Advanced nccRCC Research Articles

Changes in outcome of patients with advanced non-clear cell renal cell carcinoma from the tyrosine kinase inhibitor era to the immuno-oncology era.

The therapeutic benefit of immuno-oncology (IO) therapy for patients with advanced non-clear-cell renal cell carcinoma (nccRCC) remains unclear. We reviewed clinical data from 93 patients with advanced nccRCC who received first-line systemic therapy including IO combination therapy and tyrosine kinase inhibitor (TKI) monotherapy at our affiliated institutions. Patients were divided based on the period when the treatment was implemented as the standard of care into the IO and TKI eras. Survival and tumor response outcomes were compared between the IO and TKI eras. Of the 93 patients, 50 (54%) and 43 (46%) were categorized as IO era and TKI era groups, respectively. Progression-free survival (PFS) and overall survival (OS) were significantly longer in the IO era than in the TKI era (median PFS: 8.97 vs. 4.96months, p = 0.0152; median OS: 38.4 vs. 13.5months, p = 0.0001). After the adjustment using other covariates, the treatment era was an independent factor for PFS (hazard ratio: 0.59, p = 0.0235) and OS (hazard ratio: 0.27, p < 0.0001). Objective response and disease control rates was not significantly different between the treatment eras (26% vs. 16.3%, p = 0.268; 62% vs. 62.8%, p = 0.594). The implementation of IO therapy was significantly associated with longer survival in the nccRCC population. Further studies are needed to establish a more effective treatment strategy in this population using multiple regimens of IO combination therapy.

Anlotinib combined with sintilimab as first-line treatment in patients with advanced non-clear cell renal cell carcinoma (nccRR): Preliminary results from an exploratory prospective multicentre clinical study.

4544 Background: Non-clear cell renal cell carcinoma (nccRCC) accounts for approximately 25% of all kidney cancers, however, the effect of systemic chemotherapy is limited. We report the first results of a single-arm, phase 2 study (NCT05220267) evaluating the efficacy and safety of anlotinib (a multi-target tyrosine kinase inhibitor) combined with sintilimab (a monoclonal antibody against programmed cell death protein 1) as first-line treatment in patients with advanced nccRCC. Methods: Patients with histologically confirmed advanced nccRCC and measurable disease per RECIST v1.1 who had not previously received systemic therapy were received anlotinib (12 mg qd, d1-14, repeated every 21 days) plus sintilimab (200 mg IV Q3W) till disease progression or intolerant toxicity. The primary endpoint is progression-free survival (PFS); secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results: From April 2022 to December 2023, 43 patients were enrolled with a median age of 43 years (range: 18-79), 10 (23.3%) had papillary histology, 10 (23.3%) had FH-RCC histology, 8 (18.6%) had TFE3-RCC histology and 15 (34.9%) were unclassified. Among these participants, 34 patients were evaluable. 62.8% were IMDC intermediate- or poor-risk, 74.4% had prior nephrectomy and 100% had synchronous metastatic disease. ORR and DCR were 52.9%(95%CI 0.35-0.70)and 94.1%(95%CI 0.80-0.99), respectively.≥1 and &lt;1 Combined Positive Score of PD-L1 expression were observed in 50.0% (17/34) and 32.4% (11/34) patients respectively, and the ORR was 52.9% (95%CI: 0.278-0.770) and 45.5% (95%CI: 0.167-0.766) in the two groups. The median time of the first response was 3.7 months (range, 3.3-9.5). As of January 7, 2024, median follow-up time was 8.5m (95%CI 4.8-12.3). The median PFS was 15.1m (95%CI 13.2-15.9). Treatment-related grade 3/4 adverse events were observed in 20.9% (9/43) of the patients, encompassed hyponatremia (3 patients, 7%), proteinuria (1 patients, 2%), anemia (1 patients, 2%), Hand-foot syndrome (4 patients, 9.1%). Neither unexpected safety signals nor treatment-related death occurred. Conclusions: Our results showed promising efficacy and acceptable toxicity of anlotinib plus sintilimab for patients with advanced nccRCC. Complete results are awaited in 2024 after follow-up completion of the entire cohort. Clinical trial information: NCT05220267 .

Advanced Non-Clear Cell Renal Cell Carcinoma Treatments and Survival: A Real-World Single-Centre Experience.

