bluuebunny/crossref_metadata_2025 huggingface dataset:
ERDAFITINIB in locally advanced or metastatic urothelial carcinoma (mUC): Long-term outcomes in BLC2001.
Authors: Siefker-Radtke Arlene O. , Necchi Andrea , Park Se Hoon , García-Donas Jesús , Huddart Robert A , Burgess Earle Frederick , Fleming Mark T. , Rezazadeh Arash , Mellado Begona , Varlamov Sergei , Joshi Monika , Duran Ignacio , Tagawa Scott T. , Zakharia Yousef , Fu Min , Santiago-Walker Ademi E. , Monga Manish , OHagan Anne , Mosher Silvia , Loriot Yohann ,   BLC2001 Study Group
Published: May 2020

5015

Background: Erdafitinib (JNJ-42756493; ERDA) is the only pan-FGFR kinase inhibitor with US FDA approval for treatment of adults with mUC with susceptible FGFR3/2 alterations (alt) and who progressed on ≥ 1 line of prior platinum-based chemotherapy (chemo). Approval was based on data from the primary analysis of the pivotal BLC2001 trial1. Here we report long-term efficacy and safety data from the 8 mg/d continuous dose regimen in BLC2001. Methods: BLC2001 (NCT02365597) is a global, open-label, phase 2 trial of pts with measurable mUC with prespecified FGFR alt, ECOG 0-2, and progression during/following ≥ 1 line of prior chemo or ≤ 12 mos of (neo)adjuvant chemo, or were cisplatin ineligible, chemo naïve. The optimal schedule of ERDA determined in the initial part of the study was 8 mg/d continuous ERDA in 28-d cycles with uptitration to 9 mg/d (ERD 8 mg UpT) if a protocol-defined target serum phosphate level was not reached and if no significant treatment-related adverse events (TRAEs) occurred. Primary end point was the confirmed objective response rate (ORR=% complete response + % partial response). Key secondary end points were progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Results: Median follow-up for 101 patients treated with ERDA 8 mg UpT was ~24 months. Confirmed ORR was 40%. Median DOR was 5.98 mos; 31% of responders had DOR ≥ 1 yr. Median PFS was 5.52 mos, median OS was 11.3 mos. 12-mos and 24-mos survival rates were 49% and 31%, respectively. Median treatment duration was 5.4 mos. The ERDA safety profile was consistent with the primary analysis. No new TRAEs were seen with longer follow-up. Central serous retinopathy (CSR) events occurred in 27% (27/101) of patients; 85% (23/27) were Grade 1 or 2; dosage was reduced in 13 pts, interrupted for 8, and discontinued for 3. On the data cut-off date, 63% (17/27) had resolved; 60% (6/10) of ongoing CSR events were Grade 1. There were no treatment-related deaths. Conclusions: With a median follow-up of 2 yrs, ERDA in mUC + FGFR alt showed a manageable safety profile and consistent efficacy, with median OS of 11.3 mos. 31% had a DOR ≥12 mos and 31% were alive at 24 mos. ERDA monotherapy vs. immune checkpoint inhibitor (PD-1) or chemo is being further analyzed in a randomized control study (THOR; NCT03390504).Reference: Loriot Y, et al. N Engl J Med. 2019;381:338-48. Clinical trial information: NCT02365597 .
Final results of PEANUT: Pembrolizumab and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as salvage therapy for metastatic urothelial carcinoma (UC).
Authors: Giannatempo Patrizia , Calareso Giuseppina , Bandini Marco , Marandino Laura , Raggi Daniele , Farè Elena , Colecchia Maurizio , Pederzoli Filippo , Gallina Andrea , Madison Russell , Briganti Alberto , Ross Jeffrey S. , Montorsi Francesco , Necchi Andrea
Published: May 2020

5017

Background: Pembrolizumab (pembro) is a new standard of care in chemotherapy (CT) pre-treated patients (pts) with metastatic UC. Nab-paclitaxel demonstrated preliminary activity in advanced UC. In the PEANUT study (NCT03464734) we investigated their combination in advanced UC after CT failure. Methods: In an open-label, single-arm, phase 2 trial, pts received 200 mg pembro, intravenously (IV), on D1 and 125 mg/m2 IV nab-paclitaxel on D1 and D8, every 3 weeks, until disease progression (PD) or unacceptable toxicity. Inclusion criteria were: predominant UC histology, failure of ≤2 platinum-based CT for metastatic disease. Response was evaluated by RECIST v.1.1 criteria every 2 cycles. Biomarkers included PD-L1 combined positive score (CPS) and comprehensive genomic profiling on tumor and blood samples (FoundationONE and FoundationACT assay). The primary endpoint was the progression-free survival (PFS). The target was to detect an improvement in the median PFS from ≤3.0 months (H0) to ≥5.0 months (H1). Results: Between 01 and 12/2019, PEANUT study enrolled 65 pts: 24% were female, median age was 69 yrs (IQR: 61-73); 25% had failed > 1 prior systemic therapies; 35% had ECOG-performance status 1; 33% had liver metastases. The median TMB was 6.9 mut/Mb. After median follow-up (FUP) of 5.5 months, 34 pts have relapsed (52.3%). The median PFS was 5 months (95%CI: 3-not reached). The 3-month PFS was 60.7% (95%CI: 49.8-74.1). The confirmed objective response-rate (ORR) was 47.7% (95%CI: 35.2-60.4): 22 partial responses and 9 complete responses (13.8%). The median duration of response was not reached, and 4 pts (6.1%) are long-term responders ( > 12 months). Grade 3 treatment-related adverse events (TRAE) were seen in 20 pts (30.7%). Most common any-grade TRAE included alopecia (76%), neutropenia (33.3%) and asthenia (33%). Neither TMB nor CPS were significantly associated with PFS on univariable analyses. In matched tumor/blood samples, objective responses were seen in 8/10 pts with PI3KCA mutations (80%); 6/10 pts with RB1 alterations (60%); 5/12 pts with DNA damage repair gene alterations (41.7%). Conclusions: Pembro-nab-paclitaxel, the first salvage CT-immunotherapy combination in UC, demonstrated a good tolerability, promising PFS and a clinically meaningful ORR in II-III line setting of advanced UC. As more mature data on biomarker selection emerges, this combination warrants additional studies in either second-line or earlier disease settings. Clinical trial information: NCT03464734 .
Phase II neoadjuvant (N-) gemcitabine (G) and pembrolizumab (P) for locally advanced urothelial cancer (laUC): Interim results from the cisplatin (C)-ineligible cohort of GU14-188.
Authors: Kaimakliotis Hristos Z. , Adra Nabil , Kelly William Kevin , Trabulsi Edouard John , Lauer Richard C. , Picus Joel , Smith Zachary L , Walling Radhika , Masterson Timothy A. , Calaway Adam C , Koch Michael O. , Sonderman Elizabeth , Fu Pingfu , Goolamier Gordon , Eitman Cheryl , Ponsky Lee Evan , Hoimes Christopher J.
Published: May 2020

