bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinicopathologic and survival differences between African Americans and Caucasians with renal cell carcinoma.
Authors: Wang Shirley , Cheaib Joseph G. , Patel Sunil H. , Alam Ridwan , Metcalf Meredith , Jing Yuezhuo , Trock Bruce , Allaf Mohamad , Ged Yasser , Pierorazio Phil , Singla Nirmish
Published: February 2022

296

Background: The incidence of renal cell carcinoma (RCC) has gradually increased over the past decades, particularly among African Americans (AA). Lifestyle and other factors such as high blood pressure and tobacco exposure are associated with its incidence. We aim to compare differences in clinicopathologic characteristics and survival outcomes between AA and Caucasian patients undergoing nephrectomy for RCC. Methods: A retrospective single institutional analysis was performed on AA or Caucasian patients undergoing nephrectomy for RCC between 1996 and 2021. Baseline clinical and pathologic characteristics were compared by race. Survival outcomes, including cancer-specific survival (CSS) and overall survival (OS), were assessed by Kaplan-Meier methods and multivariable Cox regression analysis (MVA). Results: We included 2,439 patients (445 AA, 1987 Caucasians). AA patients were female-predominant compared to Caucasians (54.8% vs. 35.7%, p<0.01). AA patients were more likely to have a history of hypertension (44.0% vs. 40.3%, p<0.001) and diabetes (14.4% vs. 11.4%, p<0.001). Caucasian race was associated with higher pathologic stage (p<0.001), positive nodal status (3.8% vs. 1.1%, p=0.016), and metastatic disease at presentation (3.7% vs. 1.8%, p=0.042). AA had more papillary variant compared to Caucasians (36 v 15.7%, p<0.01). The 5-year CSS across all stages was better for AA vs. Caucasians (93.1% vs. 89.7%, p=0.01), but after adjusting for covariates, race was not significant for CSS on MVA (HR 0.89 (95% CI 0.57-1.38), p=0.8). Similar findings were seen in OS. We performed additional sub-analyses on patients with stage pT1a (n=665) and locally advanced (pT3-4, n=431) clear cell RCC. Among these sub-groups, no significant differences were seen by race. Conclusions: Within our institutional cohort, AA patients with RCC undergoing nephrectomy did not exhibit worse pathologic characteristics at presentation or inferior survival outcomes compared to their Caucasian counterparts. There were notable differences among baseline clinical characteristics and histology by race. Socioeconomic and molecular analyses will help elucidate biological differences and identify socially actionable strategies to improve outcomes among patients with RCC.
Effectiveness of first-line therapy in patients with advanced non-clear renal cell carcinoma (nccRCC).
Authors: Laramee Sophie , Ghosh Sunita , Kollmannsberger Christian K. , Hansen Aaron Richard , Wood Lori , Soulieres Denis , Canil Christina M. , Saleh Ramy , Castonguay Vincent , Bjarnason Georg A. , Basappa Naveen S. , Breau Rodney H. , Heng Daniel Yick Chin , Pouliot Frederic , Kapoor Anil , Lalani Aly-Khan A.
Published: February 2022

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]
Real-world experience (RWE) of safety and efficacy of 6-weekly pembrolizumab 400mg (pem6w) plus axitinib (axi) in patients (pts) with advanced renal cell carcinoma (aRCC).
Authors: Ansel Sonam , Ray-Chaudhuri Anirban , Jones Robert J. , Stares Mark , Ding Tze-en , Symeonides Stefan N. , Crearie Christine , Slater Sarah , Cascales Garcia Maria Almudena , Sundaramurthy Aravindhan , Malik Jahangeer , Thomson Nicola , Pringle Marie , Barmack Gillian , Venugopal Balaji
Published: February 2022

309

Background: The KEYNOTE 426 trial demonstrated pem 200mg plus axi twice daily (bd) is effective in aRCC. Pharmacokinetic modelling of pem 400 mg every six weeks demonstrated similar observed exposures to pem 200 mg every three weeks. In NHS Scotland, pem6w + axi was used during the COVID-19 pandemic to reduce hospital visits and for pts’ convenience. Here, we evaluate the RWE of pem6w + axi in aRCC. Methods: Electronic medical records of pts on pem6w + axi between 1 May 2020 & 1 Jun 2021 in two large cancer centers in Scotland were analyzed retrospectively for pts’ characteristics, treatment related adverse events (TRAE) and efficacy. Results: Total of 93 pts were identified (Table). At data cut off of 8 Sep 2021, with a median follow-up of 7 months (mo) (inter-quartile range (IQR) 5 mo; range 0-15 mo), 73 pts (78%) were alive. Clinician assessed radiological response was evaluable in 87 pts. Overall response rate (ORR) including partial response + complete response was noted in 49 pts (56%) with median time to response of 80 days (d). Clinical benefit rate including pts with ORR and stable disease was seen in 72 pts (83%). At data cut off, 24 pts (26%) had progressed with a median time to progression of 117 d (IQR: 85d). Median overall and progression free survival were not reached and follow-up continues. 81 pts (87%) had any grade and 28 pts (30%) had grade 3/4 TRAE. Immune related AE (irAE) of any grade occurred in 60 pts (65%) and grade 3/4 in 19 pts (20%). Common grade 3/4 irAE were transaminitis (10%), colitis (8%), nephritis (2%) and skin (2%). 28 (30%) and 14 pts (15%) respectively required steroids and hospitalisation for irAE with median hospital stay 6 d (range: 2-43 d). 10 pts suffered a second irAE requiring steroids and 5 pts had a second hospital stay with median hospital stay of 6 d. Any grade AE and grade 3/4 AE related to axi occurred in 67 (72%) and 14 pts (15%) respectively. Axi dose was escalated from 5mg to 7mg bd in 12 pts (13%), reduced to 3mg bd in 35 pts (38%) and 2mg bd in 10 pts (11%). 21pts (23%) on Pem and 15pts (16%) on axi discontinued treatment due to TRAE. Conclusions: Our RWE demonstrates that pem6w + axi appears to have comparable safety profile to pem 200mg + axi reported in Keynote 426 study, with the added benefits of less frequent hospital visits. Further follow up continues for efficacy in this heterogeneous pts population. Pt characteristics, total=93 (%).[Table: see text]
A VA Federal Supply Schedule (VAFSS)–based cost-effectiveness analysis of immunotherapy-tyrosine kinase inhibitor (IO-TKI) regimens and sunitinib in the treatment of metastatic renal cell carcinoma (mRCC).
Authors: Kohli Manish , Cutshall Zachary , Dougherty Maura , Nelson Richard , Yoo Minkyoung
Published: February 2022