Non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous group of cancer. Treatment recommendations are extrapolated from ccRCC and lack solid evidence. Here, we review advanced nccRCC patients treated at our institute. We collected retrospective data on all advanced nccRCC pts treated at the Istituto Oncologico Veneto from January 2008. We compared overall response rate (ORR), progression free survival (PFS) and overall survival (OS) according to histological subtypes and type of systemic treatments. Kaplan-Meier method, log-rank test and Cox regression were used to estimate and compare PFS and OS. Of 1370 RCC patients, 289 had a diagnosis of nccRCC and 121 were eligible for the analysis. Fifty-three pts showed papillary histology (pRCC), 15 chromophobe; 37 unclassified RCC (NOS-RCC), 16 other histologies. Pts with chromophobe and other hystologies showed poorer survival rates compared to pRCC and NOS-RCC (mOS 10.7 vs. 20.7 vs. 30.7, p = 0.34). Pts treated with combination regimens achieved a better OS (30.7 vs. 13.7, p = 0.10), PFS (12.7 vs. 6.4, p = 0.10) and ORR (42.4% vs. 13.9%, p = 0.002) than those treated with monotherapy. IMDC and Meet-URO score retained their prognostic value. Our retrospective real-life cohort of advanced nccRCC patients shows that immunotherapy-based combinations could improve ORR, PFS and OS compared to TKI monotherapy. Prospective trials for nccRCC patients utilizing novel therapies are ongoing and their results eagerly awaited.

Immune landscape of patients with metastatic non-clear cell renal cell carcinoma (nccRCC) treated with atezolizumab plus bevacizumab.

4535 Background: The treatment of metastatic nccRCC remains an area of unmet clinical need. A multicenter phase II trial of atezolizumab/bevacizumab in patients with advanced nccRCC or any RCC type with ≥ 20% sarcomatoid differentiation (NCT02724878) demonstrated clinical activity of these agents, with objective response rates of 50% in patients with sarcomatoid clear-cell RCC (sccRCC) and 26% in patients with nccRCC. We aim to understand the intratumoral and circulating factors that impact immunotherapy response in this population. Methods: We collected blood samples prior to therapy and on-treatment (following 2 cycles of therapy) and quantified levels of plasma soluble factors (cytokines and growth factors) using a fluorescent bead array platform. We used high dimensional flow cytometry on peripheral blood mononuclear cells to analyze the composition and phenotype of peripheral immune cells. Immunohistochemistry and immunofluorescence were performed on available formalin-fixed, paraffin-embedded tumor tissue samples (archival or on-study biopsy) collected prior to the start of therapy. We assessed relationships between biomarkers and outcomes using pairwise Wilcoxon rank-sum test and log-rank tests, and univariate Cox regression models. Results: We collected blood samples from 60 patients with paired tumor samples from 38 patients. Baseline circulating inflammatory cytokines MIP-1b, IL-1, MCP-1, IL-6, and IL-13 were highly correlated with one another, forming an “inflammatory module” that was increased in IMDC-poor risk patients and associated with worse progression-free survival (PFS) (p = 0.028). At baseline, elevated circulating VEGF-A was associated with a lack of response (p=0.03) and worse PFS (p=0.021). Whereas a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit as defined by Braun et al. (Nat Med. 2020) (p=0.01) and improved overall survival (p=0.006). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes: reductions in CD4+ PD-L1+ (HR:0.62[0.49-0.91], p=0.016) and CD8+ PD-L1+ T cells (HR:0.59[0.39-0.87], p=0.009) correlated with improved PFS. Within the tumor, a higher percentage of terminally exhausted (PD-1+, TIM-3+ and/or LAG-3+) CD8+ T cells at baseline was associated with worse PFS (p=0.028). Conclusions: Among patients with advanced nccRCC or sccRCC, a baseline high systemic inflammatory state and high circulating VEGF-A are associated with worse outcomes after treatment with atezolizumab and bevacizumab. High levels of intratumor terminally exhausted CD8+ T cells were associated with worse PFS. These results highlight the importance of an integrative approach to explore biomarkers of response in advanced variant histology RCC which may inform future therapeutic approaches.

Anlotinib combined with sintilimab as first-line treatment in patients with advanced non-clear cell renal cell carcinoma: Preliminary results from an exploratory prospective clinical study.

