bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase 2, randomized, open-label, multicenter study of sintilimab and anlotinib in combination with gemcitabine plus cisplatin (GemCis) as first-line therapy in patients (pts) with advanced biliary tract cancer (BTC): SAGC.
Authors: Jingjing Li , Qi Xu , Wei Qing , Han Zhe , Cong Luo , Zhang Fabiao , Ying Jieer
Published: June 2022

4100

Background: BTC has a higher incidence in China rather than worldwide, with extremely poor prognosis, and the efficacy of standard first-line therapy (GemCis) is rather limited. TOPAZ-1 study suggested immunotherapy + GemCis as first line in advanced BTC significantly improved OS and PFS vs placebo + GemCis with manageable safety, but the median OS was just 12.8 months. SAGC is the first randomized controlled phase 2 trial to evaluate first-line immunotherapy + antiangiogenic targeted drug + GemCis in advanced BTC. Methods: In this randomized controlled study, pts previously untreated for unresectable locally advanced, recurrent, or metastatic BTC were randomized 1:1 to receive sintilimab (200mg every 3 weeks [Q3W]) and anlotinib (10mg po qd, Days 1-14 Q3W) in combination with GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on Days 1 and 8 Q3W) for up to 8 cycles, followed by sintilimab (200mg every 3 weeks [Q3W]) and anlotinib (10mg po qd, Days 1-14 Q3W) or GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on Days 1 and 8 Q3W) for up to 8 cycles until disease progression or unacceptable toxicity. The primary objective was to assess the 1-year overall survival (OS). Secondary endpoints included OS, progression-free survival (PFS), objective response rate (ORR), and safety. Results: At data cutoff for this interim analysis (11 November, 2021), 48 pts were randomized to sintilimab + anlotinib + GemCis (n=26) or GemCis (n=22). The primary objective was not meet: the 1-year OS was 52.5% with sintilimab + anlotinib + GemCis and 36.3% with GemCis (p=0.437), but there was a trend of nominal OS benefit in patients treated with sintilimab + anlotinib + GemCis. PFS was significantly improved with sintilimab + anlotinib + GemCis vs GemCis (6.4m vs 5m; p=0.014). ORR was 37.5% with sintilimab + anlotinib + GemCis and 26.7% with GemCis. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 69.2% of pts receiving sintilimab + anlotinib + GemCis and38.7% of pts receiving GemCis. TRAEs led to discontinuation of any study medication in 7.7% of pts receiving sintilimab + anlotinib + GemCis and 9.1% of pts receiving GemCis. Conclusions: In pts with advanced BTC, sintilimab + anlotinib + GemCis could improve OS and PFS vs GemCis with manageable safety, indicating sintilimab + anlotinib + GemCis may be a new first-line standard of care regimen. Research Sponsor: Innoventbio Biologics, Inc, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Clinical trial information: NCT04300959.
Genomic profile of intrahepatic cholangiocarcinoma with MTAP loss.
Authors: Tang Tin-Yun , Ross Jeffrey S. , Rodon Ahnert Jordi , Javle Milind M.
Published: June 2022