312

Background: Recent FDA approvals for mRCC treatment have resulted in increased effectiveness, drug choices, and costs. We performed a cost effectiveness analysis (CEA) of six recently approved IO-TKI drug combinations and sunitinib. Methods: We used a Markov simulation model from the healthcare sector perspective with a lifetime time horizon. The 7 treatment drug strategies considered in this model included: (1) atezolizumab + bevacizumab (AB), (2) avelumab + axitinib (AA), (3) pembrolizumab + axitinib (PA), (4) nibolumab + ipilimumab(NI), (5) nibolumab + cabozantinib (NC), (6) lenvatinib + pembrolizumab (LP), and (7) sunitinib (S). Input parameters of drug effectiveness and toxicities to construct the model were based on published randomized studies that led to drug approvals. Direct costs for treatment were derived using the VA Federal Supply Schedule (VAFSS). Markov model simulates patient transition between 3 health states at monthly intervals: progression free, progressive disease, and death. The cost-effectiveness outcome in our model were and life-years (LYs), progression-free life-years (PFLYs) gained, and quality-adjusted life-years (QALYs) with utility values based on published literature. Results: The table highlights results of the CEA. The least expensive drug combination was NI ($442,218) while the most expensive was LP ($963,610). AA yielded the most LYs (5.51) and QALYs (5.62) and LP yielded the most PFLYs (1.64) while NL yielded the least LYs (4.35) and PFLYs (1.47) and LP yielded the least QALYs (4.19). AB and S were absolutely dominated strategies yielding less effectiveness and cost more in terms of effectiveness measures. Depending on acceptable willingness-to-pay (WTP) and effectiveness measures, PA or AA were the most cost-effective strategies. Conclusions: Our analyses suggest that based on direct cost acquisition using VA FSS, PA or AA were cost-effective strategies for mRCC with WTP of $20,000 to $200,000 per QALY.[Table: see text]
The effect of anti-cancer therapy on immunological response to COVID-19 vaccination.
Authors: Jackson-Spence Francesca , Toms Charlotte , Yang Yu-Hsuen , Walshaw Lani , Riddell Anna , Cutino-Moguel Maria-Teresa , Szabados Bernadett , Propper David , Powles Thomas
Published: February 2022

319

Background: The efficacy of SARS-COV-2 vaccination has been demonstrated in healthy individuals. Immune responses are less well characterised in cancer patient groups, especially those receiving anticancer therapy (e.g. immune therapy, chemotherapy and targeted therapies. We aim to assess the immune response to the SARS-COV-2 vaccination in patients with solid organ cancer on different systemic anti-cancer therapies. Methods: All patients received 2 doses of COVID-19 mRNA vaccination as part of the UK National vaccination programme; with the second booster dose administered within 12 weeks of the first dose. All patients received either BNT162b2 (Pfizer/BioNTech) or ChAdOx1 S (AstraZeneca) vaccines. Sequential serum samples were collected pre-booster dose vaccination (baseline/within -30 days) and after second dose SARS-COV-2 vaccination, at 14-35 days and 36-63 days. Presence and titres of serum Anti-SARS-CoV-2 Spike protein (S) antibody titres were measured. Seroconversion is defined as a response ≥0.8 U/ml, and maximum response to Anti-S is defined as ≥250 U/ml. Responses were measured in 3 patient groups according to the type of anti-cancer therapy: chemotherapy (CHT group), immune therapy (IO group) and targeted therapies, mainly VEGF TKI (TT group). Results: Overall, 61 patients were recruited: 45.9%(28/61) in CHT group, 32.8% (20/61) in IO group and 21.3% (13/61) in the TT group. Baseline characteristics were comparable between patient groups. In response to the booster dose vaccination at 14-35 days, the number of patients who seroconverted was 79.3% (23/29), 94.7% (18/19) and 84.6% (11/13) in the CHT, IO and TT groups, respectively. At this same time point, 51.7% (15/29) in the CHT group achieved maximum anti-S titre levels (≥250 U/ml), compared with 78.9% (15/19) of patients in IO group and 69.2% (9/13) of patients in TT group. All 3 groups demonstrated a significant increase in Anti-S antibodies at 14-35 days after second dose vaccine when compared to pre-booster serum levels, with the largest increase seen in the IO group with a mean Anti-S increase of 149.1 U/ml (SD±105.0, p < 0.0001) followed by the TT group mean increase 120.2 U/ml (SD ±110.8, p < 0.01) and the CHT group, mean increase 83.0 U/ml (SD ±108.4, p < 0.001). Anti-S antibody levels were sustained at 36-63 days post-booster across all groups. However only IO patients had a sustained immune response to vaccination, with median Anti-S titres level of ≥250 U/ml and a significant drop was seen in the CHT group (median Anti-S level 138, p < 0.05). Conclusions: Anti-S titres increase following vaccination in all 3 groups but remain most sustained in the IO group at 36-63 days post-vaccination. Chemotherapy and other targeted therapy treated patients may benefit from early COVID-19 vaccine boosters, compared to patients receiving immune therapy.
Using tele-mentoring to optimize quality of care and quality of life for patients with renal cell carcinoma (TOQQ-RCC).
Authors: Wulff-Burchfield Elizabeth Marie , Potts Maryellen , Knight Catherine , Klemp Jennifer R.
Published: February 2022