e16546 Background: Non-clear cell renal cell carcinoma (nccRCC) accounts for approximately 25% of all kidney cancers, includes papillary RCC, chromophobe RCC, unclassified RCC, and rare entities. Because nccRCC has different molecular characteristics from clear cell carcinoma, drug regimens routinely used for clear cell carcinoma are not very effective in controlling the growth of nccRCC cells. Novel combination regimen of angiogenic inhibitors and immune checkpoint inhibitors has demonstrated significant anti-tumor activity in certain subtypes. The purpose of this trial (NCT05220267) is to evaluate the efficacy and safety of anlotinib (a multi-target tyrosine kinase inhibitor that effectively inhibit VEGFR, FGFR, PDGFR, c-KIT, c-MET and RET) combined with sintilimab (a monoclonal antibody against programmed cell death protein 1) as first-line treatment in patients with advanced nccRCC. Methods: This study is a prospective, single-arm, open-label, phase II clinical trial. Patients aged 18 years or older, without prior systematic treatment, with histologically confirmed advanced nccRCC (defined as TNM staging IV, unresectable locally recurrent or metastatic disease), and ECOG PS 0-1 were considered eligible for enrollment. Patients were treated with oral anlotinib (12 mg once daily on days 1-14, repeated every 21 days) plus intravenous sintilimab (200 mg, once every 3 weeks) till disease progression or intolerant toxicity. The primary endpoint is progression-free survival (PFS) and the secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results: Between April 2022 and January 2023, 18 patients (of 13 patients were male) were enrolled (successfully screened and treated with therapeutic regimen at least one time) with a median age of 46 years (range, 18–79). 72.2% of patients had received prior radical nephrectomy and 6% of patients received radiotherapy. PD-L1 expression was determined in 11 patients, of which 5/11(45.5%) had CPS &gt; 1 and 3/11 (27.3%) had CPS &gt; 10. At data cutoff (31 January 2023), 9 patients were evaluable and median (95% CI) follow-up time was 3.7 (0.6-6.8) months, the ORR and DCR were 22.2% (95% CI, 2.8-60.0) and 100% (95% CI, 66.4-100.0), respectively. The median PFS was not reached. The most frequently reported treatment-related adverse events were grade 1 and grade 2 included hand-foot syndrome 55.6%, hyperuricemia 38.9%, proteinuria 33.3%, hoarseness 33.3%, diarrhea 27.8%, hyperthyroidism 27.8%, pharyngitis 27.8%, hypercholesterolemia 27.8%, hyperglycemia 27.8%. Only 4 patients (22.2%) happened grade 2 AEs. No higher grade AEs were observed. Conclusions: Anlotinib combined with sintilimab were preliminary shown promising efficacy with a favourable toxicity profile for patients with advanced nccRCC. Clinical trial information: NCT05220267 .

Efficacy of first-line (1L) immunotherapy (IO)-based regimens in patients with sarcomatoid and/or rhabdoid (S/R) metastatic non-clear cell renal cell carcinoma (nccRCC): Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

4519 Background: Patients with advanced RCC with S/R components exhibit poor clinical outcomes. IO-based combination therapies demonstrated substantial efficacy among patients with metastatic S/R ccRCC, compared to VEGF targeted therapy (VEGF-TT). Recent trials showed promising activity of IO-based regimens in patients with advanced nccRCC. We sought to assess the efficacy of IO regimens among patients with S/R nccRCC. Methods: Patients with advanced nccRCC treated with 1L IO regimens (IO/IO or IO/VEGF-TT) or 1L VEGF-TT monotherapy (sunitinib or pazopanib) were included. Cases were categorized as S/R or non-S/R. The primary outcomes were overall survival (OS) and time to treatment failure (TTF) in patients with S/R nccRCC receiving 1L IO or VEGF-TT. Overall response rate (ORR) was a secondary outcome. OS and TTF were compared between groups (IO vs. VEGF-TT) using Cox regression models adjusted for age, IMDC risk groups, and nccRCC subtype. ORR was compared between groups (IO vs. VEGF-TT) using a logistic regression adjusted for the same confounders. Results: Overall, 103 patients with S/R nccRCC were included, of whom 33 (32%) received 1L IO regimens. Median follow-up was 31 months. After adjustment for confounding factors, patients with S/R nccRCC treated with IO regimens presented with significantly improved survival outcomes as compared to those receiving VEGF-TT (median OS [mOS]: NR vs. 7.1 and mTTF: 9.4 vs. 2.9 mos for IO regimens and VEGF-TT, respectively). Similarly, a higher ORR was seen in patients with S/R nccRCC receiving IO regimens versus VEGF-TT (34.1 vs. 10.9%, respectively). Among 430 patients with non-S/R nccRCC (IO regimens: n=44), no significant differences in survival outcomes between regimen classes were seen (mOS: 24.4 vs. 14.8 and mTTF: 4.2 vs. 5.0 mos for IO regimens and VEGF-TT, respectively). Conclusions: To our knowledge, this represents the largest effort to characterize the outcomes of patients with S/R nccRCC treated with IO regimens. Patients with S/R nccRCC appear to derive a substantial and selective benefit from IO regimens (vs. VEGF-TT). These data support the use of IO-based regimens in patients with S/R nccRCC. [Table: see text]

Cabozantinib in combination with atezolizumab in non-clear cell renal cell carcinoma: Extended follow-up results of cohort 10 of the COSMIC-021 study.