5019

Background: Patients (pts) with laUC who are C-ineligible have inferior survival compared to counterparts who receive C based N-therapy and have a pathologic response at radical cystectomy (RC). Cohort 2 (C2) of the GU14-188 trial is designed to assess the tolerability and efficacy of N- G and P in laUC pts who are C-ineligible. Methods: Eligible pts for C2 were surgical candidates and C-ineligible with cT2-4aN0M0 bladder UC or mixed histology. Enrollment followed a Simon 2-stage design for H0 of interval futility which was rejected at stage 1, and fully enrolled. Pts were treated with N- G (1000mg/m2) on days 1, 8, and 15 of a 28 day cycle (cy) for a total of 3 cy, and overlapped with P 200mg every 3wks starting on cy 1 day 8 x 5 doses. Minimum criteria for evaluation of safety: 1 dose of P, and for efficacy: 2 doses P and RC. The primary endpoint of pathologic muscle invasive response rate (PaIR, ≤pT1N0) was assessed at RC and designed for 86% power, 4% significance to detect PaIR difference from 18 to 40%. Molecular subtyping is planned. Results: 37 pts were enrolled to C2 with a median (mdn) age of 72, 70% male, 55% > cT2. C-ineligibility was due to renal function (49%), hearing (30%), neuropathy (12%). Mdn per-pt doses given (intended) for P:5(5) and G:9(9). The PaIR was 51.6% (95%CI 0.35, 0.68), P0 (ypT0N0) rate of 45.2%, and neither correlated with baseline PD-L1 score. Downstage to PaIR occurred in 57% of pts with cT2, and 47% of > cT2. Mdn time to RC from last dose was 5.6wks. Six were not included in the primary analysis: 3 (8.1%) did not have RC due to progression (RFS censored), 2 did not receive required protocol therapy, and 1 withdrew consent. At mdn follow up of 10.8mo (4-24), the estimated 12mo RFS, OS, and DSS is 74.9%, 93.8%, and 100%, respectively. Treatment related AE included grade (gr) 3/4 neutropenia (24%), anemia (13%), and platelets (5%). There were no gr 4 non-heme AE, and of 14 (36%) pts with gr 3, 12 did not preclude RC. Of these, there were 4 gr 3 investigator assessed immune related adverse events (IAirAE) of pneumonitis (5%), colitis (3%), and AST elevation (3%). Though IAirAE improved, protocol therapy was discontinued in 3 pts: 2 did not have RC due to progression. Conclusion: N- G with P in C-ineligible pts with laUC is feasible with manageable toxicity, and has a pathologic downstage rate comparable to standard of care in the C-eligible population. G and P warrants further study with component contribution as a C- free N- option in laUC. Clinical trial information: NCT02365766 .
Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT #02844816).
Authors: Black Peter C. , Tangen Catherine , Singh Parminder , McConkey David James , Lucia Scott , Lowrance William Thomas , Koshkin Vadim S , Stratton Kelly Lynn , Bivalacqua Trinity , Sharon Elad , Kassouf Wassim , Porten Sima P. , Bangs Richard Carlton , Plets Melissa , Lerner Seth P. , Thompson Ian Murchie
Published: May 2020

5022

Background: Radical cystectomy (RC) is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC), but many patients are unfit for surgery or elect bladder preservation. Based on the reported efficacy of atezolizumab in metastatic urothelial carcinoma and the known expression of PD-L1 in NMIBC after BCG therapy, this trial was designed to evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This single arm phase II registration trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year aimed to enroll 135 (70 CIS and 65 non-CIS) eligible patients with histologically proven BCG-unresponsive high risk NMIBC who were unfit for or declined RC. Here we report on the subset with CIS (with or without concomitant Ta/T1) among patients who received at least one protocol treatment. The primary endpoint was pathological complete response (CR) rate at 6 months as defined by mandatory biopsy with a null hypothesis of 30% and alternative of 50% with a 1-sided alpha = 0.05 and 96% power. The 3 month CR rate, defined by cytology, cystoscopy and for-cause biopsy, is reported here as a secondary endpoint, in addition to safety. Results: Seventy-five eligible CIS patients were enrolled. Two received no treatment and are not evaluable. Of 73, median patient age was 73.4 years and median number of prior BCG doses was 12. Concomitant Ta/T1 tumor was found in 30 (41.1%) patients, including T1 disease in 16 (21.9%). A CR was observed in 30 (41.1%; 95% CI 29.7%, 53.2%) patients at 3 months and 19 (26.0%; 95% CI 16.5%, 37.6%) at 6 months. Any possibly or probably treatment-related adverse event (AE) was observed in 61 (83.6%) patients. The most frequent AEs were fatigue 36 (49.3%), pruritis 8 (11.0%), hypothyroidism 8 (11.0%), and nausea 8 (11.0%). Grade 3-5 AEs occurred in 9 (12.3%) patients and there was one treatment-related death (myasthenia gravis with respiratory failure and sepsis). Conclusion: The observed response to atezolizumab at 3 and 6 months in patients with BCG-unresponsive CIS was similar to that reported in recent similar trials and meets the benchmark for initial CR defined by the FDA guidance. This trial provided no new safety concerns. The duration of response will determine if this is a suitable treatment option for patients with BCG-unresponsive high risk CIS. Clinical trial information: 02844816 .
CD68+ tumor-associated myeloid cells as the target of adenosine-induced gene products and predictor of response to adenosine blockade with ciforadenant (cifo) in renal cell cancer (RCC).
Authors: Voss Martin H , Hotson Andrew N. , Willingham Stephen , Hughes Brett Gordon Maxwell , Merchan Jaime R. , Fong Lawrence , Chu Michael , George Saby , Munneke Brian , Mobasher Mehrdad , Miller Richard A.
Published: May 2020

