tbuckley/cabot-search huggingface dataset:
Chemoradiation versus cystectomy for locally advanced bladder cancer: A global, propensity-matched retrospective cohort study.
Authors: James David Mackey, Khaled Atieh
Journal: Journal of Clinical Oncology (2024)

e16603 Background: Prior studies have attempted to determine whether chemoradiation is comparable to cystectomy for treatment of locally advanced bladder cancer. Some studies have shown no significant difference, while others indicate a small benefit in favor of cystectomy. The purpose of this study was to use the large, multi-institutional TriNetX database to evaluate for differences in overall survival and development of metastatic disease between the two treatments at five years. Methods: The TriNetX research database was used for this study. Two patient cohorts were created by utilizing International Classification of Disease-10 (ICD-10) codes and Current Procedural Terminology (CPT) codes. Both cohorts of patients were required to have a diagnosis of bladder cancer (C67) and were prohibited from having any known sites of metastatic disease (C78 or C79). The cystectomy cohort was constructed by using CPT codes 51590, 51595, or 51596. Chemoradiation treatment was identified by encounters for chemotherapy and radiation occurring on the same day (Z51.11 and Z51.0). The chemoradiation cohort was prohibited from having any cystectomy surgery, and the cystectomy cohort was prohibited from having had any radiation treatment. The cohorts were then balanced by propensity score matching and the greedy nearest neighbor algorithm for age, race, gender, and ethnicity. This resulted in 232 patients in each arm. The cohorts were then compared for the outcome of death at 5 years, as well as the development of metastases to lymph nodes, lung, bone, liver, and peritoneum (C79.51, C78.0, C77, C78.7, C79.89). Results: Patients who underwent chemoradiation had significantly higher mortality at five years than those that underwent cystectomy (38.4% vs 20.3%, RR 1.89, 95% CI (1.40,2.56), P value &lt; 0.0001). Patients treated with chemoradiation were also six times more likely to develop metastatic disease to lymph nodes, lung, bone, liver, or peritoneum (31.0% vs 5.2%, RR 6, 95% CI (3.3,10.8), P value &lt; 0.0001). Conclusions: Patients with stage II or III bladder cancer can be treated with either cystectomy or chemoradiotherapy. Both options are Category 1 recommendations of the National Comprehensive Cancer Network, with patient preference often a deciding factor. This study found that the development of metastatic disease and mortality may be more substantial than previously believed, suggesting that bladder cancer is a relatively chemoradiation resistant malignancy.
Avelumab (A) as neoadjuvant therapy in patients (pts) with muscle-invasive urothelial carcinoma (MIUC): Survival data of AURA trial, Oncodistinct 004.
Authors: Jeremy Blanc, Aurélien Carnot, Philippe Barthelemy, Vinciane Casert, Lionel Staudacher, Jan Van den Brande, Brieuc Sautois, Vincent Vanhaudenarde, Emmanuel Seront, Veronique Debien, Lieveke Ameye, Nuria Kotecki, Jean Christophe Fantoni, Thibault Tricard, Thierry Andre Roumeguere, Ahmad Awada, Nieves Martinez Chanza
Journal: Journal of Clinical Oncology (2024)

