lu-cG250 RIT and two cycles of combination treatment were equally effective.Enhanced therapeutic efficacy was achieved when two agents ([177Lu]Lu-cG250 RIT and sunitinib) that on their own did not induce satisfactory response levels, are combined. Our findings provide a promising new therapeutic strategy for patients with advanced RCC.

Outcomes of patients with advanced non-clear cell renal cell carcinoma treated with first-line immune checkpoint inhibitor therapy

BackgroundImmune checkpoint inhibitors (ICI) have demonstrated impressive activity in metastatic clear-cell renal cell carcinoma (ccRCC) and have become standard treatment options for patients with advanced disease. Data supporting the effectiveness of ICI-based therapy in advanced non-clear cell RCC (nccRCC) is more limited. MethodsWe performed a retrospective analysis using the International Metastatic RCC Database Consortium (IMDC) to evaluate the outcomes of patients with advanced nccRCC. Patients were classified into three groups based on first-line therapy: ICI-based therapy (monotherapy or combination), vascular endothelial growth factor (VEGF) inhibitor monotherapy, or mammalian target of rapamycin (mTOR) inhibitor monotherapy. The primary outcome was overall survival (OS). Secondary outcomes were time to treatment failure (TTF) and objective response rate (ORR). We used the Kaplan–Meier method to compare OS and TTF between treatment groups and Cox proportional hazards models to adjust for prognostic covariates. ResultsWe identified a total of 1145 patients with metastatic nccRCC. The most common subtype was papillary RCC (54.9%). For first-line therapy, 74.3% received VEGF monotherapy, 15% received mTOR monotherapy, and 10.7% received ICI-based therapy. Median OS in the ICI group was 28.6 months, versus 16.4 months in the VEGF group and 12.2 months in the mTOR group. Median TTF in the ICI group was 6.9 months, versus 5.0 months in the VEGF group and 3.9 months in the mTOR group. ORR was 27.2% in the ICI group, 14.5% in the VEGF group, and 9% in the mTOR group. After adjusting for the IMDC risk group, histological subtype, and age, the hazard ratio for OS was 0.57 (95% CI 0.42–0.78, p < 0.0001) for ICI versus VEGF and 0.50 (95% CI 0.36–0.71, p < 0.0001) for ICI versus mTOR. ConclusionsIn advanced nccRCC, first-line ICI-based treatment appears to be associated with improved OS compared to VEGF and mTOR targeted therapy. These results should be confirmed in prospective randomised trials.

Recent Advances in Tivozanib plus Nivolumab Combinatorial Strategies in Renal Cell Carcinoma

The treatment landscape of advanced renal cell carcinoma (aRCC) has witnessed significant benefits from the introduction of VEGF TKI/ICI (vascular endothelial growth factor receptor tyrosine kinase inhibitor/immune checkpoint inhibitor) combination in the first-line treatment. Such outcome benefits could extend to the relapsed/refractory setting with an effective, well-tolerated novel combination. Since the U.S. FDA approval of tivozanib monotherapy for the treatment of adult patients with relapsed or refractory advanced RCC following two or more prior systemic therapies,1 there is growing interest in exploring its full potential in combination with anti-PD-1 like ICI agents. In this roundtable discussion, internationally renowned cancer experts brainstorm the potential immunomodulatory capabilities of tivozanib plus nivolumab combination as first-liane and beyond settings in patients with metastatic RCC. The expert panel also explore potential data from previous and ongoing clinical trials and shared their perspectives about a tolerable safety profile and promising antitumor efficacy

Maturation of overall survival (OS) in TIVO-3 with long-term follow-up.