4102

Background: Recent data suggests a role for immune-checkpoint inhibition in the management of intrahepatic cholangiocarcinoma (iCCA). Chromosomal 9p21 loss with CDKN2A/MTAP co-deletion commonly occurs in iCCA and may correlate with poor response to immunotherapy. Methods: 2,508 cases of intrahepatic cholangiocarcinoma underwent comprehensive genomic profiling with the FoundationOne CDx assay. PD-L1 expression was measured with IHC using the Dako 22C3 antibody and measured with the tumor proportion score (TPS) method. Prevalence of different selected genomic alterations in tumors with MTAP loss was compared against MTAP intact tumors using Fischer’s exact test. Results: In 2,508 cases analyzed, 15.5% of tumors were found to have MTAP loss. Of these, 98.7% had concomitant CDKN2A and 9p21 loss. No significant difference in immune biomarkers in MTAP loss versus wildtype (WT) was seen. PD-L1 low positive at 13.2% vs 19.2%, PD-L1 high positive at 2.9% vs 6.5%, median tumor mutational burden at 2.5 vs 2.5 and MSI high at 0.0% vs 1.6% in MTAP loss vs WT, respectively. There were no significant differences between MTAP loss and WT in potentially actionable mutations including FGFR1/2 mutations (12.4% vs 10.7%), PIK3CA (6.40% vs 6.60%), ERBB2 (4.10% vs 5.30%) and KRAS G12C (1.20% vs 1.10%) in MTAP loss vs WT, respectively. The table depicts significant genomic differences between these subgroups. Conclusions: This represents the largest iCCA cohort with MTAP loss to our knowledge. Given the historical data regarding 9p21 loss and poor response to immunotherapy, efforts targeting MTAP loss through synthetic lethality or other novel combinational therapeutics are justified.[Table: see text]
Australasian Gastrointestinal Trials Group (AGITG) CONTROL NET Study: 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) and capecitabine plus temozolomide (CAPTEM) for pancreas and midgut neuroendocrine tumours (pNETS, mNETS)—Final results.
Authors: Pavlakis Nick , Ransom David Turner , Wyld David , Sjoquist Katrin Marie , Wilson Kate , Gebski Val , Murray James , Kiberu Andrew Ddembe , Burge Matthew E. , Macdonald William , Roach Paul , Pattison David A. , Butler Patrick , Price Timothy Jay , Michael Michael , Lawrence Benjamin James , Bailey Dale L. , Leyden Simone , Zalcberg John Raymond , Turner Harvey
Published: June 2022

4122

Background: CAPTEM is an accepted regimen for patients (pts) with advanced pNETs. Single agent PRRT is now a standard of care for progressive WHO Grade 1/2 mNETs. High activity was seen with PRRT/CAPTEM in a single arm Phase I/II trial. This study aims to determine the activity of combining CAPTEM with PRRT in mNETs and pNETs pts. Methods: Non-comparative randomised open label parallel group phase II trial with 2:1 randomisation to PRRT/CAPTEM (experimental arm) vs. PRRT (mNETs control) and CAPTEM (pNETS control). PRRT/CAPTEM: 7.8GBq 177Lu Octreotate (Lutate) given intravenously (IV) on day 10 every 8 weeks for 4 cycles, with concurrent oral capecitabine 750mg/m2 b.i.d. days 1-14 and temozolomide 75mg/m2 b.i.d. days 10-14 every 56 day cycle, up to 4 cycles. PRRT alone: 7.8GBq 177Lu Octreotate (Lutate) given intravenously (IV) on day 1 every 8 weeks for 4 cycles. CAPTEM alone: Oral capecitabine 750mg/m2 b.i.d. days 1-14 and days 29-42; Oral temozolomide 75mg/m2 b.i.d. days 10-14 and 38-42 every 56 day (8w) cycle. Primary endpoint: Progression free survival (PFS). mNETS: At 15 months, assuming PFS 66.4% in control arm; target PFS ³ 80%; pNETS: At 12 months, assuming PFS 60% in control arm; target PFS ³ 75%. Secondary endpoints: Objective tumor response rate (complete or partial) (OTRR), overall survival (OS), adverse events (AEs). Results: 75 pts enrolled (Dec 2015 – Nov 2018): mNETs 33 PRRT/CAPTEM, 14 PRRT, median follow up (mFU) 60.3 months; pNETS 19 PRRT/CAPTEM, 9 CAPTEM, mFU 57.5 months (mo). Late Grade 3/4 haematologic AEs: mNETS: 2/32 (6%) PRRT/CAPTEM pts and 4/13 (31%) PRRT pts. Events included myelodysplastic syndrome (40 mo), leukaemia (60 mo), pancytopenia (50 mo), anaemia (32 mo), thrombocytopenia (7 mo). No late haematologic G3/4 AEs were reported in the pNETS cohort. No late renal toxicity was identified in all study arms. Conclusions: CONTROL NETs is the first randomized trial to demonstrate efficacy for PRRT in pNETs, in addition to a standard of care. Extended follow up confirms durable CAPTEM/PRRT activity, with superior PFS in pNETs. Late haematologic toxicity was seen in both mNET PRRT arms but was not higher with additional CAPTEM. The activity of CAPTEM/PRRT in pNETs should be tested in the phase III setting. Clinical trial information: ACTRN12615000909527. [Table: see text]
Comparative analysis of the targetable landscape in KRAS-mutant and wild-type pancreatic adenocarcinoma.
Authors: Knepper Todd C , Kim Dae Won , Mauer Elizabeth , Ronski Karyn , Gulhati Pat
Published: June 2022