4516 Background: Immunotherapy in the perioperative setting of MIUC appears promising. The AURA trial (NCT03674424) investigated the addition of avelumab to neoadjuvant dose-dense MVAC (ddMVAC) or cisplatin-gemcitabine (CG) respectively, followed by surgery in the cisplatin-eligible cohort. The primary endpoint was previously reported with high pathological complete response (pCR) rates with each cisplatin-based regimen. In the cisplatin-ineligible cohort, pts were randomized to neoadjuvant A alone or in combination with paclitaxel-gemcitabine (PG) followed by surgery. Avelumab monotherapy showed encouraging pCR but the addition of PG did not provide any benefit. Here, we report the survival data from cisplatin-eligible and ineligible cohorts of the AURA trial. Methods: In the cisplatin-eligible cohort, 79 pts were randomly assigned to the ddMVAC-A (n=39) or CG-A (n=40) groups. In the cisplatin-ineligible cohort, 58 pts were randomly assigned to the PG-A (n=29) or A (n=29) groups. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method at 12 months and 36 months for the overall cohort and by subgroups. Results: Median follow-up was 33 months and 45 deaths were reported. In the cisplatin-eligible cohort, 12-month DFS was 92% (95% CI, 83-96%) and 36-month DFS was 72% (95% CI, 57-83%). For ddMVAC-A group: 97% and 77%, respectively. For CG-A group: 86% and 68%. Overall, 12-month OS was 89% (95% CI, 80-95%) and 36-month OS was 73% (95% CI, 61-83%). For ddMVAC-A: 95% and 87%. For CG-A: 84% and 61%. Among the ypT0N0 pts, no events were registered within 12 months of follow-up showing a DFS rate of 100% for both arms. At 36 months no events were reported for pts treated with ddMVAC-A and two for CG-A showing DFS rates of 100% and 78% respectively. In the cisplatin-ineligible cohort, 12-month DFS was 60% (95% CI, 46-72%) and 12-month OS was 71% (95% CI, 57-81%). For PG-A: 52% and 67%. For A: 68% and 75%. Among the ypT0N0 pts, no DFS events occurred within 12 months. Data for 36-month are not yet mature. Overall, the main cause of death was disease progression (73%). Conclusions: The addition of neoadjuvant avelumab to cisplatin-based chemotherapy results in a high DFS and OS at 12 and 36 months respectively, especially in pts with complete response to neoadjuvant treatment. Combination with ddMVAC regimen offers robust activity. Cisplatin-ineligible pts had lower survival outcomes with no benefit of PG addition. Clinical trial information: NCT03674424 . [Table: see text]
Systemic treatments in favorable and very favorable risk metastatic renal cell carcinoma (mRCC): Real world evidence from the International mRCC Database Consortium (IMDC).
Authors: Martin Zarba, Evan Ferrier, Connor Wells, Talal El Zarif, Naveen S. Basappa, Hedyeh Ebrahimi, Rana R. McKay, Lori Wood, Benoit Beuselinck, Cristina Suárez, Kosuke Takemura, Aly-Khan A. Lalani, Haoran Li, Lavinia Anne Spain, Arnoud J. Templeton, Thomas Powles, Georg A. Bjarnason, Guillermo de Velasco, Toni K. CHOUEIRI, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2024)

4514 Background: The role of immunotherapy combinations in mRCC with IMDC favorable risk is controversial. A very favorable subgroup of favorable risk patients (primary diagnosis to systemic therapy ≥3yr, Karnofsky Performance Status 90 or 100% and absence of brain, liver, or bone metastasis) has been described by Schmidt A. et al., which require characterization in the immuno-oncology combination era. Methods: Using the IMDC, we selected mRCC patients with IMDC favorable risk who started systemic therapy during 2016-2023 and examined the favorable risk group and the subset of very favorable risk patients. First line systemic therapy was divided into 3 groups: Ipilimumab + Nivolumab (IPI/NIVO), combination of anti PD1/PDL1 and VEGF (IO-VEGF) (Pembrolizumab and Axitinib or Lenvatinib, Avelumab and Axitinib, or Nivolumab and Cabozantinib), and Vascular endothelial growth factor (VEGF) inhibitors (Pazopanib or Sunitinib). The primary outcomes were 2-year overall survival (2y OS) in the favorable and very favorable risk population. Secondary outcomes included Response Rate (RR), treatment duration (TD) and time to next treatment (TTNT). We used unadjusted survival rates at 2 years, with Cox regression model with TKI mono as reference. Results: 611 favorable risk patients were eligible for analysis, of which 165 (26.9%) had very favorable risk disease. Median age at diagnosis was 62 years, 73.8% were male, 87.1% had clear cell histology, 5% had sarcomatoid features, and 97,2% had a prior nephrectomy. With a median follow up of 33 months, outcomes are summarized in the table. Conclusions: No significant difference in survival between different treatment regimens in the favorable risk population was detected yet. In the very favorable risk population, there was a statistically significant decrease in 2 year overall survival with IPI-NIVO (HR 3.19) which, if validated, could underline the necessity of targeting the VEGF pathway in this population. Further prospective trials and longer follow-up are required to confirm these findings. [Table: see text]
Partitioned overall survival: Comprehensive analysis of survival states over 4 years in CheckMate 9ER comparing first-line nivolumab plus cabozantinib versus sunitinib in advanced renal cell carcinoma (aRCC).
Authors: Charlene Mantia, Opeyemi Jegede, Hollis Viray, Michael B. Atkins, Lisa Rosenblatt, Xin Yin, David F. McDermott, Meredith M. Regan
Journal: Journal of Clinical Oncology (2024)

