tbuckley/cabot-search huggingface dataset:
Pembrolizumab plus lenvatinib (P+L) versus alternate therapies in first-line (1L) for advanced renal cell carcinoma (aRCC): A network meta-analysis (NMA).
Authors: Kevin Yan, Pratik Rane, Manuela Schmidinger, Avivit Peer, Eric Druyts, Joseph E. Burgents, Murali Sundaram
Journal: Journal of Clinical Oncology (2024)

422 Background: Patients with advanced renal cell carcinoma (aRCC) have poor prognosis resulting in significant burden. In the KEYNOTE-581/CLEAR trial, pembrolizumab plus lenvatinib (P+L) as 1L therapy showed statistically significant and clinically meaningful improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) versus sunitinib in patients with aRCC. This NMA synthesized evidence from randomized clinical trials (RCTs) to indirectly compare the relative treatment effects of P+L vs alternate therapies in treatment-naïve aRCC. Methods: A systematic literature review was conducted to identify systemic therapies in 1L aRCC. A Bayesian NMA with fixed-effect models was performed to indirectly compare P+L to alternate therapies using sunitinib as the common comparator in 1L aRCC. Hazard ratios (HRs) for OS and PFS were calculated with 95% credible intervals (CrIs). NMAs assuming constant hazard ratios (HRs) and time-varying HRs were performed for OS and PFS. For the proportion of patients experiencing response, a binomial likelihood and logit link were used, and relative effects were expressed as odds ratios (OR). Results: A total of 33 unique RCTs met the inclusion criteria and were included in the analyses. The constant HR analysis resulted in no significant differences in OS between P+L and alternatives in network. Results showed statistically significant higher ORR for P+L compared to nivolumab + ipilimumab (N+I) (OR=3.19; 95% CrI: 2.14, 4.82) and pembrolizumab + axitinib (P+A) (OR=1.84; 95% CrI: 1.21, 2.80). The analysis also favored P+L over nivolumab + cabozantinib (N+C) (OR=1.35; 95% Crl: 0.86, 2.12) and avelumab + axitinib (A+A) (OR=1.46; 95% Crl: 0.96, 2.23), but was not statistically significant. The constant HR analysis showed that P+L resulted in a statistically significant improvement in PFS compared to N+I (HR=0.55; 95% CrI: 0.40, 0.75), A+A (HR=0.68; 95% Crl: 0.49, 0.96) and P+A (HR=0.69; 95% CrI: 0.51, 0.94). The analysis also favored P+L over N+C (HR=0.81; 95% Crl: 0.58, 1.14), but was not statistically significant. Conclusions: NMA indicates P+L has higher ORR and improved PFS compared to other regimens in 1L aRCC. No significant differences in OS were observed between P+L and competing interventions.
Pembrolizumab plus lenvatinib (P+L) versus alternative therapies in first-line (1L) advanced renal cell carcinoma (aRCC) by IMDC risk status: A network meta-analysis (NMA).
Authors: Pratik Rane, Kevin Yan, Manuela Schmidinger, Avivit Peer, Eric Druyts, Joseph E. Burgents, Murali Sundaram
Journal: Journal of Clinical Oncology (2024)