5025

Background: Adenosine in the tumor microenvironment (TME) is immunosuppressive and may play a role in resistance to immunotherapy. We described an adenosine induced gene expression signature (AS, Fong, Cancer Disc 2020) that correlates with response to therapy with cifo, an adenosine A2A receptor antagonist, as monotherapy or in combination with atezolizumab in refractory RCC. These genes express chemokines that signal through CCR2 and CXCR2 to recruit myeloid cells including immunosuppressive tumor associated-M2 macrophages, which are thought to mediate resistance to anti-PD(L)1 treatment. We now identify tumor infiltrating CD68+ myeloid cells as the effector cell for adenosine mediated immunosuppression. Methods: 82 RCC pts have been treated in an ongoing Phase 1/1b trial evaluating cifo (100mg po bid) monotherapy or combination with atezolizumab (840mg IV q 2 weeks). Tumor biopsies, obtained at screening and on therapy, are available for analysis in 32 pts to date. RNA expression was measured in tumors using Nanostring. Immunohistochemistry (IHC) for CD68 was performed on biopsies with CD68+ tumors defined as > 4% tumor area containing CD68+ cells. Results: Pt characteristics are median age 63; median prior therapies 3, with 72% failing prior anti-PD(L)1. Gene expression of M2 markers consisting of CD68 (p = 0.0008) and CD163 (p = 0.03) was higher in baseline samples from AS+ compared to AS- pts. By IHC, 10 pts had CD68+ cells infiltrating the tumor; 9 of 10 AS+. Tumor regression was observed in 6 of 10 CD68+ pts (N = 3 monotherapy and 3 combination) including 4 partial responses (PR, RECIST). No PRs and 2 minor responses were seen in 22 pts who were CD68- (p < 0.005). Median time to progression was not reached for CD68+ vs 2 mo for CD68-. Paired biopsies showed a significant reduction in infiltrating CD68+ cells (p = 0.03) with treatment including 2 of 2 evaluable PRs. Conclusions: Adenosine immunosuppression is mediated by M2 macrophages, which can be reversed by cifo. Enumerating tumor infiltrating CD68+ cells may be a valuable biomarker for identifying pts that will respond to adenosine blockade. Clinical trial information: NCT02655822 .
Clinical outcomes and economic burden for bladder cancer patients: An analysis from a Swedish cancer registry.
Authors: Bellmunt Joaquim , Powles Thomas , Henriksson Roger , Steinberg Gary D. , Batyrbekova Nurgul , Schain Frida , Fleming Sarah , Shalaby Waleed , Siefker-Radtke Arlene O.
Published: May 2020

5026

Background: To investigate the clinical and economic disease burden for patients (pts) with non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC), and metastatic urothelial carcinoma (mUC) using a Swedish bladder cancer registry. Methods: Pts diagnosed with bladder cancer in the Stockholm Gotland region between 2005-2013 were included and followed until May 31, 2015 or until death. MIBC was classified if a T, N, M at diagnosis was T2, T3, T4, N1, N2, N3, or M1, otherwise pts were classified as NMIBC. All diagnostic and therapeutic interventions were captured and differentiated. Inpatient and outpatient healthcare resource utilization (days) and associated costs (US $) were also analyzed. Results: 3587 bladder cancer pts were identified (NMIBC-2728; MIBC-859) with a median observation time of 49.7 (Q1-Q3: 27.8-78.7) versus 17.2 (Q1-Q3: 6.5-39.3) months. 5-year survival for patients with NMIBC at diagnosis was 71.3% (95% CI; 69.5-73.3) and 26.4% (95%CI; 23.4-29.8) for MIBC. By year 1, survival for MIBC-T2, T3, and T4 was 66%, 41.7%, and 28.4%, respectively. Progression from NMIBC to MIBC was estimated in 19.4% (528/2728) of pts. In year 1, 84% (2,275/2,728) of TURBT procedures were performed on NMIBC pts. Over the next 2-10 years of follow-up, 11,035 repeat TURBT procedures were undertaken in this cohort. In the 859 MIBC pts, 607 TURBT procedures and 333 radical cystectomies occurred in year 1. In the same cohort, 28.3% (243/859), 15.5% (78/505), and 8.6% (29/338) received systemic chemotherapy in years 1, 2, and 3, respectively. Total health resource utilization (HRU) cost for the NMIBC and MIBC cohorts is provided in Table. Median HRU cost per person-year was estimated at $30,470 for MIBC versus $9,228 for NMIBC in year 1. For MIBC-T2, T3, and T4, median cost per person-year was $30,154, $33,917, and $38,959 in year 1, respectively. Conclusions: This retrospective analysis accomplished its primary purpose to provide a real-world understanding for the clinical and economic impact of bladder cancer over a 10-year period when treatment interventions were relatively consistent. Total HRU Costs for Patients with NMIBC and MIBC per Follow-up Year (Years 1 to 5). [Table: see text]
Assessing the potential cost-effectiveness of the addition of atezolizumab to first-line platinum chemotherapy in advanced urothelial cancer: Implications for value-based pricing.
Authors: Khaki Ali Raza , Diamantopoulos Leonidas Nikolaos , Zimmerman Marita , Garrison Louis P. , Grivas Petros
Published: May 2020