684 Background: In the COSMIC-021 phase 1b study (NCT03170960) evaluating cabozantinib plus atezolizumab in advanced solid tumors, this combination therapy demonstrated encouraging clinical activity in patients with advanced non-clear cell renal cell carcinoma (nccRCC) with a median follow-up of 13 mo (Pal. JCO 2021). Results after extended follow-up in nccRCC are presented. Methods: Patients with advanced nccRCC and ECOG PS 0/1 who had ≤1 prior VEGFR-targeting tyrosine kinase inhibitor (TKI) were eligible. Prior treatment with TKIs targeting MET or immune checkpoint inhibitors was not allowed. Patients received cabozantinib 40 mg PO QD plus atezolizumab 1200 mg IV Q3W until unacceptable toxicity or progression; dose reductions of cabozantinib (40 mg QD to 20 mg QD, then to 20 mg QOD) were permitted to manage adverse events. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by the investigator; other endpoints included safety, duration of response (DOR), PFS, and OS. Results: The study enrolled 32 patients with nccRCC (2 from dose escalation phase, and 30 from expansion phase of the study): median age, 62 y; male, 81%; ECOG PS 0/1, 75%/25%; histology, papillary/chromophobe/clear cell/other, 47%/28%/3%/22%; sarcomatoid feature, 13%; IMDC risk favorable/intermediate/poor, 50%/41%/9%; ≥3 tumor sites, 56%; tumor sites, lung/kidney/bone/liver, 50%/25%/16%/16%; prior nephrectomy, 63%; prior VEGFR TKI, 22%; 0/1 lines of prior therapy (locally advanced/metastatic setting), 81%/19%. As of July 21, 2022, median follow-up was 37.2 mo (range 32.1–58.5) with 5 (16%) patients remaining on study treatment. ORR by investigator was 31% (all PRs) and disease control rate was 94% (Table); median DOR was 8.1 mo. Median PFS was 9.3 mo (95% CI 5.5–12.3), and median OS was not reached (95% CI 23.0–NE). PFS and OS estimates at 12 mo were 34% and 84%, respectively; 24-mo estimates were 6% and 70%. Treatment-related AEs occurred in 97% (grade 3/4, 53%); the most common AEs included diarrhea (69%), palmar-plantar erythrodysesthesia (50%), fatigue (44%), dysgeusia (41%), hypertension (31%) and nausea (31%). One grade 5 treatment-related AE of pulmonary hemorrhage occurred. Treatment-related AEs leading to discontinuation of both study treatments occurred in 13% of patients. Conclusions: Extended 3-year follow-up reinforces the encouraging clinical activity of cabozantinib plus atezolizumab in advanced nccRCC with a manageable safety profile. Clinical trial information: NCT03170960 . [Table: see text]

The role of immunotherapy in non-clear cell renal cell carcinoma.

The category of non-clear cell renal cell carcinoma (nccRCC) includes several clinically, histologically, and molecularly diverse entities. Traditionally, they comprise type 1 and type 2 papillary, chromophobe, unclassified, and other histologies (medullary, collecting duct carcinoma, and translocation-associated). Molecular knowledge has allowed the identification of some other specific subtypes, such as fumarate hydratase-deficient renal cell carcinoma (RCC) or succinate dehydrogenase-associated RCC. In addition, it has recognized some alterations with a possible predictive role, e.g., MET proto-oncogene receptor tyrosine kinase (MET) alterations in papillary tumors. Standard therapies for the management of advanced clear cell RCC (ccRCC), i.e., vascular endothelial growth factor receptor (VEGFR) pathway inhibitors and mammalian target of rapamycin inhibitors, have shown poorer results in nccRCC patients. Therefore, there is a need to improve the efficacy of the treatment for advanced nccRCC. Immunotherapy, especially immune checkpoint inhibitors (ICIs) targeting programmed death 1/programmed death ligand 1 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4), has demonstrated a significant survival benefit in several malignant neoplasias, including ccRCC, with a proportion of patients achieving long survival. The combinations of ICI or ICI + VEGFR tyrosine kinase inhibitors (TKIs) are the standard of care in advanced ccRCC. Unfortunately, major pivotal trials did not include specific nccRCC populations. In recent years, several studies have retrospectively or prospectively evaluated ICIs alone or in combination with another ICI or with TKIs in nccRCC patients. In this article, we review data from available trials in order to elucidate clinical and molecular profiles that could benefit from immunotherapy approaches.

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.

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.

Sequential immunotherapy in rare variant renal cell carcinomafinal report of UNISoN (ANZUP 1602): Nivolumab then ipilimumab + nivolumab in advanced nonclear cell renal cell carcinoma.