421 Background: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk criteria is a widely used prognostic model in advanced RCC. Pembrolizumab plus lenvatinib (P+L) demonstrated a significant improvement in ORR, PFS, and OS versus sunitinib in subjects with cc aRCC in the KEYNOTE-581/CLEAR trial. This NMA indirectly compared the efficacy of P+L to other therapies in 1L aRCC subjects within IMDC risk groups using data from randomized clinical trials (RCTs). Methods: A systematic literature review was conducted to identify systemic therapies in 1L aRCC. Trials reporting results for IMDC favorable risk and/or intermediate+poor risk groups were included. A Bayesian NMA with fixed-effect models was performed to indirectly compare P+L to alternate therapies using sunitinib as the common comparator. Hazard ratios (HRs) for OS and PFS were calculated with 95% credible intervals (CrIs). The NMAs assuming constant hazard ratios (HRs) for OS and PFS were performed for all IMDC risk group categories. For the proportion of patients experiencing response, a binomial likelihood and logit link were used, and relative effects were expressed as odds ratios (OR). Results: For the IMDC favorable risk subgroup, P+L demonstrated statistically significant increase in ORR compared to nivolumab + ipilimumab (N+I) (OR=5.35; 95% CrI: 2.59, 11.41) and nivolumab (OR=8.41; 95% CrI: 1.84, 43.77). For PFS, P+L resulted in a statistically significant improvement in PFS compared to N+I (HR=0.31, 95% CrI: 0.17-0.56). For OS, no significant differences were observed compared to other alternatives in the network. For the IMDC intermediate+poor risk subgroup, P+L demonstrated statistically significant increase in ORR compared to nivolumab + cabozantinib (N+C) (OR=1.77; 95% CrI: 1.02, 3.10), N+I (OR=3.15; 95% CrI: 1.94, 5.10), and nivolumab + ipilimumab + cabozantinib (N+I+C) (OR=2.34; 95% CrI: 1.34, 4.12), pembrolizumab + axitinib (P+A) (OR=2.65; 95% CrI: 1.57, 4.44) and nivolumab (OR=4.68; 95% CrI: 1.84, 12.02). For PFS, P+L resulted in a statistically significant improvement compared to N+I (HR=0.59; 95% CrI: 0.41, 0.84) (P+A) (HR=0.64; 95% CrI: 0.44, 0.93), and avelumab + axitinib (A+A) (HR=0.65; 95% CrI: 0.46, 0.93). For OS, no significant differences were observed compared to other alternatives in the network. Conclusions: PFS analysis favored P+L over all alternative therapies in the network in favorable or intermediate+poor IMDC risk groups. ORR analysis favored P+L over all alternative therapies in the network in intermediate+poor IMDC risk groups. No significant difference in OS was observed between P+L and other alternative therapies in the network.
A phase II study of neoadjuvant tislelizumab and axitinib in patients with locally advanced non-metastatic clear cell renal cell carcinoma (accRCC).
Authors: Shun Zhang, Changwei JI, Guangxiang Liu, Hongqian Guo
Journal: Journal of Clinical Oncology (2024)

420 Background: PD-1/PD-L1 combined with vascular endothelial growth factor (VEGF) inhibitors improves survival in patients with advanced renal cell carcinoma (RCC), but the role of perioperative application in patients with localized RCC has not been established. In this phase II trial, we investigate the safety and role of tislelizumab and axitinib in downsizing tumors in patients with non-metastatic clear cell RCC prior to surgical resection. Methods: In this investigator-initiated study, 20 patients with high-risk non-metastatic ccRCC (clinical stage T2a-4 and/or N1, M0 lesions) were enrolled to receive 12 weeks of neoadjuvant ticelizumab and axitinib prior to nephrectomy. The primary endpoint was the objective response rate (complete and partial response) after neoadjuvant treatment according to RECIST v1.1. Secondary endpoints were disease-free survival (DFS), overall survival (OS), surgical outcome and safety. Results: By September 2023,13 eligible pts were enrolled. 11 pts have completed neoadjuvant therapy, with a median age of 60 (range 45-73) years, among whom 9 pts underwent surgery as planned without any delay. One patient progressed during treatment and received further systemic therapy. In 9 pts evaluable for efficacy, the investigator-assessed confirmed ORR was 55.5%. The median reduction of primary renal tumor size was 26.2% (range 12.5-45%). Pathologic results showed that one patient (11.1%) achieved a complete response (CR) by RECIST 1.1 and four patients achieved a partial response (PR). One patient who was considered unresectable became resectable at the end of treatment. Two patients were converted from radical to partial nephrectomy. The most common neoadjuvant therapy-related AEs were hematologic toxicity, hypothyroidism, nausea, vomiting, decreased appetite, fatigue, diarrhea, and elevated ALT/AST. There were no Gr4/Gr5 TRAEs. No direct intraoperative complications and no drug-related surgical complications postoperatively. Conclusions: As a neoadjuvant therapy for accRCC, the combination of tislelizumab and axitinib has clinical efficacy and a manageable safety profile. Clinical trial information: NCT05172440 .
Safety of intraoperative tranexamic acid use on the risk of venous thromboembolism (VTE) in patients undergoing robotic assisted radical cystectomy (RARC).
Authors: Mohamed E. Ahmed, Jack R. Andrews, Ahmed M. Mahmoud, Prabin Thapa, Abhinav Khanna, Paras Shah, Vidit Sharma, R. Houston Thompson, Igor Frank, R. Jeffrey Karnes, Matthew K. Tollefson
Journal: Journal of Clinical Oncology (2024)