5031

Background: Data from interim analysis of IMvigor130 trial showed that 1st line treatment of advanced urothelial cancer (aUC) with atezolizumab (Atezo) + platinum-based chemotherapy (PBC) significantly improved progression-free survival (PFS), but not overall survival (OS), vs PBC. Switch maintenance anti-PD(L)1 after completion of PBC as 1st line therapy is an alternate strategy, recently reported to significantly prolong OS. We aimed to compare cost-effectiveness of combined treatment (Atezo+PBC) vs PBC based on IMvigor130. Methods: We used a partitioned-survival model to evaluate the potential cost-effectiveness of treatment with A) Atezo+PBC (gemcitabine with cisplatin or carboplatin) or B) PBC alone with checkpoint inhibitor pembrolizumab at progression (standard-of-care). PFS and OS curves were extracted from IMvigor 130 and parametric models were fit to approximate outcomes with Atezo+PBC with the hazard ratio (HR) from the trial used to project outcomes for PBC alone. We used a health-care payer perspective with a two-year time horizon. Model outputs — costs, life-years, quality-adjusted life years (QALYs) — were used to calculate an incremental cost-effectiveness ratio (ICER). A scenario analysis evaluated the “value-based price” needed for Atezo+PBC to be cost-effective; a one-way sensitivity analysis was also performed. Results: Results of the cost-effectiveness analysis are summarized in the table. The mean projected incremental cost of Atezo+PBC compared to PBC was $59,604 for a mean incremental gain of 0.09 life-years and 0.07 QALYs. This resulted in an ICER of $629,755/life-year and $895,800/QALY, respectively. A 33% reduction would be needed in the price of atezolizumab to make Atezo+PBC cost-effective at an ICER of $150,000/QALY. Results were sensitive to cost of pembrolizumab at progression, the cost of Atezo+PBC, and the OS HR between Atezo+PBC and PBC. Conclusions: Combined chemoimmunotherapy with atezolizumab and PBC would likely not be cost-effective for the first-line treatment of aUC. However, with a price rebate of 33%, it would approach being cost-effective at a widely used cost-effectiveness threshold. [Table: see text]
Impact of timing of antibiotic use on clinical outcomes in patients with urothelial cancer treated with immune checkpoint inhibitors (ICIs).
Authors: Weinstock Chana , Bandaru Pradeep , Fernandes Laura L , Chang Elaine , Girvin Andrew , Tang Shenghui , Agrawal Sundeep , Suzman Daniel L. , Singh Harpreet , Brave Michael Holman , Xu James , Goldberg Kirsten B. , Ibrahim Amna , Theoret Marc Robert , Pazdur Richard , Beaver Julia A.
Published: May 2020

5045

Background: Although recent evidence has suggested that patients who receive antibiotics (ABX) during the course of ICI treatment might decrease overall survival (OS) (1), our previous analysis did not support a difference in OS in urothelial cancer patients who did and did not use ABX during the course of ICI treatment without regard to timing (2). This updated analysis aims to addresses the question of timing; specifically, use of ABX in the 30-day window pre- or post- initiation of ICI treatment. Methods: We pooled data from 7 trials that led to drug approval and which included 1747 patients with advanced urothelial cancer treated with an ICI. Five trials enrolled patients who received prior platinum and 2 enrolled cisplatin-ineligible patients. Concomitant medication datasets were searched for systemic ABX use. The association between ABX use and survival was evaluated using Kaplan-Meier estimates and Cox proportional hazards regression models stratified by study. Results: Overall, 56% of patients were exposed to antibiotics (ABX+) and 43% were not exposed (ABX-). In an exploratory analysis, median OS was similar between arms: 9.7 vs. 9.3 months in ABX+ vs. ABX- patients, respectively (HR 0.96). However, OS results differed in the 27% of patients who were exposed to antibiotics in the 30-day window pre- or post- initiation of ICI treatment, for whom median OS was 4.7 months vs. 11.5 months in the ABX+ vs. ABX- patients, respectively (HR 1.8). This remained true after controlling for baseline risk prognostic factors (Bajorin and Bellmunt scores). Similar trends were observed for progression-free survival (PFS). Conclusions: Patients treated with ABX while on therapy with an ICI for urothelial cancer had similar OS outcomes to those not treated with ABX. However, in an exploratory analysis looking at ABX use in the 30-day window pre- or post-initiation of ICI treatment, OS appeared decreased in ABX+ vs ABX- patients. Our exploratory analyses appear to show an association of OS/PFS with timing of antibiotics. References: 1) Routy B, Science (2017) 2) Weinstock C, ASCO 2019, abstract. [Table: see text]
Phase Ib/II neoadjuvant (N-) pembrolizumab (P) and chemotherapy for locally advanced urothelial cancer (laUC): Final results from the cisplatin (C)- eligible cohort of HCRN GU14-188.
Authors: Hoimes Christopher J. , Adra Nabil , Fleming Mark T. , Kaimakliotis Hristos Z. , Picus Joel , Smith Zachary L , Walling Radhika , Trabulsi Edouard John , Hoffman-Censits Jean H. , Koch Michael O. , Cary Clint , Abouassaly Robert , Eitman Cheryl , Fu Pingfu , Goolamier Gordon , Calaway Adam C , Ponsky Lee Evan , Kelly William Kevin
Published: May 2020