4155

Background: Pancreatic adenocarcinoma (PC) is the fourth leading cause of cancer deaths, with increased incidence among patients (pts) younger than 50 years old (yo). Small cohort studies suggest early-onset PC (EOPC, diagnosis at < 50 yo) tumors may have a unique biology, harboring a higher proportion of KRAS wild-type status ( KRASWT) and enrichment of targetable mutations/fusions compared to non-EOPC. In addition, therapy targeting oncogenic fusions in KRASWT tumors has shown meaningful responses in PC pts. Here, we investigate the prevalence of fusions, mutations, and homologous recombination deficiency (HRD) in KRASWT PC to identify potential targets for therapeutic intervention, and compare EOPC to non-EOPC to better characterize EOPC differences. Methods: De-identified records from 4,956 PC pts with tumor biopsies sequenced using the Tempus xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage; full transcriptome RNA-seq) were retrospectively reviewed. Fusions were detected from RNA-seq data via the Tempus bioinformatics pipeline. Mutations identified included germline and/or somatic single-nucleotide variants and insertions/deletions. HRD status was determined from RNA-seq data by the Tempus HRD test. Significance was determined as FDR-corrected p-values < 0.05. Results: Across the entire cohort, 21% tumors were KRASWT. HRD was more frequent in KRASWT (7.9%) compared to KRASMUT (3.1%) tumors ( P< 0.001). Significant somatic mutational differences between the KRASWT and KRASMUT cohorts included BRAF (5.0% vs 0.2%) , CDKN2A (5.4% vs 25%), ARID1A (3.6% vs 8.6%), CTNNB1 (1.3% vs 0.3%), and TSC2 (1.2% vs 0.1%) (all P< 0.001). Actionable rearrangements were enriched in the KRASWTcohort (10% vs 2.1%, P< 0.001); the most common fusion partners include NRG1, MET, RAF1, BRAF, NTRK1-3, FGFR 1-4, and RET. TMB-high (10 muts/Mb) and MSI-high were more common in KRASWT (2.9% and 1.0%) compared to KRASMUT (1.7% and 0.4%) tumors ( P= 0.015). Additionally, 382 pts were classified as EOPC. KRASWT tumors comprised 30% of EOPCs, 22% of the 50-70 yo cohort, and 17% of the > 70 yo cohort. Germline (pathogenic/likely pathogenic) alterations in BRCA1 and BRCA2 were more frequent in EOPCs (2.0% and 4.5%) compared to the 50-70 yo (0.4% and 1.7%) and > 70 yo (0.4% and 0.8%) cohorts ( P= 0.015 and < 0.001, for BRCA1 and BRCA2 respectively). There were no statistical differences in actionable genes detected in EOPC vs non-EOPC. HRD was found at higher frequency in EOPC (5.4%) and decreased in age cohorts 50-70 yo (4.7%) and > 70 yo (2.5%) ( P = 0.047). Rearrangements were more common in EOPC compared to non-EOPC (10% vs 1.1%, P< 0.001). Conclusions: HRD, TMB-H/MSI-H and oncogenic rearrangements are more prevalent in KRASWT PC when compared with KRASMUT. These molecular analyses may provide additional therapeutic options for PC pts, warranting comprehensive genomic and transcriptomic profiling for this population.
RC48-ADC for metastatic urothelial carcinoma with HER2-positive: Combined analysis of RC48-C005 and RC48-C009 trials.
Authors: Sheng Xinan , He Zhisong , Shi Yanxia , Luo Hong , Han Weiqing , Yao Xin , Shi Benkang , Liu Jiyan , Hu Changlu , Liu Ziling , Guo Hongqian , Yu Guohua , Ji Zhigang , Yu Shiying , Hu Yi , Guo Jianming , Ying Jianming , Fang Jianmin , Zhou Aiping , Guo Jun
Published: June 2022