641 Background: Perioperative blood transfusion is associated with an increased risk of adverse events and tranexamic acid (TXA) use has been proposed to decrease the need for perioperative blood transfusion. Herein, we seek to investigate the impact of intraoperative TXA on perioperative risk of VTE in a subset of patients who underwent robotic-assisted radical cystectomy (RARC) for bladder cancer. Methods: We queried the prospectively maintained Mayo Clinic Radical Cystectomy registry and identified patients who underwent RARC between 2004-2021 and received TXA intraoperatively. In univariable and multivariable analyses, we investigated factors associated with bleeding and VTE within 30 days post-operatively. Results: Of 2862 patients, we identified 94 patients who received TXA (IV) intraoperatively (Group A) and were propensity score matched 1:1 for age, neoadjuvant chemotherapy, pT stage, pN stage, and preoperative hemoglobin with a group who did not receive TXA; 38 patients (Group B). In univariable and multivariable models, use of TXA has no statistically significant impact on patient’s risk of bleeding or VTE. In a univariable model, number of positive lymph nodes and extent of lymph node dissection were associated with increased risk of VTE (Table 1). Conclusions: In our study, use of TXA in patient’s undergoing RARC was safe and was not associated with increased risk of VTE. [Table: see text]
A cost-effectiveness analysis assessing systemic treatments in metastatic castration-sensitive prostate cancer (mCSPC) by volume of disease.
Authors: Syed Arsalan Ahmed Naqvi, Kunwer Sufyan Faisal, Muhammad Ali Khan, Kaneez Zahra Rubab Khakwani, Holly K. Van Houten, James P. Moriarty, Bijan J. Borah, Parminder Singh, Daniel S Childs, Vidit Sharma, Stephen A. Boorjian, Mitchell R. Humphreys, Oliver Sartor, Ewan Kemar Cobran, Irbaz Bin Riaz, Alan Haruo Bryce
Journal: Journal of Clinical Oncology (2024)

93 Background: The treatment paradigm for mCSPC patients has rapidly evolved over the last few years with the emergence of triplet therapy and prognostication by volume of disease. However, the health economic implications of triplet therapy by disease volume remain unclear. Methods: A Markov model where patients transitioned between the progression-free, progression and death states was developed. State utilities were derived from the LATITUDE trial. Point probabilities for overall survival, progression-free survival, grade ≥ 3 and 5 toxicities were obtained from the eligible mCSPC phase III clinical trials. Medicare Advantage and commercial total paid amounts (2022 US$) of treatments were obtained from OptumLabs Data Warehouse. Costs and disutilities of adverse events were derived from published literature. Half-cycle corrected costs and utilities were accrued monthly over a 20-year lifetime horizon and were discounted at 3%. Monte Carlo simulation was used to calculate incremental cost-effectiveness ratios (ICERs). A willingness-to-pay (WTP) threshold of US$100,000 was used. Results: In terms of Medicare Advantage payer’s perspective (Table), docetaxel (D)+ADT was observed to provide additional 0.068 QALYs compared to ADT at an ICER of US$16,544 per QALY in high volume disease. Compared to D+ADT, abiraterone (AAP) triplet provided additional 1.03 QALYs at US$56,641 per QALY. Compared to AAP triplet, apalutamide (APA)+ADT provided additional 0.048 QALYs at US$5,846,248 per QALY in high volume disease. In low volume disease, D+ADT provided 0.45 more QALYs at US$20,690 per QALY compared to ADT alone. Compared to D+ADT, AAP triplet provided an additional 1.51 QALYS at US$44,267 per QALY. In terms of total paid commercial costs, AAP triplet provided an additional 1.19 QALYs compared to ADT at US$91,952 per QALY in high volume disease. In low volume, D+ADT provided additional 0.38 QALYs at US$22,058 per QALY compared to ADT. Compared to D+ADT, AAP triplet provided a 0.97 QALY gain at US$105,958 per QALY. Compared to AAP triplet, darolutamide (DARO) triplet provided a 0.47 QALY at US$689,196 per QALY. Compared to DARO triplet, APA+ADT provided an additional 0.49 QALYs at an ICER of US$971,389 per QALY. All other treatments (not reported here) were dominated. Conclusions: At the selected WTP of US$100,000 per QALY, AAP triplet therapy was most likely the cost-effective strategy in overall mCSPC population particularly in patients with high volume disease. However, these results should be interpreted with careful accounting for timing of metastases. [Table: see text]
Cabozantinib plus pembrolizumab as first-line therapy for cisplatin-ineligible advanced urothelial carcinoma (PemCab).
Authors: Rohit K. Jain, Umang Swami, Mehmet Asim Bilen, Kenneth M. Boucher, Jacqueline T Brown, Jad Chahoud, Sumati Gupta, Neeraj Agarwal, Guru P. Sonpavde, Benjamin L. Maughan
Journal: Journal of Clinical Oncology (2024)