5047

Background: Patients (pts) with laUC who are C-eligible for N- therapy may benefit from combination chemo-immunotherapy. Cohort 1 (C1) of the GU14-188 trial is a phase 1b/2 trial designed to assess the tolerability and efficacy of N- gemcitabine (G), C, and P in pts with laUC. The current standard of care is ddMVAC with a pathologic non-muscle invasive rate (PaIR, ≤pT1N0) of ~44%. Methods: Eligible pts for C1 were surgical candidates and C-eligible with cT2-4aN0M0 bladder UC. Enrollment followed a Simon 2-stage design for H0 of interval futility which was rejected at stage 1, and fully enrolled. Phase 1b (no DLT) /2 treatments were the same: P 200mg q3wks on day 8 x5 doses; with C (70mg/m2) day 1, and G (1000mg/m2) days 1 and 8 of a 21 day cycle (cy), for 4 cy; followed by radical cystectomy (RC). Minimum criteria for evaluation of safety: 1 dose of P, and for efficacy: 2 doses P and RC. The primary endpoint of PaIR was assessed at RC and designed for 86% power with 4% significance to detect a difference from 23 to 48%. Secondary endpoints include relapse free survival and overall survival. Results: 43 pts were enrolled to C1 with a median (mdn) age 64, 63% male, 51% > cT2. Mdn per-pt doses given (attempted) for: P:5(5), C:4(4), G:8(8). The PaIR was 61.1% (95%CI 0.45, 0.75), P0 (ypT0N0) rate of 44.4%, and did not correlate with baseline PD-L1 score. Downstage to PaIR occurred in 53% of cT2, and 74% of cT3/4. Mdn time to RC from last dose was 5.3wks. Seven were not included in the primary analysis: 4 (9.3%) without RC, 1 progressed, 1 lost to f/u during C1, 1 did not receive required protocol therapy. There was 1 death on post-RC day 9 due to mesenteric ischemia. Of 4 pts who did not have RC, 3 refused and 1 due to gr4 thrombocytopenic purpura; 4pts are alive and without recurrence at mdn f/u of 32mo. One pt with presumed gr3 MI during cy 4 had a negative inpt cardiac workup and completed therapy and RC without further AE. One gr4 hyponatremia and ten gr3 events did not preclude RC (2-each thromboembolism, elevated creatinine, hyponatremia;1-each: dehydration, emesis, neutropenic fever, infection). Gr 3/4 cytopenias occurred in 57% of pts. At mdn f/u of 34.2mo (3.9-47.4), the estimated 36mo RFS, OS, and DSS is 63%, 82%, and 87%, respectively. Conclusion: Neoadjuvant GC with P in laUC has manageable toxicity and has improved pathologic outcomes compared to historic controls. Durable long-term survival in those with- and without -RC is noteworthy in this advanced cohort. KEYNOTE 866, NCT03924856, is a Phase III study of GC with perioperative P. Clinical trial information: NCT02365766 .
Application of IMDC criteria across first-line (1L) and second-line (2L) therapies in metastatic renal-cell carcinoma (mRCC): New and updated benchmarks of clinical outcomes.
Authors: Dudani Shaan , Gan Chun Loo , Wells Connor , Bakouny Ziad , Dizman Nazli , Pal Sumanta K. , Wood Lori , Kollmannsberger Christian K. , Szabados Bernadett , Powles Thomas , Beuselinck Benoit , Donskov Frede , Hansen Aaron Richard , Bjarnason Georg A. , Canil Christina M. , Srinivas Sandy , Agarwal Neeraj , Liow Elizabeth Chien Hern , Choueiri Toni K. , Heng Daniel Yick Chin
Published: May 2020

5063

Background: In patients with mRCC, the International mRCC Database Consortium (IMDC) criteria have been validated as a prognostic tool in patients treated with targeted therapy in the 1-4L settings and with 2L Nivolumab (Nivo). However, it is unknown whether the IMDC criteria can be used to risk stratify in recently approved 1L IO combination therapies, including Ipilimumab + Nivolumab (IOIO) and Axitinib + Pembrolizumab/Avelumab (IOVE). We sought to assess the ability of the IMDC criteria to risk stratify with the use of novel 1L IO combinations and provide updated benchmarks for older 1L and 2L treatments. Methods: Patients with mRCC starting systemic therapy between 2010-2019 were identified through the IMDC. IMDC risk score was calculated at the time of starting the line of therapy of interest. The primary endpoint was overall survival (OS) from time of initiating the treatment of interest. Results: From a total of 6596 unique patients, 5043 treated in the 1L setting and 2498 treated in the 2L setting were included in the analysis. Across the entire cohort, median age was 61, 73% were male, 16% had sarcomatoid features, 79% underwent nephrectomy and 88% had clear-cell histology. IMDC risk groups for 1L and 2L treatment were 17%, 57%, 27% and 10%, 60%, 30% for favourable-, intermediate- and poor-risk disease, respectively. IMDC criteria appropriately risk stratified into 3 prognostic groups in 1L IOIO and 1L IOVE combinations, in addition to older treatments: 1L VEGF TT, 2L VEGF TT, 2L Nivo and 2L Everolimus. Results are displayed in Table. Due to the novelty of 1L IO combinations, median follow up time was shorter and thus landmark OS values are presented. Conclusions: IMDC criteria may be used to risk stratify in recently approved 1L IO combination therapies in addition to older 1L and 2L treatments. These data provide contemporary benchmarks for OS that may be used for patient counseling and trial design. [Table: see text]
Characterizing sites of metastatic involvement in metastatic clear-cell, papillary, and chromophobe renal cell carcinoma.
Authors: Dudani Shaan , de Velasco Guillermo , Wells Connor , Gan Chun Loo , Donskov Frede , Porta Camillo , Fraccon Anna , Pasini Felice , Lee Jae-Lyun , Hansen Aaron Richard , Bjarnason Georg A. , Beuselinck Benoit , Pal Sumanta K. , Yuasa Takeshi , Kroeger Nils , Kanesvaran Ravindran , Reaume M. Neil , Canil Christina M. , Choueiri Toni K. , Heng Daniel Yick Chin
Published: May 2020