4557 Background: Maturity of survival data is a consideration in the value assessment and confident clinical application of oncology drugs based on trial evidence. TIVO-3 supported FDA-approval of tivozanib (TIVO) in relapsed/refractory (R/R) advanced RCC, meeting the primary endpoint of significantly improved PFS over sorafenib (SOR) (HR: 0.73, 95% CI, 0.56-0.95). Long-term follow-up analyses demonstrate that the PFS rate at 3-years with TIVO is &gt;5x higher than with SOR (12% vs 2%, respectively), yet a significant OS benefit for TIVO has not been observed to date. Here we report the contribution of event accumulation and data maturation on the stability of KM survival estimates. Methods: Intent-to-treat analyses of Cox proportional hazards and log-rank statistics were used to estimate the HR and 95% CI for OS in the TIVO-3 trial at prespecified (2-years after last-patient-in [LPI]; ≥251 events) and exploratory extended follow-up timepoints (≥270 events; database closure). Patients were followed for survival until death, consent withdrawal, or loss to follow-up. Results: 350 patients were randomized 1:1 to TIVO (n=175) or SOR (n=175). 2-years post LPI and a mean follow-up of 17.9 months (data cut-off August 2019), 65% of patients experienced an event (HR: 0.99, 95% CI, 0.76-1.29). Subsequent analyses are reported at 20.3 (May 2020), 21.9 (January 2021), and 22.8 (May 2021) months follow-up. Accumulation of events and HR over time is shown in the Table. After almost 23 months of follow-up and realization of 80% of events, OS HR has decreased to below 0.90, in favor of TIVO. Conclusions: Serial OS analyses using KM estimates are subject to increased curve reliability with decreased censoring and limited residual patients at risk for death. Long-term follow-up of TIVO-3 suggests early and consistent PFS benefit with TIVO over SOR is associated with an OS HR decline over-time with more events. Clinical trial information: NCT02627963. [Table: see text]

A phase 2 study of bevacizumab, erlotinib, and atezolizumab in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) associated or sporadic papillary renal cell cancer (pRCC).

TPS4604 Background: Papillary RCC accounts for 10-15% of kidney cancers and is the second most common subtype of RCC after clear cell RCC. HLRCC is a familial cancer syndrome characterized by a propensity for developing papillary kidney cancer. HLRCC-associated renal tumors are known to be clinically aggressive, with a paucity of treatment options. The combination of bevacizumab and erlotinib has shown promising activity in patients with HLRCC-associated RCC and sporadic pRCC (Srinivasan et al, ASCO 2020). We hypothesize that the addition of a PDL-1 inhibitor might provide synergistic clinical activity against these tumors. Methods: This is an ETCTN-sponsored, open-label, multicenter, phase 2 study evaluating bevacizumab, erlotinib and atezolizumab in adult and pediatric patients with advanced 1) HLRCC-associated RCC or 2) sporadic pRCC. Eligible patients will have cytologically or histologically confirmed advanced HLRCC- associated or sporadic pRCC, age ≥12 years, ECOG PS ≤2, no more than two prior regimens targeting the VEGF pathway, no prior treatment with PD-1 or PD-L1 inhibitors and adequate organ and marrow function. Patients with HLRCC-associated RCC or sporadic pRCC will be enrolled into parallel, independent cohorts. Initially, 12 adult patients with advanced HLRCC-associated RCC or sporadic pRCC will be enrolled into the safety run-in portion of the trial. If ≤ 3 dose-limiting toxicities are observed, enrollment will proceed into both cohorts and pediatric patients will be allowed to enroll. A Simon two-stage phase 2 minimax design will be used to determine accrual to each cohort. In the first stage, 12 evaluable patients will be enrolled into cohort 1) HLRCC-associated RCC or cohort 2) sporadic pRCC. If 0 of 12 patients have a CR, then no further patients will be enrolled in that cohort. If 1 or more of the first 12 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 21 evaluable patients (adult or pediatric) have been enrolled into each cohort for a total of 42 patients. Adult patients will receive a fixed dose of bevacizumab (15 mg/kg IV every 21 days) plus atezolizumab (1,200 mg IV every 21 days) and erlotinib (150 mg PO daily). Pediatric patients will receive bevacizumab (15 mg/kg IV every 21 days) plus atezolizumab 15 mg/kg (max 1,200 mg IV every 21 days) and erlotinib 85 mg/m2 (max 150 mg PO daily). The primary endpoint is to assess the complete response rate according to RECIST 1.1 in patients with advanced 1) HLRCC-associated RCC and 2) sporadic pRCC. Secondary endpoints include safety and tolerability, objective response rate, disease control rate, progression-free survival and overall survival. Key exploratory endpoints include evaluation of immunologic modulation associated with this regimen. The study has just opened to accrual. Clinical trial information: NCT04981509.

Activity of tivozanib in non-clear cell renal cell carcinoma (nccRCC): Subgroup analysis from a phase 2 randomized discontinuation trial.