539 Background: Pembrolizumab (pem) was initially approved in the first line setting for cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients (pts) with high PD-L1 expression and platinum ineligible pts regardless of PD-L1 status; this later changed to only platinum ineligible pts. There is a high disease progression (PD) rate with pem monotherapy. Cabozantinib (cabo) is a multiple receptor tyrosine kinase inhibitor targeting MET and VEGFR2 approved in multiple other malignancies as monotherapy or in combination with PD-1 inhibition. We hypothesized that combination of pem and cabo therapy will be safe and efficacious in patients with treatment naïve mUC. Methods: This is a phase II, open label, multi-center, single arm trial evaluating the tolerability and activity of pem 200 mg every 3 weeks and cabo 40 mg daily as first-line treatment for patients with mUC. Key inclusion criteria were histologically proven locally advanced or mUC, ECOG-PS 0-2, cisplatin-ineligible (including patient refusal of cisplatin), treatment naïve, and no prior PD-1/L1 therapy. The primary endpoint was objective response rate (ORR). Key secondary endpoints included progression-free survival (PFS) and overall survival (OS). There was a lead-in safety cohort of 6 pts. We hypothesized that combination therapy would improve ORR to &gt; 32%. With 35 evaluable subjects, the lower bound of the 95% confidence interval would extend no more than 26% from the observed proportion. With ≥17 objective responses, the confidence interval excludes 32%. Results: Between December 26, 2018, and April 19, 2023, 36 pts were enrolled of which 35 were evaluable for response with the median follow up of 14.4 months (95% CI 12.2 – 16.2). The median age was 72.5y [range, 47-82]; ECOG PS 0-1 in 89% pts. Responses were observed in 15 pts (ORR= 42.8%) including complete responses in 5 pts (14.3%). Stable disease was seen in 10 pts (28.6%). The disease control rate was 68.5% (25/35). Median PFS was 7.7 months (95% CI 4.2 – 11.2). Fifty-two percent of pts developed any grade treatment-related adverse events (TRAE) attributable to either cabozantinib or pembrolizumab. The most common grade 1/2 TRAE were diarrhea, anorexia, dysgeusia, weight loss, and nausea. Forty-four percent pts developed grade 3/4 TRAEs most common being hypertension, hypophosphatemia, alanine transaminase elevation, diarrhea, and fatigue. Conclusions: This novel phase II trial of pem + cabo demonstrated a manageable toxicity profile and promising efficacy as first-line therapy in mUC including patient’s ineligible for cisplatin. Further investigation with a focus on predictive biomarkers is ongoing. Clinical trial information: NCT03534804 .
Impact of HIV-HPV co-infection on inpatient penile cancer outcomes.
Authors: Ayobami Gbenga Olafimihan, Vaishali Deenadayalan, Praise Fawehinmi, Shweta Gupta
Journal: Journal of Clinical Oncology (2024)

6 Background: HPV (human papillomavirus) and HIV (Human Immunodeﬁciency Virus) are risk factors for Penile cancer (PC); HIV-HPV co-infection heightens the risk of anogenital dysplasia (PMID: 19706632, 19082746, 35630489). However, there is paucity of data on the impact of HIV-HPV co-infections on PC outcomes. We evaluated the characteristics, outcomes, and healthcare utilization of patients with PC with and without HIV-HPV co-infection (HHC) from a national sample. Methods: Healthcare Cost and Utilization Project-Nationwide Inpatient Sample database was queried to identify all PC patients with (HIV-HPV-PC) and without HIV-HPV co-infection (non-HIV-HPV-PC) from 2016-2020. The groups were compared for socio-demographic differences, medical comorbidities, inpatient mortality, length of stay (LOS), and total hospital charges (THC). Secondary outcomes included rates of sepsis, septic shock, and UTI. Statistics were performed using t-test, univariate and multivariate logistic regression. Results: Out of 11,320 PC admissions, 255 had HIV, 205 had HPV, and 30 had HIV-HPV co-infection. Patients without the co-infection were older with a mean age of 65.6 years as compared to those with HIV-HPV co-infection, who had a mean age of 52.7 years (p = 0.002). Compared to non-HIV-HPV-PC, HIV-HPV-PC patients were more likely to be Black (66.7% vs 11.3%, p&lt;0.001). The prevalence of comorbidities was similar between both groups. HIV-HPV co-infection in penile cancer patients was associated with a ten-fold higher adjusted all-cause mortality compared to those without the co-infection (adjusted odd ratio (aOR) = 10.2, p = 0.035). Mean LOS (6.0 vs 5.7 days, p = 0.8) and THC ($65,472 vs $64,627, p = 0.32) were similar between cohorts. Conclusions: HIV-HPV co-infection in penile cancer is associated with younger age, black race, and a ten-times higher adjusted all-cause inpatient mortality. [Table: see text]
Prevalence of HRR mutations in Indian patients with mCRPC.
Authors: Atul Batra, Nandini Sharrel Menon, Bharat Vaswani, Vineet Talwar, Rajat Bajaj, MV Chandrakanth, Sachin Sharadchandra Hingmire, Kumar Prabhash, Priyanshu Choudhary, Bhavana Pathania
Journal: Journal of Clinical Oncology (2024)