4537 Background: Immune checkpoint immunotherapy (ICI) is active against many cancers. Many people are failed by PD1 inhibition alone, but not all patients benefit, nor require combination ICI treatment. UNISoN (NCT03177239) previously reported outcomes in people with non-clear cell renal cell carcinoma (nccRCC) receiving nivolumab (N) monotherapy, and N plus ipilimumab (I) in those whose cancers progressed after N alone. We present the final planned report. Methods: Population, Intervention, Analysis: Participants (pts) with advanced nccRCC with good performance status (ECOG 0/1) received N 240mg q2w alone (Part 1). Those with cancers refractory to N at 3 months were offered combination I (1mg/kg) + N (3mg/kg) q3w for up to 4 doses, followed by N 240mg q2w for a maximum total of 12 months of N (Part 2). UNISoN was powered to identify a clinically-relevant objective tumor response rate (OTRR) of 30% (assuming 15% was not relevant) among people receiving I+N in Part 2. Results: 85 pts with a representative spectrum of nccRCC histologies were enrolled and received N. Amongst the total population enrolled to UNISoN Part 1/2, mOS was 24 (16-28) months and 12m OS was 65% (54%-74%); of those proceeding to Part 2, the mOS was 10 (6-17) months only. Overall, 17% (10%-27%; 14/83) and 10% (3%-23%; 4/41) of pts experienced a response from N alone or I+N, respectively. 41 pts refractory to N received I+N. Overall in Part 2, the median time on treatment was 2.1 (95% CI 1.8, 2.8) months, the median number of cycles was 3; median follow-up at final analysis was 22 (16-30) months. In this population, the median PFS was 2.6 (2.2-3.8) months and 12m PFS was 11% (4%-23%). 13% (7%-22%) of patients were free of progression or death at 24 months. The primary endpoint was not met; only 80% of pts failed by N were assessable for response in Part 2. Overall tumor responses from N alone or I+N were more common in pts with papillary histology; pts with chromophobe histology had poor outcomes. No late toxicity safety signals were observed. Conclusions: Some pts with nccRCC benefit from N alone, or addition of I when disease is inadequately controlled by N alone, however most pts have limited benefit from ICI. More effective therapeutic options are needed for the majority of people with rare variant renal cell carcinomas. Novel markers of response are required to more rapidly predict pts who will progress on N. Translational research to identify predictive biomarkers of response is ongoing. Clinical trial information: NCT03177239.

Outcomes with novel combinations in nonclear cell renal cell carcinoma (nccRCC): ORACLE study.

4545 Background: Despite recent advances in the treatment of clear cell RCC, there is a paucity of data to guide management of nccRCC due to the heterogeneity and rarity of these tumors. The clinical activity of combination therapies (including IO-IO, IO-VEGF, VEGF-mTOR) in subtypes of advanced nccRCC is unknown. Methods: In this multicenter retrospective analysis, we evaluated the efficacy of combination systemic therapies in patients with nccRCC. Eligible patients included those with nccRCC as determined by local genitourinary pathology review and receipt of one of three combination regimens during any line treatment (IO-IO, IO-VEGF, mTOR-VEGF). The primary endpoint was objective response rate (ORR) assessed by investigator review. Secondary endpoints were progression- free survival (PFS), disease control rate (DCR), and overall survival (OS). Results: Among 128 included patients, median age was 57 years; 66% were male and 65% white. Histologies included papillary (37%), unclassified (33%), chromophobe (16%), translocation (9%), and other (5 %). Among all patients, 69% had prior nephrectomy; 80% were IMDC intermediate/poor risk; 20% had sarcomatoid and/or rhabdoid differentiation, 27% and 29% had liver and bone metastasis respectively and 63% received combination treatment as first line. Comparison of outcomes based on treatment regimen, line of treatment and subtype is shown in the table. Median PFS and OS were longer with IO/IO and IO/VEGF compared to VEGF/ mTOR at 8.5, 9.5 and 3.7 months and 24.4, 18.2 and 15.4 months respectively. Conclusions: Antitumor activity was observed with novel combinations in nccRCC in both frontline and later line setting. Optimal management of nccRCC remains an unmet need and prospective data is warranted to guide treatment selection for this population. [Table: see text]

ALTER-UC-001: Phase II trial of anlotinib plus everolimus as first-line treatment for advanced non–clear cell renal cell carcinoma.

TPS4598 Background: For patients (pts) with recurrent or stage IV non-clear cell renal cancer (nccRCC), the medical treatment guidelines recommend the first choice to participate in clinical trials, or use TKI drugs such as sunitinib, and mTOR inhibitors such as everolimus. Anlotinib is a novel multi-target tyrosine kinase inhibitor (TKI). It’s antitumor targets include vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and c-kit. This a single-center, single-arm, phase II trial which will evaluate the efficacy and tolerability of anlotinib hydrochloride plus everolimus as first-line therapy in pts with nccRCC (NCT05124431). Methods: Key inclusion criteria are: age ≥18 years; histologically confirmed advanced nccRCC, advanced disease is defined as TNM stage IV, not available for surgery, locally recurrent or metastatic renal cell carcinoma; no prior systemic drug therapy for advanced disease; Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Approximately 30 pts will be assigned to receive anlotinib hydrochloride: 12 mg every 21 days (14 days on treatment from Day 1-14, 7 days off treatment from Day 15-21) by oral, and everolimus 5mg qd, continued for up to 1 year (∼17 cycles ) or until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR). Radiographic imaging will be performed every 6 weeks. Secondary endpoints included overall disease control rate (DCR), progression free survival (PFS), and over survival (OS). Adverse events will be monitored throughout the study and graded according to CTCAE V5.0. Recruitment have begun in Jan. 2022. Research Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Clinical trial information: NCT05124431.