326

Background: Overall survival from metastatic renal cell carcinoma (RCC) has risen in recent years due in part due to therapies such as immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI). TKI and ICI have unique and high-impact side effect profiles, and deficits persist in clinicians’ understanding of patient tolerance of and response to treatment, particularly in rural and community practices. We developed a tele-mentoring series to improve knowledge and clinical care gaps in ICI and TKI toxicity assessment and management for persons treated for RCC. Methods: Rural and community cancer care teams were invited by the Masonic Cancer Alliance, the outreach network of The University of Kansas Cancer Center, to participate in a five session Project ECHO (Extension for Community Health Outcomes) didactic and case-based educational series. Topics included distress screening, shared decision-making for RCC treatment, ICI and TKI toxicity assessment and management, at-home ICI administration, and implementing toxicity monitoring protocols. A mixed-methods approach collected data from participants pre- and post-TOQQ-RCC series. Clinician interviews assessed current practice protocols and were transcribed and analyzed thematically. Organizational Readiness for Implementing Change (ORIC) was administered pre- and post-TOQQ-RCC intervention; mean scores were calculated to determine readiness for change in toxicity monitoring and management protocols. Participant engagement and satisfaction were assessed; satisfaction measure included a Likert-like scale of poor, fair, average, good, and outstanding. Results: Fifty-two attendees from 11 cancer care institutions across Kansas and Missouri registered for the TOQQ-RCC sessions. An average of 15 participants attended each session including physicians, advanced practice providers, nurses, and other disciplines. Session evaluations rated content/delivery as good or outstanding. Themes from qualitative analysis revealed patient education as a primary barrier to effective toxicity identification and management. One-third of participants completed ORIC post-assessment; mean ORIC scores dropped by a mean 0.4 (10%) post-TOQQ-RCC series, indicating decreased readiness to implement changes to toxicity monitoring and management protocols. Conclusions: Rural and community oncology clinicians are willing to engage in tele-mentoring to improve knowledge and clinical care gaps regarding ICI and TKI toxicity assessment and management. Decrease in ORIC scores post-TOQQ-RCC series may indicate increased understanding of the complex processes and resources required to institute meaningful improvement to toxicity monitoring and management protocols for patients treated in rural and community settings. Future directions will include formal organizational needs assessments.
Changes in perception of immunotherapy over time among patients with advanced genitourinary cancers.
Authors: Malhotra Jasnoor , Philip Errol James , Govindarajan Ameish , Meza Luis A , Zengin Zeynep Busra , Salgia Sabrina , Muddasani Ramya , Chawla Neal Shiv , Castro Daniela , Chehrazi-Raffle Alex , Dizman Nazli , Bergerot Paulo Gustavo , Hsu Joann , Dorff Tanya B. , Pal Sumanta K. , Bergerot Cristiane Decat
Published: February 2022

328

Background: Previous studies have shown that a significant proportion of patients with metastatic genitourinary cancers harbor inaccurate expectations of cure prior to starting treatment with immunotherapy. This study sought to compare changes in perceptions of immunotherapy reported before, and three months after, the start of therapy, as well as treatment side-effects and quality of life. Methods: This longitudinal study enrolled patients diagnosed with advanced genitourinary cancers (bladder, renal, and prostate cancers) prior to commencing immunotherapy. Patients’ perceptions were assessed prior to starting treatment (T0) and three months later (T1). Patients responded to the same survey at both time points assessing expectations of side effects, clinical outcomes (expectation of cure) and quality of life (Functional Assessment of Chronic Illness Therapy-General). Results: Among the 30 patients enrolled, the median age was 67 years old (range, 44-91); most were male (70%), married (80%), and well-educated (70%). Renal cell carcinoma (70%) was the most common form of cancer. Before starting immunotherapy (T0), patients expected (1) fewer side effects (83%) compared with other types of cancer treatment, (2) great efficacy in preventing tumor progression (90%). and (3) increased survival (90%). Notably, the expectation of cure with immunotherapy treatment had changed over time (T0 = 24% vs T1 = 7%; P = 0.001) and overall quality of life had increased (median at T0 = 90 vs T1 = 98; P = 0.01). Three months into treatment (T1), patients perceived themselves as less active (T0 = 70% vs T1 = 63%; P = 0.02), however just 16% reported severe side effects, including fatigue (10%) and diarrhea (10%). In general, patients were satisfied with the management of these side effects (60%). The majority of patients perceived improvement in their condition (50%) and were satisfied with their treatment (60%). Conclusions: This longitudinal study suggests that inaccurate perceptions of cure with immunotherapy may recede over time, with an increased proportion of patients estimating a more accurate (and lower) chance of cure after 3 months of treatment. Patients also reported improved quality of life despite these adjusted expectations of cure.
Variance of mean baseline health-related quality of life across phase III clinical trials in metastatic renal cell carcinoma.
Authors: Henegan John Clark , Bell Francis Garner
Published: February 2022