183 Background: Prostate cancer is the 12 th most common cancer in India. Almost all patients with metastatic prostate cancer progress to castration-resistant prostate cancer. Ph3 studies demonstrated benefit of PARPi for patients with mutations in HRR pathway. However, the prevalence of HRR gene mutations in Indian patients with mCRPC is not known. This non-interventional multicenter study aimed to determine the prevalence of HRR gene mutations in the Indian patients with mCRPC. Methods: The study included mCRPC patients from 8 centres across India. A total of 213 patients were screened, of which 192 patients completed the study. Comprehensive molecular profiling on tumour tissue was performed using next-generation sequencing (NGS) to identify 15 HRR gene mutations. The QC-passed libraries were sequenced to a minimum depth of &gt;250X on a validated Illumina sequencing platform. Results: NGS analysis revealed HRR gene mutations (Pathogenic, likely pathogenic and VUS) in 41/192 (21.4%, 95% CI: 15.78, 27.83)) of the patients (Table). Among the HRR gene mutations identified, BRCA2 mutations were the most prevalent.68/192 (35%) patients failed tumor testing and underwent reflex germline testing. Among patients having no known family history, 24 patients (12.5%) harboured a HRR gene mutation. Most patients (n=23, 12.0%) had Gleason score of 9 to 10. Conclusions: Pathogenic and likely pathogenic HRR gene mutations were prevalent in approximately one-fifth of the mCRPC patients in India. 64.5% patients had a successful test result on the tumor tissue sample. [Table: see text][Table: see text]
Comparison of financial toxicity among patients with non-metastatic versus metastatic renal cell carcinoma.
Authors: Michael D. Staehler, Ulka N. Vaishampayan, Sumanta Kumar Pal, Pavlos Msaouel, Ithaar Derweesh, Dena Battle
Journal: Journal of Clinical Oncology (2024)

408 Background: Little is known about the financial impact of renal cell carcinoma (RCC). We sought to ascertain real world data on financial implications and how financial toxicity (FT) impacts quality of life in patients with localized RCC versus patients with metastatic RCC. Methods: An online survey was conducted by the Kidney Cancer Research Alliance (KCCure), a non-profit patient advocacy organization, from 7/22 to 9/22. The survey included questions about costs and financial concerns and the COST questionnaire. Pearson’s correlation (r) and Kendal’s tau test were used to analyze the COST questionnaire, financial burden and hardship. Results: Out of 1062 responders 623 had localized RCC. Out of these patients 395 did not recur and 204 were willing to answer questions related to cost and financial hardship. 289 responders had metastatic disease and were on systemic therapy and 177 pts answered the COST questionnaire. In localized disease 28% reported that their diagnosis has not reduced their income, in 26% the diagnosis had reduced their income very much.31% experienced insurance denials for imaging, 30% faced delays in care due to pre-approval requirements, 45% faced high out-of-pocket costs for medical care. 24% of patients reported taking a hardship withdrawal from a retirement account, 28% stopped funding or lowered contributions to an existing retirement account, 20% borrowed from friends or family. In metastatic patients 14% reported difficulties to pay their premiums. 28% reported that their medical situation has not reduced their income and 26% claimed that their disease reduced their income very much. 36% reported high out of pocket costs are a barrier to care. 44% have received financial support through a manufacturer or a foundation. Median COST score in non-metastatic RCC was 32 (range 19-44)) and was significantly correlated to age, NCCN distress score, risk of recurrence and supplement intake (p &lt; 0.05). Metastatic patients had a significantly higher median COST score of 22 (range 4-36)) that was also correlated to age, NCCN distress score, time since diagnosis and supplement intake (p &lt; 0.05). Conclusions: RCC imposes financial hardship on patients. Younger patients with a higher NCCN distress score and a shorter time since diagnosis are more likely to suffer financial hardships. Patients are willing to pay for supplements. Financial counseling should be considered in these patient subgroups regardless of stage. [Table: see text]