A systematic review of immune checkpoint inhibitors (ICI) in non-clear cell renal cell cancer (nccRCC) subtypes.

353 Background: ICI were approved for advanced RCC treatment either alone or combined with another ICI or a tyrosine kinase inhibitor. While most trial data derive from clear cell (cc) histology, the differential activity of ICI in nccRCC subtypes is not entirely known. The aim of this analysis is to summarize the reported activity of ICI-based therapies in ncc-subtypes or in tumors with sarcomatoid/rhabdoid features. Methods: A systematic literature search following PRISMA guidelines was performed. PubMed, GoogleScholars and ASCO Database were searched for the key-words “renal cell cancer” and “immune check point inhibitors” and equivalents. Publications between July 2016 - July 2021 were considered. All original articles reporting outcomes of ICI in at least 5 patients with an advanced nccRCC were eligible. Case reports, reviews, out of scope publications and articles with no full text available were excluded. Results: This study included a total of 14 publications, mostly case series except one phase II and one phase IIIb/IV trial. The table below summarizes the different histological subtypes included in these studies, more frequently papillary (10-88%), chromophobe (0-34%) and unclassified (4-27.5%) RCC. As for first line (L), ICI monotherapy elicited an overall response ratio (ORR) of 5-26.7%, a median progression free survival (mPFS) of 2.2-4.2 months (m) and a median overall survival (mOS) of 16.3-28.9m. ICI combination therapy associated with a higher ORR of 14.2-33%, a mPFS of 2.4-8.3m and a mOS not reached (NR). In ≥2ndL, ICI alone elicited an ORR of 9.4-22.6%, a mPFS of 3.5-7.1m and a mOS of 11.6m-NR. ICI combination therapy was superior, with a reported ORR of 31-44.4%, a mPFS of 4.3-5.6m and a mOS NR. Overall, ICI therapy elicited a higher ORR in papillary tumors (5-50%). Unclassified RCC response was more variable (0-66.7%). Chromophobe tumors had a lower ORR of 0-20%. ICI therapy outcomes among nccRCC with sarcomatoid/rhabdoid features were of an ORR of 0-42.1%, a mPFS of 2.3-6.9m and a mOS of 25.5m–NR. Nonetheless, outcomes were inferior in ncc comparing to cc tumors. Conclusions: The observed activity of ICI-based therapies was heterogenous among nccRCC subtypes. Combination regimens, papillary subtype and sarcomatoid/rhabdoid features were associated with higher responses. These findings might help treatment decisions and require further validation.[Table: see text]

Effectiveness of first-line therapy in patients with advanced non-clear renal cell carcinoma (nccRCC).

304 Background: Current treatment principles for advanced nccRCC have been largely extrapolated from guidelines for clear cell RCC. Given the emerging randomized data for select nccRCC subtypes, real-world outcomes for these patients are informative particularly in the contemporary checkpoint inhibitor era. Methods: We performed an analysis using the Canadian Kidney Cancer information system (CKCis), a prospective database involving 14 academic centers, on nccRCC patients undergoing first-line systemic therapy between January 2011 – December 2019. Treatment groups were defined as receipt of: vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGF-TKI), mammalian target of rapamycin inhibitors (mTORi), and PD-1/PD-L1 immune checkpoint inhibitors (ICI, mono- or combination therapy). Primary outcome was 1-yr overall survival (OS) rate. Secondary outcomes were median time to treatment failure ((TTF, months), defined as treatment discontinuation, change or death) and objective response rate (ORR, %). Results: We identified 265 nccRCC patients: 204 (77.0%) received VEGF-TKI, 19 (7.2%) received mTORi and 42 (15.8%) received ICI-based first-line therapy (Table). Overall, median age was 64 years, 75% were male, 84% were classified as IMDC intermediate/poor risk, and 16% underwent prior nephrectomy. Twenty-three percent of patients were enrolled in clinical trials. Patients received primarily sunitinib (81%) or pazopanib (15%) in the VEGF-TKI group (other: 4%), while mTORi-treated patients received temsirolimus (74%) or everolimus (26%). For the ICI-based treatment group, most patients received combination therapy as ipilimumab-nivolumab (71%) or pembrolizumab-axitinib (26%), with 3% receiving ICI monotherapy. 1-yr OS was 65.2% for VEGF-TKI, 57.9% for mTORi and 69.0% for ICI-treated patients. Median TTF was 3.3 for VEGF-TKI, 3.5 for mTORi and 7.1 mos for ICI-treated patients. ORR was 17%, 5%, and 37% respectively for the VEGF-TKI, mTORi and ICI-treated groups. Conclusions: We describe the effectiveness of first-line therapy for patients with nccRCC from a national database. This real-world data suggests an association between first-line ICI-based therapies and improved outcomes, albeit with cabozantinib not available for the indication during this time. Our data supports consensus recommendations for preferred use of ICI-based or VEGF-TKI over mTORi as first-line therapy in nccRCC.[Table: see text]

Safety and efficacy of nivolumab plus ipilimumab in patients with advanced non-clear cell renal cell carcinoma: results from the phase 3b/4 CheckMate 920 trial

BackgroundCheckMate 920 (NCT02982954) is a multicohort, phase 3b/4 clinical trial of nivolumab plus ipilimumab treatment in predominantly US community-based patients with previously untreated advanced renal cell carcinoma (RCC) and clinical...