4507 Background: Immunotherapy regimens can be associated with prolonged disease control after treatment discontinuation without the need for further anticancer therapy. An integrated, comprehensive partitioned survival analysis describes how patients spend overall survival (OS) time, on/off treatment, with/without toxicity. Previous analysis of first-line (1L) nivolumab (NIVO) + ipilimumab (IPI) for aRCC in CheckMate 214 showed treatment-free survival (TFS) twice as long vs sunitinib (SUN). TFS and survival states for immune checkpoint inhibitor plus tyrosine kinase inhibitor (TKI) combination are of interest. Methods: Overall, 651 patients (pts) with aRCC were randomized to receive 1L NIVO + cabozantinib (CABO) or SUN in the CheckMate 9ER trial; treatment continued until progression or intolerance, NIVO for at most 24 months. Minimum follow-up was 4 years. We partitioned area under the Kaplan–Meier (KM) OS curve into 3 survival states, defined from randomization: time on 1L protocol therapy, TFS, and survival after subsequent systemic therapy (second line [2L]) initiation. TFS and protocol therapy were subdivided as mean times with/without reported grade 2+ treatment-related adverse events (TRAEs). Areas under and between KM curves were estimated by 48-month restricted mean times to event. Bootstrapped 95% CIs for between-group differences are reported. Results: At 4 years post randomization, KM estimates of OS were 49.2% vs 40.2% of pts assigned to NIVO+CABO vs SUN, respectively; 17.6% vs 4.7% of pts were surviving treatment-free, and 15.8% vs 8.2% were continuing on 1L protocol therapy. Over the 48-month period since randomization (Table), the mean TFS (95% CI) was 2.4 (0.8–3.9) months longer after treatment with NIVO+CABO than SUN. At least half of TFS was spent with toxicity in both treatment groups, resulting in difference in mean TFS (95% CI) without toxicity of 0.7 (−0.4 to 1.8) month. The NIVO+CABO group spent a mean (95% CI) of 8.5 (6.2–10.8) months more survival time on 1L protocol therapy, whereas the SUN group spent a mean (95% CI) of 6.5 (4.4–8.6) months more survival time after 2L therapy initiation. Conclusions: Over the 4-year period since initiation of 1L therapy for aRCC, the longer OS achieved with NIVO+CABO was accompanied by 1.5 times longer mean time surviving treatment-free before 2L therapy compared with SUN, a smaller difference than seen for NIVO + IPI vs SUN. [Table: see text]
Correlation of circulating tumor DNA (ctDNA) dynamics with clinical response in patients with muscle-invasive bladder cancer (MIBC) undergoing trimodality therapy (TMT).
Authors: Ilana B. Epstein, Stephanie A. Berg, Charlene Mantia, Matthew Mossanen, Anurag Saraf, Mark A. Preston, Arvind Ravi, Filipe Lf Carvalho, Timothy Clinton, Daniel Aaron Roberts, Luke Peng, Bradley Alexander McGregor, Joaquim Bellmunt, Jacob E. Berchuck, Kent William Mouw
Journal: Journal of Clinical Oncology (2024)