4520

Background: RC48-ADC (Disitamab Vedotin) is a novel humanized anti-HER2 antibody-drug conjugate (ADC). RC48-ADC demonstrated a promising efficacy with a manageable safety profile in HER2-positive locally advanced or metastatic UC patients who failed to platinum based chemotherapy in RC48-C005 and RC48-C009 trials. Here are the pooled results of the two studies with the supplementary efficacy, safety and updated OS data. Methods: Both of the two trials are single-arm, multi-center, phase II trials. Eligible patients were 18̃80 years old, with central-laboratory confirmed, histologically HER2-postive (IHC2+,3+), unresectable mUC. Patients had at least one line of systemic chemotherapy. The primary endpoint was objective response rate (ORR). Progress-free survival (PFS), overall survival (OS), and safety were also assessed. Results: RC48-C005 and RC48-C009 enrolled HER2-positive locally advanced or metastatic UC patients from Nov 2017 to Sep 2020. 107 mUC patients (80 males; median age 63 y [40-79]) were enrolled. 64.5% patients had received ≥ 2 lines systemic chemotherapy. 90.7% patients had visceral metastases. As of 04 Sep 2021 (data cutoff), The overall confirmed ORR as assessed by the BIRC was 50.5% (95% CI: 40.6%, 60.3%). Similar responses were observed in prespecified subgroups. cORR was 52.1% (25/48) for patients with liver metastasis and was 55.6% (15/27) in patients with previous PD-1/L1 treatment. The cORR was 62.2% (28/45) for HER2 IHC2+&FISH+ or IHC3+ patients, 55.6% (5/9) for HER2 IHC2+&FISH unknown patients, and 39.6% (21/53) for HER2 IHC2+&FISH- patients respectively. DCR was 82.2% (95% CI:73.7%, 89.0%). The mPFS was 5.9 (95% CI:4.2, 7.2) months. The mOS was 14.2 (95% CI:9.7, 18.8) months. The median OS follow up time was 19.1 months. Most common treatment-related AEs were hypoaesthesia (50.5%), Leukopenia (49.5%), aspartate aminotransferase increased (43.0%), neutropenia (42.1%), alopecia (40.2%), asthenia (39.3%), alanine aminotransferase increase (35.5%), decreased appetite (31.8%). The grade ≥3 TRAEs (≥5%) only included hypoaesthesia (15.0%), neutropenia (12.1%) and r-GT increased (5.6%). Conclusions: RC48-ADC showed continuously a promising efficacy with a manageable safety profile in HER2-postive mUC patients who had failed at least one line systemic chemotherapy. Clinical trial information: NCT03507166, NCT03809013.
Long-term outcomes in patients with advanced urothelial carcinoma (UC) who received avelumab first-line (1L) maintenance with or without second-line (2L) treatment: Exploratory analyses from JAVELIN Bladder 100.
Authors: Bellmunt Joaquim , Powles Thomas , Climent Duran Miguel Angel , Sridhar Srikala S. , Gurney Howard , Costa Nuno , Di Pietro Alessandra , Huang Bo , Gupta Shilpa , Grivas Petros
Published: June 2022