329

Background: Health-related quality of life (HRQoL) instruments in clinic trials provide insight into the impacts a disease and therapy have on a person’s well-being. Baseline measurements of global HRQoL reflect a trial population’s quality of life at the start of a trial. It is unknown how baseline mean HRQoL values vary across trials. Our hypothesis: The HRQoL for trials populations would decrease with later lines of therapy but would not be affected by chronological time. Methods: The year the first patient was enrolled in a trial, the number of prior lines of therapy, the HRQoL instrument(s) used, and the trial’s name was recorded along with the intervention arm’s global HRQoL summary statistics (i.e., mean value, standard deviation, and number of respondents). The intervention arm (as opposed to a combination of both arms of the study) was analyzed since the HRQoL at baseline was often balanced between the two arms but baseline HRQoL summary statistics for the entire trial population was not typically available. The baseline HRQoL means were compared across trials using common HRQoL instruments via one-way ANOVA (https://statpages.info/anova1sm.html). A p-value of less than 0.05 indicated there was a significant difference in mean HRQoL values somewhere among the various groups. The Tukey honestly significantly different post-hoc test was used to evaluate which groups were significantly different from others. Results: Mean baseline HRQoL varied significantly across trials for the FKSI-19 (p < 0.001) and the EQ-5D (p = 0.004) instruments. Conclusions: While HRQoL varied across trials for the FKSI-19 and the EQ-5D instruments, post-hoc tests indicated that only the FKDI-19 varied as hypothesized by line of therapy. The EQ-5D baseline HRQoL values variation correlated more by year of first participant. Future research should focus on the applicability of the EQ-5D and EQ-VAS HRQoL instruments in a modern population of patients with metastatic RCC.[Table: see text]
Real-world clinical outcomes of patients (pts) with metastatic renal cell carcinoma (mRCC) in current immune-oncology (IO) and tyrosine kinase inhibitors (TKIs) era.
Authors: Shah Neil J. , Sura Sneha , Shinde Reshma , Shi Junxin , Perini Rodolfo F. , Puneet Singhal , Robert Nicholas J. , Vogelzang Nicholas J. , Motzer Robert J.
Published: February 2022

331

Background: IO agents and TKIs have revolutionized treatment landscape of mRCC pts. Despite robust clinical trials’ data for these agents, real-world (rw) clinical outcomes data, especially from community setting in the US is limited. Methods: This retrospective cohort study included mRCC pts who received 1L treatment with either, pembrolizumab + axitinib (P+A) (IO+TKI), ipilimumab + nivolumab (I+P) (IO+IO) or cabozantinib, sunitinib, pazopanib and axitinib (TKI monotherapy (mono)) between 1/1/2018 and 9/30/2020 from The US Oncology Network of 480 sites. Patients were followed until 12/31/2020 to collect data on rw-time on treatment (rwToT), rw-time to next treatment (rwTTNT) and overall survival (OS). Kaplan-Meier analyses were performed to examine clinical outcomes. Results: We identified 1,538 eligible pts, of which 18% (n = 279) received P+A, 42% (n = 641) I+N and 40% (n = 618) TKI mono. The median follow-up duration for P+A, I+N and TKI mono cohort was 7.2 (range 0.0 - 20.5), 8.5 (range 0.0 - 32.3) and 7.8 (range 0.0 - 35.3) months, respectively. Majority of pts had clear cell histology (P+A - 82%, I+N - 86%, and TKI mono - 72%) and intermediate/poor IMDC risk score (P+A - 87%, I+N - 94%, and TKI mono - 81%). Median OS was not reached for P+A and was similar for I+N and TKI mono cohort (NR, 27.6, and 26.9 months, p=0.237, respectively). The median rwToT (13.6 vs. 5.8 vs. 3.4 months, p<0.0001) and rwTTNT (16.4 vs. 8.3 vs. 8.4 months, p<0.0001) was higher for P+A cohort compared to I+N and TKI mono cohort, respectively. Similar clinical outcomes results were noted for subgroup of pts with intermediate and/or poor IMDC risk score (Table). Conclusions: In this rw US community oncology-based study, longer treatment exposure (rwToT, rwTTNT) was noted in P+A compared to I+N or TKI mono. These rw endpoints may reflect treatment exposure, tolerability and/or compliance.[Table: see text]
Systemic therapy in patients with metastatic Xp11.2 translocation renal cell carcinoma.
Authors: Yan Xieqiao , Li Siming , Chi Zhihong , Si Lu , Cui Chuanliang , Kong Yan , Zhou Li , Tang Bixia , Wu Xiaowen , Mao Lili , Wang Xuan , Lian Bin , Bai Xue , Dai Jie , Guo Jun , Sheng Xinan
Published: February 2022