e16606 Background: Trimodality therapy (TMT) is a curative treatment option for patients with muscle-invasive bladder cancer (MIBC). Plasma circulating tumor DNA (ctDNA) is associated with treatment response and clinical outcomes following cystectomy for bladder cancer, but the association of plasma ctDNA with treatment response and clinical outcomes in patients with MIBC treated with TMT is poorly understood. Methods: Select patients with MIBC who received TMT at Dana-Farber/Brigham and Women’s Cancer Center between June 2023 and January 2024 who underwent pre-TMT ctDNA evaluation with the commercially available Signatera assay were included in this analysis. Individual chart review was performed to collect demographic and clinical data including disease stage, histopathology, imaging, and treatment details. Results: Pre-treatment ctDNA results were available for 16 patients. Nine of the 16 patients had at least one post-treatment result available while the remaining 7 patients have not yet completed their first post-TMT ctDNA test. Seven of 16 patients had detectable ctDNA prior to TMT initiation. Of these 7 patients, 4 had at least one post-treatment ctDNA result available (median 11.2 weeks following TMT), and 3 of 4 patients converted to having undetectable ctDNA following TMT and were also free of disease as determined by routine post-TMT surveillance including radiographic, cytologic and cystoscopic assessment. The single patient who had persistent detectable ctDNA following TMT developed radiographic evidence of metastatic disease 3 months following TMT and died from bladder cancer 2 months later. Five patients with undetectable ctDNA prior to TMT had at least one post-TMT ctDNA result available. All five of these patients remained ctDNA-negative following TMT and have had no clinical evidence of recurrence. Conclusions: Plasma ctDNA measured using the Signatera assay can be performed in MIBC patients undergoing TMT and appears to correlate with clinical response to TMT at early time points. Larger cohorts with longer follow-up will be required to define the association between plasma ctDNA status and clinical outcomes following TMT. [Table: see text]
Association of body mass index (BMI) with survival outcomes in patients with metastatic renal cell carcinoma (mRCC).
Authors: Rohit Vivek Goswamy, Ahmet Yildirim, Yujin Choi, Mengting Wei, Yuan Liu, Jacqueline T Brown, Bassel Nazha, Dylan J. Martini, Caitlin Hartman, Greta Russler McClintock, Tony Zhuang, Haydn Kissick, Wayne Bernard Harris, Bradley Curtis Carthon, Omer Kucuk, Viraj A. Master, Mehmet Asim Bilen
Journal: Journal of Clinical Oncology (2024)

e16535 Background: Recent data have reported on obesity as a probable protective factor in metastatic RCC (mRCC). Current knowledge and expanding data suggests a higher BMI (overweight and obese patients) have better survival outcomes. We hypothesize that mRCC patients studied at our institution, Emory’s Winship Cancer Institute, will display similar clinical outcome trends. Methods: We conducted a retrospective analysis of patients with mRCC treated at Winship Cancer Institute between 1/1/2018 and 8/31/23. Overall survival (OS) and progression-free survival (PFS) were defined as months from treatment initiation to death or clinical/radiographic progression, respectively. The correlation between BMI and OS/PFS was studied in 399 patients diagnosed with metastatic RCC under systemic therapy. The groups were divided into overweight and obesity (BMI &gt; 25 kg/m2) and underweight or normal (BMI &lt; 25 kg/m2). Univariate (UVA) and multivariate (MVA) analyses were carried out for OS and PFS using Cox proportional hazard model. Results: A total of 401 eligible patients were included with a median follow up of 60 months. Median age was 66 years (range = 18-95), 71% were male, 29% were female, and 81% had clear cell histology. 36% received checkpoint inhibitor (CPI) monotherapy, 28% received combination CPI, and 26% received CPI in combination with tyrosine kinase inhibitor (TKI). 4% received other therapies. Lower BMI (&lt;25) at initiation of systemic therapy was significantly associated with worse OS and PFS (table). Conclusions: Lower BMI at baseline and during therapy was associated with worse clinical outcomes. This helps validate the association between obesity and improved survival, a potential "obesity paradox." Results should be validated in a larger, prospective study to further understand the complex relationship between BMI, lipid metabolism, and clinical outcomes in mRCC. [Table: see text]
Safety and efficacy profile of belzutifan, a hypoxia-inducible factor-2α inhibitor, in patients with renal cell carcinoma: Meta-analysis and systematic review.
Authors: Nouman Shafique, Zainab Javeed, Shammas Bajwa, Umar Ghaffar, - Muhibullah, Jawad Ahmed, Sarmad Zain, Navneet Kaur, Ali Ghaffar, Digbijay Kunwar, Sabeeh Farooqui, Abdul Ghani Iqbal, Syed Mujtaba Ali Naqvi, Abdul Qadeer, Amna Ehsan, Iqra Shafiq, Adeena Shafique, Umer Rizwan, Rida Hussain, Abhi Lohana
Journal: Journal of Clinical Oncology (2024)