4560

Background: Avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) vs BSC alone in patients (pts) with advanced UC that had not progressed with 1L platinum-based chemotherapy (median OS, 23.8 vs 15.0 months; HR, 0.76 [95% CI, 0.631-0.915]; 2-sided p = 0.0036). Avelumab 1L maintenance is now considered standard of care per international guidelines. However, data on outcomes in pts who receive 2L treatment after avelumab 1L maintenance are limited. We report a descriptive analysis of outcomes in pts enrolled in the avelumab + BSC arm of the JAVELIN Bladder 100 trial based on receipt of 2L treatment. Methods: In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), eligible pts had unresectable locally advanced or metastatic UC without progression with 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin. Pts were randomized 1:1 to receive avelumab + BSC or BSC alone. Exploratory analyses of time from randomization to end of 2L treatment and OS were performed in the avelumab + BSC arm in subgroups defined by 2L treatment administered by investigators after discontinuation of study treatment. Results: In the avelumab + BSC arm (n = 350), median follow-up at data cutoff (June 4, 2021) was 38.0 months. 185 pts (52.9%) had discontinued avelumab 1L maintenance treatment for any reason and received 2L treatment, whereas 122 (34.9%) had discontinued avelumab and did not receive 2L treatment. Median OS (95% CI) in subgroups is shown in the Table. In 43 pts (12.3%) who were still receiving avelumab, median treatment duration was 154.6 weeks (range, 106.7-216.0). Among pts who received 2L treatment, median time from end of avelumab 1L maintenance to start of 2L treatment was 1.35 months (range, 0.3-30.9) and median time from randomization to end of 2L treatment was 11.7 months (95% CI, 9.7-13.8). 2L treatment comprised rechallenge with platinum-based chemotherapy in 75 pts (21.4%) or other 2L treatment in 110 pts (31.4%), including 2L anti–PD-(L)1 therapy in 11 pts (3.1%). Additional data based on different types of 2L treatment will be presented. Conclusions: In this exploratory analysis from the JAVELIN Bladder 100 trial with extended follow-up, approximately 60% of pts (185/307 pts) who had discontinued avelumab received 2L treatment. Long-term OS was observed in pts who received avelumab 1L maintenance with or without 2L treatment. Clinical trial information: NCT02603432. [Table: see text]
Landscape of fibroblast growth factor receptor (FGFR) genomic alterations (GA) in urothelial bladder cancer (UBC).
Authors: Bou Zerdan Maroun , Bratslavsky Gennady , Jacob Joseph M , Huang Richard S.P. , Kravtsov Oleksandr , Parimi Vamsi , Lin Douglas I. , Graf Ryon , Danziger Natalie , Ross Jeffrey S. , Goldberg Hanan , Basnet Alina
Published: June 2022

4568

Background: Urothelial bladder carcinomas (UBC) with genomic alterations (GA) in the Fibroblast Growth Factor Receptor ( FGFR) genes have been postulated to be less responsive to immune checkpoint inhibitors (ICI). Immune microenvironment of these tumors could be altered due to suppression of interferon signaling pathways. Here, we present comprehensive genomic profiling (CGP) of FGFR altered UBC to study the underlying immunogenomic mechanisms of response and resistance. Methods: 4,035 UBC underwent hybrid capture based CGP. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined using 114 loci. Programmed death ligand (PD-L1) expression in tumor cells was assessed by IHC (Dako 22C3). Results: 894 (22%) of UBC featured FGFR GA ( FGFR1 3.7%; FGFR2 1.1%; FGFR3 17.4%). Gender and age distribution was similar in all groups. FGFR3 cases had lower GA/tumor and 14.7% GA were fusions. ERBB2 amplification was significantly higher in FGFR1/2 altered UBC compared with FGFR3 altered UBC. MTOR pathway GA were highest in FGFR3 altered UBC. FGFR3 altered UBC featured significantly higher frequencies of biomarkers predicting resistance to ICI including lower TMB, lower PD-L1 expression and higher frequencies of GA in MDM2. FGFR3 driven UBC also features significantly higher frequencies of CDKN2A/B loss and MTAP loss which have also recently been linked to IO drug resistance. Conclusions: UBC harboring FGFR GA have increased frequency of alterations that have been linked to ICI resistance. Further evaluation of FGFR-based biomarkers in UBC clinical trials focused on the assessment of the patient response to ICI appears warranted. [Table: see text]
Outcomes of patients with advanced urothelial cancer who develop infection while on treatment with pembrolizumab.
Authors: Kieser Ryan Blair , Xu Jiaqiong , Burns Ethan , Muhsen Ibrahim , Shah Shivan M , Umoru Godsfavour , Mylavarapu Charisma , Sun Kai , Zhang Yuqi , Crenshaw Aubrey , Esmail Abdullah , Guerrero Carlo , Gong Zimu , Gee Kelly , Heyne Kirk , Singh Monisha , Zhang Jun , Efstathiou Eleni , Bernicker Eric , Abdelrahim Maen
Published: June 2022