4542 Background: Non-clear cell renal cell carcinoma (nccRCC) is a blanket term for a collection of heterogenous and biologically diverse RCC histologies including (but not limited to) papillary, chromophobe and unclassified subtypes. Tivozanib is a selective VEGFR tyrosine kinase inhibitor with demonstrated activity in RCC with clear cell component. Here we report efficacy of tivozanib in a histologically diverse nccRCC subset included in a phase 2 study. Methods: We conducted a subgroup analysis of patients with nccRCC enrolled in the study 201 (NCT00502307), a phase 2 randomized discontinuation trial of tivozanib in patients with RCC who had no prior VEGF targeted treatment. Clinical outcomes including overall response rate (ORR), disease control rate (DCR, defined by CR+PR+SD), and progression free survival (PFS) were examined. Safety outcomes for all patients are reported in the original publication (Nosov, JCO 2012). Results: Of the 272 patients enrolled, 46 (16.9%) patients had nccRCC. [11 (4%) papillary, 2 (0.7%) chromophobe, 2 (0.7%) collecting duct, and 31 (11.4%) unclassified/mixed]. Of the 46 nccRCC patients, the ORR was 17.4% by investigator (INV) review and 15.2% by independent radiology review (IRR). The DCR was 80.4% by INV and IRR. The median PFS was 6.7 months (204 days) (95%CI: 125-366 days) by IRR (Figure 1). Of note, 14 patients with SD after 16 weeks on tivozanib were randomized to 12 weeks of placebo and may have progressed during that timeframe before unblinding and resuming tivozanib. Safety was not analyzed by histology but there were no new safety signals and was consistent with tivozanib labelling in the ITT population. Conclusions: Tivozanib demonstrated activity and a favorable safety profile in patients with nccRCC. This data adds to the body of evidence supporting VEGFR TKI use in advanced RCC including in non-clear cell histologies. Clinical trial information: NCT00502307. [Table: see text]

Diagnostic impact of 18F-FDG PET/CT imaging on the detection of immune-related adverse events in patients treated with immunotherapy.

Immunotherapy is an effective treatment method for cancer cells with humoral and cellular immune mechanisms of action but triggers an inflammatory response and disrupts standard protective immune tolerance. Early detection of immune-related adverse events (irAEs) on PET/CT is crucial for patient management and subsequent therapy decisions. In this study, we aimed to evaluate the impact of 18F-FDG PET/CT on detecting of irAEs in patients receiving immunotherapy. Forty-six patients with advanced RCC (n: 32), malign melanoma (n: 9), lung cancer (n: 4), and laryngeal carcinoma (n: 1), who underwent 18F-FDG PET/CT imaging for response assessment after immunotherapy, were enrolled in the study. Newly detected findings associated with irAEs on posttreatment PET/CT images were compared with the pretreatment PET/CT, both qualitatively and semi-quantitatively. Twenty-eight (61%) patients developed irAEs as observed on PET/CT. Enteritis/colitis was the most frequent irAE visualized on PET/CT with 13 patients (28.2%), followed by gastritis (17.3%), thyroiditis (13%), and myositis/arthritis (13%). Hepatitis (6.5%), pneumonitis (6.5%), sarcoid-like reaction (4.3%), and hypophysitis (4.3%) were observed to a lesser extent. The median time between the appearance of irAEs on PET/CT and the initiation of immunotherapy was 4.3months. There were no significant differences in age, sex, and treatment response status of patients with and without irAEs. 18F-FDG PET/CT plays a fundamental role in cancer immunotherapy with the potential to show significant irAEs both in the diagnosis and in follow-up of irAEs. IrAEs were present on PET/CT images of more than half of the patients who received immunotherapy in our study.

The clinicopathological profile of Renal cell carcinoma at BP Koirala Memorial Cancer Hospital

Introduction: Renal cell carcinoma accounts for 3-5%of all oncological diagnoses. In this study, we aim to assess the clinicopathological profile of Renal cell carcinoma in a cancer hospital of Nepal. Method: This is a retrospective study conducted at BP Koirala Memorial Cancer hospital Nepal. All patients with localized and locally advanced RCC who underwent radical or partial nephrectomy at our hospital between Jan 2012 to Dec 2018 were included. Normally distributed continuous variables were expressed as median, mean ± standard deviation (SD). Categorical variables were expressed as frequencies and percentages of an appropriate denominator. Results: Among 94 patients with RCC, the median age was 55 years (53.56 ±12.83). Most of the patients were male (56.4%, n=53) and Hindu by religion (67.02%, n=63). Eighty-three percent (n=78) of patients were smokers, 58.5 % (n=55) were hypertensive and 40.4% (n= 38) had history of diabetes mellitus. The most common symptom was incidental renal mass (42.55%, n=40). Ninety-five percent (n=89) of the patients underwent radical nephrectomy and five percent (n=5) of the patients underwent partial nephrectomy. The median duration of postoperative hospital stay was 8 days. The most common histological finding was Clear cell type (86.17, n=81) followed by papillary cell type (10.63%, n= 10) followed by chromophobe type (2.12%, n=2), and duct of Bellini( 1.06%, n=1). Most of the patients had pathological T2 (41.48%, n=39) disease followed by T3 (26.59%, n=25) disease. Conclusion: Smoker males in the fifth to sixth decade of life are at risk for developing RCC. Radical Nephrectomy is the standard of care with Clear cell carcinoma as the most common histological subtype.