e16531 Background: Hypoxia-inducible Factor-2α (HIF-2α) is a transcription factor that accumulates in clear cell renal cell carcinoma (ccRCC) and is responsible for genes involved in oncogenesis. Belzutifan is a HIF-2α inhibitor that has shown promising anti-tumor effects in patients with ccRCC. Our objective is to summarize the available literature on the safety and efficacy profile of the drug. Methods: An electronic search was conducted on PubMed, Embase, and Cochrane from inception till January 31 st , 2024. We identified patients aged ≥ 18 years with ccRCC who received Belzutifan. We extracted data on objective response rate, complete response rate, any grade adverse effect (AE) and grade ≥3 AE. Data was analyzed using R (v.4.3) and reported as proportions with respective 95% confidence intervals (CI) on forest plots. Results: Three studies (n=168 patients) were identified that reported the use of Belzutifan in ccRCC. Our analysis showed that pooled proportion of objective response rate and complete response rate was 35% (95% CI: 24% – 47%) and 1% (95% CI: 0% – 5%) respectively. Pooled proportion of patients experiencing any grade AE and grade ≥3 AE was 98% (95% CI: 95% – 99%) and 49% (95% CI: 29% – 69%) respectively. Conclusions: Belzutifan is a novel drug that inhibits HIF-2α which in turn results in anti-tumor effects of the drug against ccRCC. The drug has an acceptable safety and efficacy profile from limited data but more studies are needed to establish a complete picture of drug’s adverse effects and clinical benefits. Pooled proportion of patients developing (A) Objective Response, (B) Complete response (C) Any adverse effect and (D) Grade ≥3 adverse effects. [Table: see text]
Impact of exposure on outcomes with enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer.
Authors: Daniel P. Petrylak, Yen Lin Chia, Evan Y. Yu, Thomas Powles, Thomas W. Flaig, Yohann Loriot, Peter H. O'Donnell, Elisabeth I. Heath, Takahiro Kojima, Se Hoon Park, Guru P. Sonpavde, Joel Picus, Nobuaki Matsubara, Wataru Obara, Vaishali Chudasama, Srinivasu Poondru, Michael Harrison, Eric Kim, Sam Joseph Brancato, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2024)

4503 Background: Enfortumab vedotin (EV) is approved in combination with pembrolizumab and as a monotherapy for locally advanced or metastatic urothelial cancer (la/mUC). EV, alone and in combination with pembrolizumab, has demonstrated an OS benefit and a generally manageable safety profile in patients (pts) with previously treated or untreated la/mUC. Dose modifications, including reductions and interruptions, are recommended to manage EV-related AEs. This analysis evaluates the association between EV plasma exposure, which is impacted by dose modifications, and safety and efficacy outcomes. Methods: Characterization of dose- and exposure-response for efficacy and exposure-response for safety outcomes included pts in EV-101 (EV monotherapy 0.75, 1.0, and 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle [3Q4W]), EV-201, and EV-301 (EV monotherapy 1.25 mg/kg 3Q4W). Time-averaged exposure up to an event of interest, C avg , was computed using a population PK model. PK assessment included multiple samples in first 2 cycles, and pre-dose samples in subsequent cycles. Results: Dose modifications were common, including dose reductions to 1.0 mg/kg (EV-201 42.1%; EV-301 35.1%) and 0.75 mg/kg (EV-201 13.6%; EV-301 11.1%). EV showed consistent improvement in median PFS and OS vs chemotherapy across all exposure quartiles in EV-301 inclusive of dose modifications (Table). Greater initial EV exposure in the first 2 cycles was associated with a higher ORR and was consistent with dose-response (0.75 mg/kg 21.4% [sample size {n} = 14]; 1.0 mg/kg 18.5% [n = 27]; 1.25 mg/kg 40-51.1% across studies [n = 613]). Lower EV exposure was associated with lower risk of EV-related Grade ≥3 rash or skin reactions, Grade ≥2 peripheral neuropathy, and Grade ≥3 hyperglycemia (P&lt;0.0001 for all). Conclusions: EV improved PFS and OS outcomes vs chemotherapy in pts with la/mUC across all exposure quartiles. The starting dose of 1.25 mg/kg 3Q4W resulted in EV exposure that maximized likelihood of response. Recommended dose modifications are effective for managing EV-related AEs and should be used as clinically indicated. Clinical trial information: NCT02091999 , NCT03219333 , and NCT03474107 . [Table: see text]
Immunotherapy For US Patients With Metastatic Cancer at the End of Life—Reply
Authors: Dan Kerekes, Sajid Khan
Journal: JAMA Oncology (2024)

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