5071

Background: There exists considerable biological and clinical variability between histologic variants of metastatic renal-cell carcinoma (mRCC). Data reporting on sites of metastatic involvement in less common histologies of mRCC are sparse. We sought to characterize the frequency of metastatic site involvement across the three most common histologies of mRCC: clear-cell (ccRCC), papillary (pRCC), and chromophobe (chrRCC). Methods: Using the International mRCC Database Consortium (IMDC) database, patients with mRCC starting systemic therapy between 2002-2019 were identified and sites of metastases at the time of systemic therapy initiation were documented. Patients with multiple sites of metastatic involvement were included in analyses of all groups to which they had metastases. The primary outcomes were prevalence of metastatic site involvement and overall survival (OS). Patients with mixed histology were excluded. Results: 10,105 patients were eligible for analysis. Median age at diagnosis was 60, 72% were male and 79% underwent nephrectomy. 92%, 7% and 2% of patients had ccRCC, pRCC, and chrRCC, respectively. Frequency of metastatic site involvement across the histologic subtypes is shown in Table. Lung, adrenal, brain and pancreatic metastases were more frequent in ccRCC, lymph node involvement was most frequent in pRCC, and liver metastases were most frequent in chrRCC. Median OS for ccRCC varied by site of metastatic involvement, ranging between 16 months (brain/pleura) and 50 months (pancreas). OS by site of metastatic involvement was compared between histologies for the four most common sites of metastases (lung, lymph nodes, bone, liver). As compared to patients with ccRCC, patients with pRCC had lower OS regardless of site of metastasis (p < 0.05). Power was limited and thus differences in OS between ccRCC and chrRCC were not detectable. Conclusions: Sites of metastatic involvement differ based on histology in mRCC. These data highlight the clinical and biologic variability between histologic subtypes of mRCC and constitute the largest cohorts of patients with metastatic pRCC and chrRCC to report on sites of metastases. Sites of Metastatic Involvement by Histology. [Table: see text]
Genomic and transcriptomic correlates of clinical benefit from immunotherapy and targeted therapy among patients with metastatic renal cell carcinoma (mRCC).
Authors: Salgia Nicholas , Dizman Nazli , Lyou Yung , Bergerot Paulo Gustavo , Hsu Joann , Byron Sara Ann , Trent Jeffrey M. , Pal Sumanta K.
Published: May 2020

5076

Background: Previous studies have delineated PBRM1 alterations as a prognostic indicator for response to nivolumab in mRCC (Miao et al Science 2018). However, further clinically-relevant biomarkers remain elusive in mRCC. Herein, we utilized genomic profiling to detect correlates of clinical benefit (CB) among patients (pts) with mRCC receiving VEGF-directed targeted therapy, immunotherapy, or both. Methods: Pts with mRCC who underwent clinical tumor-normal whole exome and whole transcriptome RNA sequencing (Ashion Analytics, Phoenix, AZ) were retrospectively identified at a single institution. Pts’ demographics and clinical variables including treatment type, treatment response, and survival outcomes were collected from an institutional mRCC database. Pts who had received immunotherapy or VEGF-directed therapy (or both) were eligible for analysis. CB was defined as pts who experienced a complete response, partial response, or maintained stable disease for at least 6 months on therapy. Two-tailed Fisher’s exact test was used to assess characteristics of genomic alterations and clinical benefit. Results: Out of 155 mRCC pts with genomic profiling, 58 pts with evaluable response and sufficient follow-up information were included in the analysis. The median age of the cohort was 63 years and 74% were male. The majority (81%) had clear cell histology. 43 pts received targeted therapy and 32 received immunotherapy (17 pts received both). No singular gene was associated with clinical benefit in the targeted therapy cohort. PBRM1 loss of function mutations were more frequent in pts on immunotherapy who experienced CB (p > 0.05). TERT promoter mutations were enriched in pts who experienced no CB on immunotherapy (p = 0.04). Differential gene expression analysis of the transcriptomes found 135 genes that were significantly upregulated in TERT-mutated samples, including SST, CYSLTR2, WNK2, and PTGES (adjusted p-value < 0.05). ENRICHR analysis found that MYC and KAT2A were key transcription factor pathways significantly enriched in pts with TERT mutation who experienced no CB from immunotherapy. Conclusions: These data support previous observations regarding the prognostic nature of PBRM1 in mRCC and offer novel findings associating TERT mutations with a lack of CB from immunotherapy. Our transcriptomic analysis implies that MYC-targeting agents and epigenetic modifiers (directed at KAT2A) could overcome immunotherapy resistance.
Use of immune checkpoint inhibitors (ICIs) after prior ICI in metastatic renal cell carcinoma (mRCC): Results from a multicenter collaboration.
Authors: Ravi Praful , Mantia Charlene , Su Christopher , Sorenson Karl , Rathi Nityam , Bakouny Ziad , Agarwal Neeraj , Costello Brian Addis , McKay Rana R. , Narayan Vivek , Alva Ajjai Shivaram , McGregor Bradley Alexander , Gao Xin , McDermott David F. , Choueiri Toni K.
Published: May 2020

5077

Background: Several ICIs are used in first and subsequent lines of therapy for mRCC, either alone or in combination with another ICI or targeted therapy (TT). There are no data on the efficacy and safety of using an ICI in patients who have already received an ICI in a prior line of therapy. Methods: We reviewed patients with mRCC at 8 institutions who received 2 separate lines of ICI therapy (ICI-1, ICI-2), including as a single-agent and/or combination with other agents. The primary outcomes were overall response rate (ORR) and time to progression (TTP) with ICI-1 and ICI-2. Immune-related adverse events (irAEs) were graded using CTCAEv5.0. Results: 65 patients were included. Median age at diagnosis of mRCC was 60 years (range 30-86) and the majority had clear cell RCC (n=56, 86%). Median follow-up was 3.5 years (95% CI 2.9-4.4). Median lines at which ICI-1 and ICI-2 were received were 1 (1-6) and 3 (2-8) respectively. Reasons for discontinuing ICI-1 were disease progression (n=47, 72%), toxicity (n=15, 23%) or other (n=3, 5%). Therapies received at ICI-2 were single-agent ICI (n=26, 40%), or combinations of ICI with another ICI (n=20, 31%), TT (n=11, 17%) or other agent (n=8, 12%). Responses to ICI-1 and ICI-2 are shown in the Table; ORR to ICI-2 was significantly lower than to ICI-1 (23% vs. 36%, p=0.044). Amongst those who responded to ICI-2 (n=14), 7 (50%) received single-agent ICI, and the remainder received ICI in combination with another ICI (n=4, 29%) or TT (n=3, 21%); 7 patients (50%) had previously responded to ICI-1. The ORR to ICI-2 was higher in responders to ICI-1 (32%) compared to those with SD (17%) or PD (15%) to ICI-1. Median TTP (mTTP) at ICI-2 was shorter compared to ICI-1 (5.3 months vs. 8.5 months, Wilcoxon p=0.024). 29 patients (45%) experienced an irAE with ICI-2; 8 (12%) and 3 (5%) had a grade 3 or 4 irAE respectively, with 3 (30%) of these patients having previously had ≥grade 3 irAE to ICI-1. There were no treatment-related deaths. Conclusions: The ORR to ICI-2 was 23%, which is comparable to that seen with ICI after prior TT. Responses were seen even amongst those receiving single-agent ICI at ICI-2 and the likelihood of response to ICI-2 was higher if a patient had previously responded to ICI-1. No increase in toxicity with ICI-2 was apparent. Additional data from prospective studies are needed to determine whether sequential ICI has a role in treatment of mRCC. [Table: see text]
Impact of human papillomavirus (HPV) infection on the outcome of perioperative treatments for penile squamous-cell carcinoma (PSCC).
Authors: Giannatempo Patrizia , Bandini Marco , Zhu Yao , Ye Dingwei , Ornellas Antonio Augusto , Watkin Nick , Ager Michael , Hakenberg Oliver W. , Heidenreich Axel , Raggi Daniele , Haidl Friederike , Marandino Laura , Pederzoli Filippo , Briganti Alberto , Montorsi Francesco , Chipollini Juan , Azizi Mounsif , Albersen Maarten , Spiess Philippe E. , Necchi Andrea
Published: May 2020