341

Background: Xp11.2 translocation renal cell carcinoma (RCC) is a unique RCC subtype with high malignant potential and poor prognosis, its natural course and response to systemic therapy are not fully understood. We analyzed the clinic features of this distinct entity and the benefit of systemic therapy in these patients. Methods: Between May 2006 and December 2019, 1113 consecutive patients diagnosed with RCC from Peking university cancer hospital (Beijing, China) were reviewed, data of the clinical characteristics and outcome of patients with metastatic Xp11.2 RCC were retrospectively collected. Tumor response to systemic therapy was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) distributions. Results: Metastatic Xp11.2 tRCC was found in 45 patients. The median PFS and median OS was 7.4 months (4.5 - 8.8) and 17.9 months (12.4 - 24.4), respectively. First-line treatment mainly included sunitinib (n = 14), sorafenib (n = 15), axitinib (n = 6), and pazopanib (n = 5), and the median PFS of these regimens were 7.4 months, 5.4 months, 9.4 months, 8.9 months, respectively. Two patients who received Vascular endothelial growth factor receptor - tyrosine kinase inhibitor (VEGFR-TKI) plus immune checkpoint inhibitor (ICI) as first line therapy had a PFS of more than 16.6 months and more than 25.6 months, respectively. Twenty-four patients received subsequent therapies, which included VEGFR-TKI/ICI, axitinib and mTOR inhibitor, the median PFS for these regimens was 8.5, 7.2 and 2.0 months, respectively. Patients with serous cavity effusion or IMDC poor risk groups had significantly shorter median PFS and median OS. Conclusions: Metastatic Xp11.2 tRCC is an aggressive disease. VEGFR-TKI agents appeared to demonstrate some efficacy, VEGFR-TKI/ICI combination might be a useful tool for the treatment of metastatic Xp11.2 tRCC.
Treatment outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC) with sarcomatoid and/or rhabdoid (S/R) features after progressive disease (PD) on immune checkpoint therapy (ICT): The MD Anderson Cancer Center experience.
Authors: Hahn Andrew Warren , Viscuse Paul Vincent , Surasi Devaki Shilpa , Bathala Tharakeswara , Wiele Andrew James , Starbuck Michael W , Campbell Matthew T , Shah Amishi Yogesh , Jonasch Eric , Gao Jianjun , Alhalabi Omar , Sircar Kanishka , Tannir Nizar M. , Msaouel Pavlos
Published: February 2022

351

Background: S/R mRCC is an aggressive disease that is associated with improved response to ICT. Studies performed prior to the approval of ICT demonstrated poor outcomes of S/R RCC with VEGF targeted therapies (TT). Here, we report outcomes of pts with S/R mRCC treated with VEGF TT after PD on ICT. Methods: We retrospectively reviewed the records of pts with mRCC with sarcomatoid (S), rhabdoid (R), or sarcomatoid plus rhabdoid (S+R) features who received VEGF TT after PD on ICT. Clinical endpoints of interest were time on VEGF TT and OS from treatment initiation. Directed acyclic graphs were used to identify confounders for adjustment in regression models. Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated using multivariable Cox regression. Multivariable models adjusted for epithelial histology, IMDC risk, prior VEGF TT, and inclusion of cabozantinib in the post-ICT VEGF TT regimen. Results: 57 pts with metastatic S/R RCC (52 with clear cell and 5 with non-clear cell histology) received a VEGF TT after PD on ICT. 46% of pts received a VEGF TT prior to ICT. After PD on ICT, 67% of pts had IMDC intermediate-risk disease; the most commonly used VEGF TT were cabozantinib (44%), either sunitinib, pazopanib, or axitinib (24%), and a VEGF TT in combination with an ICT (21%). Pts with R RCC had significantly longer time on VEGF TT compared with S RCC (adjusted HR = 0.45, 95% CI 0.21-0.94, p = 0.034), whereas the OS comparison was inconclusive (adjusted HR = 0.77, 95% CI 0.36-1.62, p = 0.486). IMDC risk classification following ICT progression was predictive of OS (adjusted HR = 2.22, 95% CI 1.07-4.61, p = 0.032), whereas, its association with time on VEGF TT was less conclusive (adjusted HR = 1.78, 95% CI 0.88-3.60, p = 0.107). Conclusions: Patients with S/R mRCC derive clinical benefit from VEGF TT after progression on ICT, and it is similar to the benefit previously described for patients without S/R features. Our findings suggest that the type of S/R features present and IMDC risk score inform the clinical benefit that VEGF TT will produce in this setting.[Table: see text]
Efficacy and safety of nivolumab plus ipilimumab (N+I) versus sunitinib (S) for first-line treatment of patients with advanced sarcomatoid renal cell carcinoma (sRCC) in the phase 3 CheckMate 214 trial with extended 5-year minimum follow-up.
Authors: Tannir Nizar M. , Signoretti Sabina , Choueiri Toni K. , McDermott David F. , Motzer Robert J. , George Saby , Powles Thomas , Donskov Frede , Tykodi Scott S. , Pal Sumanta K. , Gupta Saurabh , Lee Chung-Wei , McHenry M. Brent , Rini Brian I.
Published: February 2022