4573

Background: Over the past decade, studies have shown the benefit of immune checkpoint inhibitors (IO) in patients with advanced urothelial cancer. These agents work by reconditioning the adaptive anti-cancer immune response within the tumor microenvironment. Immune-related adverse events have been well documented, but there is limited data evaluating infections in patients treated with IO. We performed a retrospective analysis to assess the incidence of infection and its effect on morbidity and mortality in patients treated with pembrolizumab for advanced urothelial cancer. Methods: Data was collected from a network of 7 hospitals for patients who received pembrolizumab for advanced urothelial cancer from 1/1/2017-8/1/2021. Date of last follow up was 12/1/2021. Covariates compared among infected and non-infected cohorts included age, gender, race, comorbidities, ECOG, anti-infective therapy at IO initiation, and line of therapy (1L, 2L, > 2L). Univariable analysis with reported odds ratio (OR) and 95% confidence interval (CI) was used to assess risk factors for infection. Outcome measures included all-cause emergency department (ED) visits, inpatient and intensive care unit (ICU) admissions, median number of IO cycles, and overall survival (OS). OS was evaluated using the Kaplan-Meier model. All analyses were deemed statistically significant if the p-value was < 0.05. Results: A total of 51 patients were identified. Of these, 34 (66.7%) had at least one documented infection and 17 (33.3%) had no reported infections. Baseline characteristics were similar across cohorts. Compared to non-infected patients, infected patients received fewer cycles of IO (median 4 vs 8, p = 0.016). At last follow-up, 20 (58.8%) patients in the infected cohort and 4 (23.5%) in the non-infected cohort died (p = 0.017). Median OS was 7.4 months (95% CI: 3.4-24.9) among patients with infection while not reached in those without infection (p = 0.014). ED visits (p = 1.00), inpatient admissions (p = 0.21), and ICU admissions (p = 0.17) did not significantly differ between cohorts. Univariable analysis did not identify significant risks among covariates. Conclusions: The incidence of infection in patients treated with pembrolizumab for advanced urothelial cancer is high and associated with fewer cycles of IO therapy and shorter OS. Further study of infectious process prevention is of value to maximize immunotherapy benefit.
Phase II clinical study of tislelizumab combined with nab-paclitaxel (TRUCE-01) for muscle-invasive urothelial bladder carcinoma: Bladder preservation subgroup analysis.
Authors: Niu Yuanjie , Hu Hailong , Wang HaiTao , Tian Dawei , Zhao Gangjian , Shen Chong , Wu Zhouliang , Da La , Zhan Xuejian , Huang Shiwang
Published: June 2022