SWOG S1931 (PROBE): Phase III randomized trial of immune checkpoint inhibitor (ICI) combination regimen with or without cytoreductive nephrectomy (CN) in advanced renal cancer.

TPS402 Background: Kidney cancer presenting with synchronous primary tumor and metastases has demonstrated shorter survival outcome, as compared to the patients relapsing later with metastases after nephrectomy. CARMENA trial demonstrated no change in overall survival with addition of nephrectomy to sunitinib therapy. Immune checkpoint based combination therapy has now become the standard of care in frontline setting for RCC. The role of cytoreductive nephrectomy (CN) or primary resection has not been evaluated in the setting of immune checkpoint based systemic therapy. The PROBE study design attempts to answer the question whether CN has an impact on overall survival outcomes in advanced RCC within the context of immune checkpoint based combination regimens. The underlying mechanism is that the broader antigen spread and higher neoantigen load enabled by the primary tumor would enhance the efficacy of the immune therapy. CN after initial systemic therapy will potentially enable eradication of the immune resistant clones within the primary. Methods: Eligible patients with primary tumor and metastases are treated with one of the FDA approved ICI based combinations: ipililumab and nivolumab, axitinib and pembrolizumab, or axitinib and avelumab. Cabozantinib + nivolumab and lenvatinib + pembrolizumab combinations are being added into the next amendment. Urology evaluation and response assessment is required. Randomization occurs between 10-14 weeks of therapy; 1:1 to receive CN followed by systemic therapy or to continue on systemic therapy. The primary endpoint is overall survival. We estimate the median survival from time of randomization for the non-surgical arm will be 25 months. The study hypothesis is that CN will result in improvement in OS outcomes in advanced synchronous RCC post-initial systemic immune checkpoint based combination therapy. With a sample size of 302 eligible, randomized participants (151 per arm) and a one-sided alpha = 0.025, the study has 85% power to detect a 47% improvement in median survival (HR = 0.68; 1/0.68 = 1.47) Clinical trial information: NCT04510597.

Long-term PFS from TIVO-3: Tivozanib (TIVO) versus sorafenib (SOR) in relapsed/refractory (R/R) advanced RCC.

362 Background: The TIVO-3 trial supported FDA-approval of TIVO in R/R advanced RCC, demonstrating significantly improved PFS over SOR in the primary independent review committee [IRC] analysis (HR: 0.672, 95% CI: 0.52-0.87). Long-term survival without disease progression (LT-PFS) is a clinically meaningful outcome among patients with R/R mRCC and ≥2 lines of prior therapy. We assessed the proportion of TIVO-3 patients living progression-free with R/R mRCC at 6-month intervals up to 4 years post-initiation of TIVO or SOR. Methods: Exploratory analysis of LT-PFS was calculated using investigator-assessment [INV] with a data cut-off of May 24, 2021. PFS hazard ratio and landmark values of LT-PFS at 6, 12, 18, 24, 30, 36, 42 and 48 months are reported. Results include the ITT population, with censoring for missing assessments and discontinuation without PD. Cox proportional hazards and log-rank statistics were used to estimate the HR and 95% CI for INV-PFS; odds ratios (ORs) are reported for landmark timepoints up to 36-months. LT-PFS across prespecified subgroups were analyzed descriptively. Results: 350 patients were randomized to TIVO (n=175) or SOR (n=175). INV PFS was superior with TIVO vs SOR (HR: 0.624, 95% CI: 0.49-0.79). Landmark LT-PFS rates up to 48-months are consistently higher with TIVO vs SOR, with 12% vs 2% and 7.6% vs 0% at 3- and 4-years, respectively (Table). Despite low numbers of patients at risk with extended follow-up, subgroups with ≥15% LT-PFS at 3-years include IMDC favorable risk, female gender, ECOG PS0, age ≥65 years, and region NA – all confined to the TIVO arm. Conclusions: INV PFS with long-term follow-up is consistent with primary IRC PFS. Patients treated with TIVO were up to 5X more likely to experience LT-PFS compared to SOR. A clinically relevant minority of patients are alive and progression-free on TIVO at 3- and 4-years. Clinical trial information: NCT02627963. [Table: see text]