352

Background: sRCC is an aggressive histologic growth pattern in RCC with a poor prognosis and limited therapeutic options. First-line N+I provided efficacy benefits over S in patients (pts) with sRCC and intermediate/poor (I/P)-risk disease at 42 months follow-up. Here, we report an exploratory post hoc analysis of N+I vs S in pts with I/P-risk and sRCC with long-term follow-up of 5 years. Methods: Pts with clear cell advanced RCC were randomized 1:1 to N 3 mg/kg plus I 1 mg/kg every 3 weeks × 4, then N 3 mg/kg every 2 weeks vs S 50 mg once daily (4 weeks; 6-week cycles). Pts with sRCC were identified via independent central pathology review of archival tumor tissue or histological classification per local pathology. Outcomes in pts with sRCC were not prespecified. Endpoints in pts with sRCC and IMDC I/P risk included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Outcomes were also assessed per baseline tumor PD-L1 expression level (≥1% vs <1%). Safety outcomes used descriptive statistics. Results: Of 1096 randomized pts in CheckMate 214, 139 I/P-risk pts with sRCC were identified (N+I, n = 74; S, n = 65). Of all treated pts, 9 of 73 (12%) in the N+I arm vs zero of 65 in the S arm remained on treatment. The primary reason for discontinuation was disease progression (N+I, 37%; S, 71%). OS continued to favor N+I vs S (HR 0.46 [95% CI 0.29–0.71]; P = 0.0004; table). PFS benefit with N+I vs S was similarly maintained (HR 0.50 [95% CI 0.32–0.80; P = 0.0036]). Additionally, ORR was higher (61% vs 23%; P < 0.0001), median duration of response was longer (NR vs 25 months), and more pts had complete responses (23% vs 6%) with N+I vs S, respectively. Efficacy was better with N+I vs S regardless of PD-L1 expression, yet the degree of OS, PFS, and ORR benefits with N+I was greater for pts with PD-L1 ≥ 1% (Table). No new safety signals emerged in either arm. Conclusions: N+I showed clinically meaningful benefits in long-term OS, PFS, and the frequency and depth of response vs S in previously untreated pts with sRCC and I/P-risk disease, supporting N+I as a preferred first-line therapy in this population. Clinical trial information: NCT02231749. [Table: see text]
Comparison of patients with high-risk nonmetastatic clear cell renal carcinoma in adjuvant therapy trials versus nonclinical trial patients.
Authors: Hoogenes Jen , Breau Rodney H. , Bhindi Bimal , Rendon Ricardo A. , Tanguay Simon , Finelli Antonio , So Alan , Lavallee Luke , Pouliot Frederic , Lattouf Jean-Baptiste , Dean Lucas W. , Drachenberg Darrel E , Wood Lori , Basappa Naveen S. , Heng Daniel Yick Chin , Hansen Aaron Richard , Soulieres Denis , Bjarnason Georg A. , Mallick Ranjeeta , Kapoor Anil
Published: February 2022

361

Background: Characteristics of patients with high risk for recurrence non-metastatic renal cell carcinoma (nmRCC) participating in adjuvant therapy clinical trials post-nephrectomy have not been well described. We evaluated high risk nmRCC patients in the CKCis database to explore differences between trial and non-trial patients. Methods: Adult patients undergoing partial or radical nephrectomy for clear cell nmRCC between January 1, 2011 and March 31, 2021 were included. CKCis is a prospective cohort of patients from 14 Canadian academic institutions. Patients with high risk nmRCC (using modified UCLA Integrated Staging System) were included. Demographic, clinical, and survival statistics were analyzed for all patients and comparatively for the trial and non-trial groups. Results: 1459 patients, including 63 in adjuvant trials, were evaluated. 71% were male, 91% had pT3N0M0 disease. Disease characteristics including tumor size, stage, grade, location, necrosis, and margin status were similar between groups. Trial patients were younger (mean age 58.1 vs. 63.6; p < 0.0001) and had lower Charlson Comorbidity Index scores (median 4 [3,6) vs. 5 [4,6] p < 0.001). Estimated overall survival (OS) at 5 years was 80.8% (95% CI, 65,90) for trial patients and 74.8% (95% CI, 71,78.2) for non-trial patients. Recurrence-free survival at 5 years for trial patients was 48.6% (95% CI, 34,61.7) and 39.2% (95% CI, 35.2,43.1) for non-trial patients. Conclusions: Patients in adjuvant trials were younger and healthier at baseline than the average high risk nmRCC CKCis patient. Trial patients appear to have had longer time to recurrence and longer survival compared to non-trial patients, although not reaching statistical significance. Selection bias is common in clinical trials and evaluation of real-world population-based evidence of patients receiving adjuvant therapy will be important to ensure phase 3 trial results have external validity.
Association of renal cell carcinoma (RCC) metastatic to pancreas with a distinct molecular profile and immune cell population.
Authors: Chiang Ryan S. , Ashok Arya , Mauer Elizabeth , Barrett Alex , Hoerner Christian R , Khan Osama A , Kao Chia-Sui , Shah Sumit , Srinivas Sandy , Fan Alice C. , Khaki Ali Raza
Published: February 2022