4589

Background: The current strategy for bladder preservation is focused on trimodality treatment, including complete transurethral resection of bladder tumor (cTURBT), with concurrent chemotherapy and radiotherapy. Chemotherapy is usually a cisplatin-based regimen. However, many pts cannot tolerate cisplatin-based chemotherapy and radiation therapy. It fails to meet clinical needs. Meanwhile, the efficacy and safety of checkpoint inhibitors (ICIs) have now been demonstrated. We conduct a study to evaluate ICIs in combination with second-line chemotherapy agents for patients with MIBC. Methods: TRUCE-01 is a phase II trial (NCT04730219) of tislelizumab combined with nab-paclitaxel before cTURBT or radical cystectomy. Pts with pure or mixed urothelial bladder cancer (T2-4a Nx M0) received tislelizumab 200mg on days 1 plus paclitaxel 200mg on days 2 every 3 weeks (Q3W) x 3 cycles followed by cTURBT or radical cystectomy. Imaging evaluation is usually done before and after the drug administration using the same tests to assess the efficacy. Pts who choose to preserve bladder usually continue their medication after cTURBT. This abstract focuses on patients with bladder preservation. Results: Between July 2020 and November 2021, 47 pts completed at least 2 cycles of treatment, 22 (47%) pts received cTURBT, 16 (34%) pts received radical cystectomy and 9 (19%) pts refuse surgery. As for radiological response, 22 achieved complete response (CR), 16 achieved partial response (PR). In the bladder-preserving subgroup, 13 CR pts and 9 PR pts selected cTURBT, pathology showed 17 pT0, 1 pTa, 3 pT1 and 1 pTis. The median medication cycle is 9 (6-11). There were 3 pts experienced grade 3-4 adverse events (CTCAE), a grade 3 rash, a grade 3 gastric perforation and a grade 4 acute renal failure. In addition, The most common grade 1-2 adverse events include alopecia (86%), fatigue (77%), rash (41%), appetite decreases (41%), hyperglycemia (36%), fever (18%), and creatinine increased (14%). Median follow-up 357 (438-291) days with 3 recurrences and 1 death. The 1-year recurrence-free survival rate was 82%. Conclusions: The early efficacy data further support the role of tislelizumab combined with paclitaxel in bladder preservation setting with an acceptable adverse events. Patients with imaging CR or PR after neoadjuvant therapy are preferred for bladder preservation. Enrollment is ongoing. Clinical trial information: NCT04730219.
[177Lu]Lu-PSMA-617 in PSMA-positive metastatic castration-resistant prostate cancer: Prior and concomitant treatment subgroup analyses of the VISION trial.
Authors: Vaishampayan Nitin , Morris Michael J. , Krause Bernd J. , Vogelzang Nicholas J. , Kendi Ayse T. , Nordquist Luke T. , Calais Jeremie , Nagarajah James , Beer Tomasz M. , El-Haddad Ghassan , Brackman Marcia , Desilvio Michelle , Messmann Richard Adam , Sartor A. Oliver , Fizazi Karim
Published: June 2022

5001

Background: In the phase 3 VISION trial, targeted radioligand therapy with lutetium (177Lu) vipivotide tetraxetan ([177Lu]Lu-PSMA-617; 177Lu-PSMA-617) significantly prolonged radiographic progression-free survival (rPFS) and overall survival (OS) when added to standard of care (SoC) in patients with advanced prostate-specific membrane antigen (PSMA) PET-positive metastatic castration-resistant prostate cancer. Benefits were consistent across most pre-specified subgroups. In this post hoc exploratory analysis, we examined rPFS and OS in the context of prior and concomitant cancer-directed treatments. Methods: In VISION, adult patients previously treated with at least 1 androgen receptor pathway inhibitor (ARPI) and 1–2 taxane regimens were randomized 2:1 to 177Lu-PSMA-617 (7.4 GBq Q6W, up to 6 cycles) + SoC or SoC alone. Protocol-permitted SoC excluded cytotoxic chemotherapy, systemic radioisotopes, immunotherapy, or other investigational drugs. Exploratory subgroup analyses of rPFS and OS were performed by: number of prior ARPIs; taxane regimens; non-taxane regimens and immunotherapies; prior treatment with bone-sparing agents; 223Ra and PARP inhibitors; and concomitant treatment with ARPIs, radiation therapy, and bone-sparing agents. Results: Prior and concomitant treatments were generally well balanced between study groups (Table). rPFS and OS benefits with 177Lu-PSMA-617 were consistent across all prior treatment subgroups. Notably, there were benefits in patients who had not received a second prior taxane. There were also consistent benefits regardless of concomitant systemic and radiation therapy as part of SoC. Conclusions: The clinical efficacy of 177Lu-PSMA-617 was observed regardless of prior treatment or SoC chosen, suggesting that disease biology rather than prior and concomitant treatment context drives outcomes. Small differences in outcomes between subgroups may warrant further study to understand better the predictors of improved clinical benefit. Clinical trial information: NCT03511664. [Table: see text]
Event-free survival by residual cancer burden after neoadjuvant pembrolizumab + chemotherapy versus placebo + chemotherapy for early TNBC: Exploratory analysis from KEYNOTE-522.
Authors: Pusztai Lajos , Denkert Carsten , O'Shaughnessy Joyce , Cortes Javier , Dent Rebecca Alexandra , McArthur Heather L. , Kuemmel Sherko , Bergh Jonas C. S. , Park Yeon Hee , Hui Rina , Harbeck Nadia , Takahashi Masato , Untch Michael , Fasching Peter A. , Cardoso Fatima , Zhu Yalin , Pan Wilbur , Tryfonidis Konstantinos , Schmid Peter
Published: June 2022