First-line pazopanib in patients with advanced non-clear cell renal carcinoma: An Italian case series.

BACKGROUNDNon-clear cell (ncc) metastatic renal-cell carcinoma (RCC) has dismal results with standard systemic therapies and a generally worse prognosis when compared to its clear-cell counterpart. New systemic combination therapies have emerged for metastatic RCC (mRCC), but the pivotal phase III trials excluded patients with nccRCC, which constitute about 30% of metastatic RCC cases.AIMTo provide a piece of real-life evidence on the use of pazopanib in this patient subgroup.METHODSThe present study is a multicenter retrospective observational analysis aiming to assess the activity, efficacy, and safety of pazopanib as first-line therapy for advanced nccRCC patients treated in a real-life setting. RESULTSOverall, 48 patients were included. At the median follow-up of 40.6 mo, the objective response rate was 27.1%, the disease control rate was 83.3%, and the median progression-free survival and overall survival were 12.3 (95% confidence interval [CI]: 3.6-20.9) and 27.7 (95%CI: 18.2-37.1) mo, respectively. Grade 3 adverse events occurred in 20% of patients, and no grade 4 or 5 toxicities were found. CONCLUSIONPazopanib should be considered as a good first-line option for metastatic RCC with variant histology.

Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced non-clear cell renal cell carcinoma (nccRCC) (HCRN GU16-260-Cohort B).

4510 Background: The HCRN GU16-260 trial reported on the efficacy and toxicity of nivo monotherapy in treatment naïve clear cell RCC (Cohort A) and the efficacy of nivo/ipi salvage therapy in pts with tumors resistant to initial nivo monotherapy (Atkins JCO 2020.38.15_suppl.5006). Limited information is available on the effects of such an approach in pts with advanced nccRCC. Methods: Eligible pts with treatment-naïve nccRCC received nivo 240mg IV q2 wk x 6 doses followed by 360mg IV q3 wk x 4 doses followed by 480 mg q4 wk until progressive disease (PD), toxicity, or completion of 96 wks of treatment (Part A). Pts with PD prior to or stable disease (SD) at 48 wks (pSD) were potentially eligible to receive salvage nivo (3mg/kg) /ipi (1 mg/kg) q3 wk x 4 doses followed by q4 wk nivo maintenance for up to 48 wks (Part B). All pts were required to submit tissue from a metastatic lesion obtained within 12 months (mo) prior to study entry and prior to enrolling on Part B for correlative studies. Results: 35 pts with nccRCC were enrolled between 5/2017 and 12/2019 at 12 participating HCRN sites. Median age 63 (range 35-84 years); 89% male. IMDC favorable 8 (23%), intermediate 18 (51%) and poor risk 9 (26%). Of the 35 pts 19 (54%) had papillary, 6 (17%) chromophobe and 10 (29%) unclassified histology. RECIST defined ORR was 5 of 35 (14.3%) [CR 2 (5.7%), PR 3 (8.6%)], SD 16 (45.7%), PD 14 (40.0%). Immune-related ORR was 8 of 35 (22.9%). RECIST ORR by histology was: papillary - 1/19 (5%); chromophobe - 1/6 (17%); unclassified - 3/10 (30%). 9 pts (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified, 1 papillary) responding. Median PFS was 4.0 (2.7, 4.3) mo. 21 pts remain alive. None of the responders have progressed or died. 28 pts (25 PD, 3 pSD) were potentially eligible for salvage nivo/ipi (Part B), but 12 did not enroll due to symptomatic PD (2), grade 3-4 toxicity on nivo (3), or other including no biopsy tissue (7). In the 16 Part B pts, best response to nivo/ipi was: PR (1, 6%) – (unclassified/non-sarcomatoid); SD (7, 44%); PD (8, 50%). Grade 3 Treatment-related adverse events (TrAEs) were seen in 7/35 (20%) on nivo. Grade 3-5 TrAEs were seen in 7/16 (44%) on nivo/ipi with 1 pt experiencing sudden death. Correlative studies including PD-L1 status, WES and RNAseq are pending. Conclusions: Nivo monotherapy has limited activity in treatment naïve nccRCC with most responses (4 of 5) seen in pts with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivo studies. Salvage treatment with nivo/ipi was provided in 16 of 28 (57%) pts with PD/pSD on nivo monotherapy, with 1 response observed. Clinical trial information: NCT03117309.