5088

Background: PSCC patients (pts) with palpable inguinal lymph node (ILN) disease have a poor overall survival (OS). Multimodal perioperative treatments are usually offered despite the lack of clinically meaningful efficacy. Pending the availability of novel effective systemic therapy, the optimization of conventional treatments in better selected pts is needed. Methods: Within an international, multicenter database of 924 PSCC pts who received ILN dissection from USA, Europe, Brazil and China, 494 had information on HPV, and 52 (10.5%) had HPV+ PSCC, predominantly assessed with immunohistochemistry (53%). Multivariable logistic regression analyses evaluated the association between pt factors and HPV status. Multivariable Cox analyses (MVA) assessed predictors of overall mortality (OM), including HPV status, pathologically-involved ILN ratio (ILNR), extranodal extension, margin status, vascular invasion (VI), perioperative RT (pRT) and perioperative chemotherapy (pCT). Comparisons between HPV status and ILNR were performed using interaction tests. Kaplan-Meier method was used to define the OS benefit related in HPV-stratified sub-groups. Results: Median age at diagnosis was 58yrs. Overall, pCT and pRT were used in 227 (46%) and 50 (10%) pts. The median follow-up was 62 months. Neither clinical factors nor country were associated with HPV status. On MVA, ILNR (HR:1.01, p = 0.01) and extranodal extension (HR: 1.5, p = 0.02) were statistically significantly associated with OM, but HPV was not (p = 0.2). However, in the subgroup of pts who received pRT, HPV status was associated with favorable OM (HR: 0.11, 95%CI: 0.03-0.5, p = 0.004) together with negative VI (p = 0.03), and the use of adjuvant CT (p = 0.04). A significant interaction was found on OM between HPV+ status and increasing ILNR, with a cutoff at 50% (p = 0.05). Results are limited by their retrospective nature and small numbers in each subgroup. Conclusions: In the largest available dataset of ILND for PSCC, we observed that pRT seemed to be more effective in the subgroup of HPV+ PSCC. These results should be considered as hypothesis-generating and may inspire both the future prospective trials or the ongoing InPACT study.
A pooled analysis of the efficacy and safety of cabozantinib post immunotherapy in patients with advanced renal cell carcinoma.
Authors: Oya Mototsugu , Tamada Satoshi , Tatsugami Katsunori , Nakaigawa Noboru , Osawa Takahiro , Kanayama Hiro-Omi , Kondoh Chihiro , Sassa Naoto , Nishimura Kazuo , Nozawa Masahiro , Masumori Naoya , Miyoshi Yasuhide , Kimura Akiko , Kuroda Shingo , Motzer Robert J. , Choueiri Toni K. , Tomita Yoshihiko
Published: May 2020

5089

Background: While studies have demonstrated survival benefits of first-line regimens including immuno-oncology agents (IO) in advanced renal cell carcinoma (aRCC), optimal treatment following IO is unknown. In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) versus everolimus in patients (pts) with aRCC, after VEGFR-TKI therapy. The Japanese phase II C2001 study (NCT03339219), targeting a population similar to that of METEOR, showed similar efficacy and safety results. Here, we present a post-hoc pooled analysis of pts who had received prior IO therapy from METEOR and C2001. Methods: A pooled analysis was performed in pts who received 60mg/day of oral cabozantinib once daily enrolled in the METEOR or C2001. Patients were divided into two groups with previous IO treatment (pre-w/ IO subgroup) or without previous IO treatment (pre-w/o IO subgroup). Analyses of ORR, PFS, OS, and safety were performed as measures of clinical outcome in each subgroup. Results: 365 pts (pre-w/ IO subgroup: 33 pts, pre-w/o IO subgroup:332 pts) were included for efficacy analysis and 366 pts (pre-w/ IO subgroup: 33 pts, pre-w/o IO subgroup:333 pts) for safety analysis. Minor differences in baseline characteristics were noted between the analysis subgroups but are not expected to substantially affect efficacy outcomes. The ORR was 21.2% (95% CI: 9.0-38.9%) for pre-w/ IO subgroup, and 17.2% (95% CI: 13.3-21.7%) for pre-w/o IO subgroup. PFS rate and OS rate at 6 months pre-w/ IO was 65.5%, 90.8% and pre-w/o IO was 58.3%, 90.6%, respectively. Although there were some differences in the safety profile, almost all AEs were manageable by dose modifications. There were no differences in AEs associated with IO treatment, such as pneumonitis, endocrinolopathy or infusion related reaction. No new safety signals were noted in any subgroups. Conclusions: Safety and treatment efficacy of cabozantinib were maintained in the pooled analysis of pts from METEOR and C2001 irrespective of prior IO treatment. Funded by Takeda Pharmaceutical Company Limited, Tokyo, Japan. Clinical trial information: NCT03339219, NCT01865747 .
Association of T- and B-cell receptor repertoires with molecular subtypes and outcome in HER2+ breast cancer: An analysis of the NeoALTTO clinical trial.
Authors: Rediti Mattia , Venet David , Rothe Francoise , Qing Tao , Maetens Marion , Bradbury Ian , Izquierdo Miguel A. , Di Cosimo Serena , Hilbers Florentine , Bajji Mohammed , Harbeck Nadia , Untch Michael , Liu Minetta C. , Saura Cristina , Huober Jens Bodo , Nuciforo Paolo , Salgado Roberto , Loi Sherene , Pusztai Lajos , Sotiriou Christos
Published: May 2020