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Background: RCC may metastasize to diverse sites, which confers variable prognosis and treatment response. Pancreatic metastases in RCC have been associated with indolent biology, low genomic instability and decreased inflammation, which may lead to worse responses to immunotherapy. To further investigate this phenomenon, we compared the genomic landscape and immunotherapy biomarkers of metastatic RCC patients with and without pancreatic metastases. Methods: We identified a cohort from the de-identified Tempus database, consisting of patients with metastatic RCC who received next generation sequencing via the Tempus|xT assay (DNA-seq of 648 genes at 500x coverage; whole-exome capture RNA-seq). Records were included if patients had RCC diagnosis and metastases to at least one of: pancreas, liver, brain, or lung (regardless of the presence of other metastases). RCC diagnosis and metastatic sites were determined from abstracted clinical notes received at the time of sequencing. If individuals had multiple xT results, the results from the most recent sample were included (irrespective of tissue site). We compared the prevalence of somatic gene alterations (using false discovery rate corrected q-values) and immunotherapy markers among records with vs without pancreatic metastases. Statistical significance was determined via Wilcoxon rank-sum tests or Chi-squared/Fisher’s exact tests. Results: 654 patients (median age 61, 30% female, 62% clear cell) with metastatic RCC were included. 58 harbored pancreatic metastases and 596 had metastases to sites other than pancreas (36 brain, 88 liver, 358 lung, 114 brain/liver/lung combinations). Females had a significantly higher representation in the group with pancreatic metastases (43% vs 29%, p = 0.02). The group with pancreatic metastases had significantly more PBRM1 alterations (52% vs 25%, q < 0.001), and trended towards more prevalent copy number loss of ALK (22% vs 10%, q = 0.06) and NTRK3 (16% vs 6%, q = 0.08) and less prevalent alterations in CDKN2A (3% vs 13%, q = 0.08), BAP1 (2% vs 13%, q = 0.06) and MTAP (0% vs 9%, q = 0.06). Individuals harboring pancreatic metastases had similar MSI status and TMB, but had lower rates of PD-L1 positivity, lower proportions of B-cells and higher proportion of NK cells in immune cell composition (Table). Conclusions: RCC patients with pancreatic metastases have a distinct molecular profile and lower rates of PD-L1 positivity, which suggests a unique disease biology and potential non-immunogenic phenotype. Further investigation and prospective validation is needed to determine immunotherapy outcomes in this population.[Table: see text]
Utilizing the autoantibody immune response to tumor antigens for kidney cancer early detection.
Authors: Hoerner Christian R , Jhatro Michael , Waitz Rebecca , Kamath Kathy , Zhang Minlu , Dhal Abhilash , Shon John , Fan Alice C.
Published: February 2022

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Background: Kidney cancer (renal cell carcinoma, RCC), the 8th most common U.S. cancer, is in need for better cure rates through early detection (5-year relative survival for stage I RCC: ̃95%; for stage IV RCC ̃19%). Autoantibodies are common in cancer and result from the altered expression, localization, or post-translational modification of endogenous proteins in tumor cells (autoantigens) and from the expression of mutated genes that give rise to new proteins (neoantigens). In contrast to cellular immune responses in cancer, autoantibodies are less well characterized, yet hold promise to enable cancer early detection by immune amplification of the ‘cancer signal’ while retaining specificity to cancer types including RCC. Autoantibodies may therefore be useful for kidney cancer early detection and diagnosis. Our goal was to profile the autoantibody repertoire in blood from patients with clear cell RCC (ccRCC), the most common form of RCC, in order to: 1) determine if autoantibodies can be detected in patients with early-stage and late-stage ccRCC; 2) identify common epitopes amongst ccRCC patients that could suggest common RCC antigens; and 3) determine specificity and sensitivity of potential autoantibody biomarkers for ccRCC vs. other non-cancer conditions. Methods: We use the SERA platform (https://serimmune.com/publications/) to compare putative autoantibody signal in blood from 177 patients with ccRCC, 23 with benign kidney lesions, and ̃800 healthy controls. SERA utilizes a random bacterial display 12mer peptide library of 1010 diversity in conjunction with next-generation sequencing to ascertain epitope enrichment across the entire human proteome. Results: We find significant differences in epitope repertoires in ccRCC compared to the healthy human cohort. Patients with ccRCC exhibit a rich repertoire of rare, enriched epitopes which may comprise putative autoantibody signal. This epitope signal is present with high abundance in all ccRCC stages, including stage I ccRCC. In contrast, healthy controls and patients with benign kidney lesions demonstrate more restricted repertoires. However, we do not find evidence of common ccRCC antigens: epitopes are not conserved across large subsets of ccRCC patients. Conclusions: Our initial results suggest that each patient may develop an individualized tumor-associated antibody response. Whether assessing a select epitope panel in a patient’s blood could be useful for ccRCC early detection, or even epitope diversity without needing to identify specific epitopes, warrants further study.
HIF-pathway genes prognostic for progression-free and overall survival in metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Tamukong Patrick , Kuhlmann Paige , You Sungyong , Su Shengchen , Wang Yanping , Small Eric Jay , Rini Brian I. , Halabi Susan , Janes Jessica , Freedland Stephen J. , Kim Hyung Lae
Published: February 2022