Ipilimumab + nivolumab in people with rare variant renal cell carcinoma refractory to nivolumab alone: Part 2 of UNISON (ANZUP 1602) nivolumab then ipilimumab + nivolumab in advanced non-clear cell renal cell carcinoma.

4565 Background: Immunotherapy targeting PD1 is active across many cancers, but many people are failed by PD1 inhibition alone. UNISON (ANZUP 1602/NCT03177239) has previously reported the activity and outcomes of nivolumab monotherapy in people with nccRCC (OTRR 17%, PFS6 45%; part 1), and here we report the outcomes of combining ipilimumab (I) and nivolumab (N), in people whose cancers are refractory to N alone (part 2). Methods: Participants (pts) with advanced nccRCC with good performance status (ECOG 0/1), were initially enrolled and took N alone. 41 pts refractory to N were offered the combination I (1mg/kg) + N (3mg/kg) every 3 weeks for up to 4 doses. Pts with disease control after N, or N + I could continue N for up to 1 year. UNISON was powered to distinguish a clinically relevant improvement in objective tumour response rate (OTRR) from 15% to 30% in people taking I+N in part 2. Results: 85 pts were enrolled and received N. 41 pts were refractory to N, were well enough to take I+N, and had a representative spectrum of nccRCC histologies (n=41; papillary 44%, chromophobe 20%, Xp11 translocation 12%, RCC unclassified 7%, other 17%). The median time on treatment was 2.1 months, the median number of doses was 3; median follow up at the time of reporting was 20.3 months. The OTRR of I+N in pts refractory to N was 10% with 1 complete and 3 partial responses. Stable disease was experienced by 36% of pts and disease progression by 52%. The disease control rate at 6 months was 45% (95% CI: 34%, 56%). The median PFS was 2.6 months (95% CI: 2.2, 3.8). The 6 month progression-free survival (PFS) was 25% (95% CI: 13-39). Only 14% of patients were free of progression at 12 months. The safety of I+N appeared similar to previous reports. 68% of pts experienced serious adverse events, 34% treatment related SAE. One pt died from refractory pneumonitis. 11 pts (27%) experienced treatment delays or permanent treatment discontinuation. Conclusions: The primary endpoint of the study was not met. A minority of pts with nccRCC refractory to nivolumab derive benefit from combination I+N but many pts remain refractory to immunotherapy. No new safety issues were identified. More effective therapeutic options are needed for people with rare variant renal cell carcinoma. Clinical trial information: NCT03177239.

A Single-arm, Multicenter, Phase 2 Study of Lenvatinib Plus Everolimus in Patients with Advanced Non-Clear Cell Renal Cell Carcinoma

BackgroundNon-clear cell renal cell carcinoma (nccRCC) accounts for ≤20% of RCC cases. Lenvatinib (a multitargeted tyrosine kinase inhibitor) in combination with everolimus (an mTOR inhibitor) is approved for the treatment of advanced RCC after one prior antiangiogenic therapy. ObjectiveTo determine the safety and efficacy of lenvatinib plus everolimus as a first-line treatment for patients with advanced nccRCC. Design, setting, and participantsThis open-label, single-arm, multicenter, phase 2 study enrolled patients with unresectable advanced or metastatic nccRCC and no prior anticancer therapy for advanced disease. InterventionLenvatinib (18 mg) plus everolimus (5 mg) orally once daily. Outcome measurements and statistical analysisThe primary endpoint was the objective response rate (ORR) as assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety assessments. The 95% confidence intervals (CIs) for ORRs were calculated using the two-sided Clopper-Pearson method. Median PFS and median OS were estimated using the Kaplan-Meier product-limit method and their 95% CIs were estimated via a generalized Brookmeyer and Crowley method. Results and limitationsThe study (start date: February 20, 2017) enrolled 31 patients with nccRCC (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2). At the data cutoff date (July 17, 2019), the best overall response was a partial response (eight patients: papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) for an overall ORR of 26% (95% CI 12–45). Median PFS was 9.2 mo (95% CI 5.5–not estimable), and median OS was 15.6 mo (95% CI 9.2–not estimable). The most common treatment-emergent adverse events were fatigue (71%), diarrhea (58%), decreased appetite (55%), nausea (55%), and vomiting (52%). Limitations include the small sample size and single-arm design. ConclusionsLenvatinib plus everolimus showed promising anticancer activity in patients with advanced nccRCC with an ORR of 26% and is worthy of further study. The safety profile was consistent with the established profile of the study-drug combination. Patient summaryWe examined the combination of lenvatinib plus everolimus as the first therapy for 31 patients who had advanced nccRCC. We found that this treatment seemed effective, because most patients had a decrease in tumor size and manageable treatment-related side effects. Clinical registrationThis trial is registered at ClinicalTrials.Gov as NCT02915783.