511

Background: Clinicopathological and molecular features, including estrogen receptor (ER) status and PAM50 subtypes, have shown an association with immunogenicity and tumor-infiltrating lymphocyte (TIL) levels in breast cancer (BC). To investigate the complexity of the immune response in HER2+ BC, we explored the association of T- and B-cell receptor (TCR and BCR) repertoires with clinicopathological characteristics, PAM50 subtypes and outcome in the NeoALTTO phase III trial. Methods: RNA sequencing (RNAseq) data from baseline tumor biopsies were available for 254 out of the 455 patients enrolled. TCR and BCR repertoires were extracted from RNAseq data using the MiXCR software. Repertoire and diversity measures (read counts, number of clones, evenness, Gini index, Shannon entropy, length of the complementarity-determining region 3 [CDR3], top and second top clone proportions) were estimated. PAM50 subtypes were computed from RNAseq data. Univariate and multivariate (adjusted for clinicopathological characteristics, TIL levels dichotomized using the median value of 12.5% and treatment arm) Cox proportional hazard models were used for survival analysis, while logistic regressions were used for pathological complete response (pCR), defined as ypT0/is. All results reported had a false discovery rate (FDR) <0.05. Results: Higher BCR read counts, number of clones and Gini index were significantly associated with ER-negative as well as grade 3 tumors. Among the PAM50 subtypes, HER2-enriched (HER2-E) showed significantly higher BCR read counts, number of clones and Gini index along with lower evenness compared to luminal A and B, as well as higher length of CDR3 than luminal A. Of note, basal-like showed similar BCR diversity measures to HER2-E. No significant differences were noted for TCR diversity measures. In multivariate analyses, neither TCR nor BCR features were associated with pCR, while BCR evenness (HR 1.5; 95%CI 1.1-2.1) and Gini index (HR 0.66; 95%CI 0.5-0.88) were associated with event-free survival. Conclusions: BCR repertoire measures suggest a clonal expansion in HER2-E and basal-like PAM50 subtypes. Furthermore, the implementation of BCR-derived biomarkers can help to identify patients with an improved clinical outcome after neoadjuvant anti-HER2 treatment. Our findings highlight the heterogeneity of the immune response within HER2+ BC and provide support for biomarker-driven treatment strategies including immunotherapy in this BC subtype. Further validation is required. Clinical trial information: NCT00553358 .
Value of clinical treatment score post-5 years (CTS5) for late relapse risk assessment in patients with early-stage HER2+ breast cancer (BC) in the north central cancer treatment group (NCCTG) N9831 (Alliance) trial.
Authors: Pai Tanmayi , Gil Angelica , Ma Yaohua , Li Zhuo , Advani Pooja , Moreno-Aspitia Alvaro , Colon-Otero Gerardo , Perez Edith A. , Thompson E Aubrey , Chumsri Saranya
Published: May 2020

529

Background: Multiple prognostic models exist to predict late relapse risk in early stage hormone receptor-positive (HR+) breast cancer (BC). The CTS5 is one such model that has been validated in HR+ HER2-negative BC. The value of this model in HR+ HER2+ has not been established. Here, we assessed CTS5 in patients (pts) with early stage HER2+ BC treated in the NCCTG N9831 (Alliance) trial. Methods: Pts with stage I-III HER2+ HR+ BC who survived ≥ 5 years were included. The online CTS5 calculator was used to determine CTS5 score and risk group (low, intermediate, and high) based on age, tumor size, grade, and number of involved nodes. Kaplan-Meier (KM) estimates, Cox regression models, and C index were used for analysis. Results: From 3,130 pts, 1,204 pts met the criteria and were included. Median age was 49 (22-79) years and median tumor size was 2.4 (0.1-12) cm. 63.6% had grade 3 tumors, 33.6% grade 2, and 2.8% grade 1. Median follow up was 10.89 (5.01-15.32) years. Based on CTS5, 821 (68.2%) pts were classified as high risk, 289 (24%) as intermediate risk, and 94 (7.8%) as low risk. Overall, using univariate Cox regression analysis, there was no statistically significant difference in recurrence free survival (RFS) among pts with intermediate vs. low (HR 0.47 95%CI 0.18-1.22, p = 0.12) and high vs. low (HR1.23 95%CI0.57-2.67, p = 0.6) with the C index of 0.58. Among pts who received concurrent trastuzumab (H) with HR+ BC, there was also no statistical difference in RFS between high vs. low (HR 0.68 95%CI0.24-1.97, p = 0.48) with the C index of 0.55. Paradoxically, pts with intermediate risk had better RFS than low risk (HR 0.18 95%CI0.03-0.97, p = 0.05). As a continuous variable, there is also no significant improvement in RFS per 1 unit increase in CTS5 score (HR 1.19 95%CI 0.73-1.96, p = 0.49) with the C index of 0.54. After 5 years, 7.06% (n = 30/425) of HR+ pts treated with concurrent H recurred. Conclusions: The CTS5 model is not prognostic in pts with early stage HR+ HER2+ BC receiving adjuvant H. While most HR+ HER2+ pts are classified as high risk by CTS5, the recurrence between years 5-10 was low in pts who received adjuvant H. This study highlights the need to develop a new predictive model for risk of late relapse in this specific group of pts to enable clinicians to determine which pts would benefit from extended adjuvant endocrine therapy. Support: BCRF-19-161, U10CA180821, Genentech. https://acknowledgments.alliancefound.org Clinical trial information: NCT00005970 .