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Background: Clear cell renal cell carcinoma (ccRCC) is characterized by defects in the Von Hippel-Lindau/hypoxia-inducible factor (VHL/HIF) pathway. Several FDA-approved RCC therapies target the products of HIF-response genes. HIF2A is a promising new target and drugs targeting HIF2A are undergoing clinical testing. A better understanding of HIF-related genes may reveal useful biomarkers and drug targets. Methods: Gene expression was determined from 324 archival pretreatment nephrectomy specimens available from the Cancer and Leukemia Group B (CALGB) 90206, a phase III trial of patients treated with INF-α vs. INF-α plus bevacizumab. TaqMan RT-qPCR was performed on the OpenArray platform using RNA extracted from tumor tissue macrodissected based on review of H&E staining by a genitourinary pathologist. HIF pathway genes were assessed across both treatment arms, utilizing the proportional hazards model as predictors of OS and PFS, with time from randomization to death or disease progression as endpoints. Results: A total of 28 HIF-related genes (involved either in canonical or non-canonical HIF regulation) were assessed in univariate PH. Nine of these genes were associated with OS (i.e., HIF2A , VEGFC, VEGFD, TGFA, VHL, CCND1, EGFR, EGLN3 and HSP90AA1); and 6 of them were also associated with PFS (i.e., HIF2A , TGFA, VHL, CCND1 and EGLN3, and HSP90AA1). The HIF isotypes HIF1A and HIF3A were not prognostic, likewise VEGFA and VEGFB. Prolyl hydroxylase domain (PHD) proteins efficiently hydroxylate HIFα in normoxic conditions. PHD isotypes EGLN (1-3) were evaluated and only EGLN3 was associated with OS and PFS. HIF is also regulated by non-canonical pathways that function independent of oxygen concentration. HSP90AA1 was the only non-canonical pathway gene that was prognostic, and it predicted both OS and PFS. When the 9 genes that were prognostic in univariate analysis were used in a backward stepwise multivariate cox regression, VEGFD, TGFA and EGLN3 predicted OS while HIF2A, VHL and TGFA predicted PFS. Conclusions: VHL, HIF2A (but not HIF1A and HIF3A), EGLN3 (but not EGLN1 and EGLN2) and some of the HIF-response genes were prognostic of both OS and PFS. HSP90AA1 was prognostic for OS and PFS, suggesting that the non-canonical HIF pathway also plays a role in disease progression. Future studies should consider these HIF pathway genes as potential drug targets, and as predictors of response to treatments targeting the hypoxia pathway and angiogenesis.[Table: see text]
Intestinal microbiome associated with development of grade 3/4 adverse in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab plus ipilimumab (N/I) and probiotic support: Results from a phase Ib study.
Authors: Meza Luis A , Dizman Nazli , Bergerot Paulo Gustavo , Dorff Tanya B. , Lyou Yung , Frankel Paul Henry , Llamas Marian , Hsu Joann , Zengin Zeynep Busra , Salgia Nicholas , Malhotra Jasnoor , Chawla Neal Shiv , Gillece John D , Reining Lauren J , Trent Jeffrey M. , Takahashi Motomichi , Oka Kentaro , Higashi Seiya , Highlander Sarah K , Pal Sumanta K.
Published: February 2022

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Background: Treatment with N/I with the addition of CBM588, a live bacterial product comprised primarily of Clostridium butyricum, improved PFS and RR versus N/I alone when used as first line treatment for patients with mRCC (Meza et al ASCO 2021). Increased abundance of certain bacterial species in the gut microbiome have been associated with the development of treatment related adverse events (TREAs) in lung cancer patients receiving immunotherapy (Chau et al BMC Cancer 2021). However, this association has not yet been delineated in the setting of mRCC. Here, we present results of an exploratory analysis assessing the differences in stool microbiome composition between patients who experienced grade (G) 3/4 TREAs and those who did not. Methods: Patients were randomized 2:1 to receive N/I with or without CBM588. Stool collection for bacteriomic profiling was planned at baseline and after 12 weeks of therapy for all randomized patients. Whole metagenome sequencing was performed using previously published methods (Dizman et al Cancer Med 2021) and differences in microbiome composition were measured based on the occurrence of G 3/4 TREAs. Results: 30 patients were enrolled and 29 included in the study. At the time of data cutoff (April 15, 2021) the median follow up was 12.2 months (95% confidence intervals [CI], 10.6-13.8). Grade 3/4 TRAEs were experienced in 52, 50, and 53% of patients in the overall cohort, control, and intervention arms, respectively (p = NS). Among the most common G 3/4 TRAEs, subjects experienced fatigue, diarrhea, and hyperglycemia. Patients with a complete set of stool samples were included for the microbiome analysis (n = 26). In patients who experienced G 3/4 TRAEs, a significantly greater baseline abundance of Escherichia coli, Klebsiella spp. and Blautia spp. (p = 0.02, 0.03, 0.05) were seen when compared to those not experiencing G 3/4 TRAEs. In contrast, Bacteroides intestinalis and B. thetaiotamicron, were observed in significantly higher abundances in baseline stool specimens of patients who did not experience G 3/4 TREAs (p = 0.03 for both). No significant differences were seen for any of these species at the 12-week timepoint. Conclusions: We are among the first to investigate the differences in baseline stool microbiome in mRCC patients experiencing G 3/4 TRAEs while receiving immunotherapy. Our results suggest that certain taxa of bacteria are predictors of the development of serious TRAEs. Larger cohorts are needed to corroborate these findings. Clinical trial information: NCT03829111.