503

Background: KEYNOTE-522 (NCT03036488) tested the benefit from adding pembrolizumab (pembro) to chemotherapy (chemo) in patients (pts) with early TNBC. The primary results showed statistically significant and clinically meaningful improvements in pCR and EFS with pembro.Prior studies have shown the prognostic value of the residual cancer burden (RCB) method to quantify the extent of residual disease after neoadjuvant chemo. In this exploratory analysis, we assessed EFS by RCB in KEYNOTE-522. Methods: 1174 pts with previously untreated, nonmetastatic, stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2:1 to pembro 200 mg Q3W or placebo (pbo) given with 4 cycles of paclitaxel + carboplatin, then 4 cycles of doxorubicin or epirubicin + cyclophosphamide. After definitive surgery, pts received pembro or pbo for 9 cycles or until recurrence or unacceptable toxicity. Dual primary endpoints are pCR and EFS. RCB was assessed by the local pathologist at the time of surgery. The association between RCB categories (RCB-0, -1, -2, -3, corresponding to increasingly larger residual cancer) and EFS was assessed based on a Cox regression model with treatment as a covariate. Results: Median follow-up was 39.1 months at data cutoff (23 MAR 2021). Pembro shifted RCB to lower categories across the entire spectrum (Table). The HRs (95% CI) for EFS were 0.70 (0.38 - 1.31) for RCB-0 (equivalent to pCR), 0.92 (0.39 - 2.20) for RCB-1, 0.52 (0.32 - 0.82) for RCB-2, and 1.24 (0.69 - 2.23) for RCB-3. The most common EFS event in both arms was distant recurrence, which occurred in fewer pts in the pembro arm in all RCB categories. Conclusions: Increased RCB score was associated with worse EFS. Pts with residual disease had lower RCB values in the pembro arm, including fewer pts with RCB-3. Pembro + chemo prolonged EFS vs chemo alone in the RCB-0, -1, and -2 categories; the small sample size limits interpretation in the RCB-3 category. The small subset of pts with extensive residual disease (RCB-3) in both arms, 5.1% and 6.7%, respectively, had a poor prognosis. These results highlight the importance of neoadjuvant treatment with pembro for improving survival in pts with early TNBC, and identified a subset of pts for whom additional therapies will be needed. Clinical trial information: NCT03036488. [Table: see text]
Association of RB1 mutational status with overall genomic landscape in neuroendocrine prostate cancer (NEPC).
Authors: Grivas Petros , Bratslavsky Gennady , Jacob Joseph M , Kravtsov Oleksandr , Necchi Andrea , Spiess Philippe E. , Wise David R , Danziger Natalie , Parimi Vamsi , Sokol Ethan , Tukachinsky Hanna , Levy Mia Alyce , Ross Jeffrey S.
Published: June 2022

5063

Background: NEPC is a high-grade aggressive form of prostate cancer. We queried whether RB1 mutation status would impact the genomic features of NEPC in RB1 mutated vs non-mutated cases. Methods: From a series of 13,496 cases of clinically advanced PC, we identified 415 cases (3.1%) with a diagnosis of small cell PC or NEPC as determined by the submitting physician. They were sequenced using a hybrid capture-based FDA-approved clinical genomic profiling (CGP) assay to detect all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining 1-49% and high staining ≥50% expression. Results: 253 (61%) of NEPC feature GA in RB1 (RB1 mut+). This contrasts with a 5.8% frequency of RB1 GA in the non-NEPC (P <.0001). The RB1 mut+ NEPC featured a slightly greater number of pathogenic GA/tumor than the RB1 mut- NEPC (5.1 vs 4.2). Age and TMPRSS2-ERG fusion frequency were similar between the groups. RB1 Mut- NEPC was associated with significantly higher amplifications (amp) and total GA in AR compared to RB1 mut+ NEPC. RB1 mut+ NEPC featured significantly greater frequency of PTEN GA. GA frequencies in targetable kinases and DNA repair GA including BRCA1/2 and ATM linked to PARP inhibitor (PARPi) response were similar in both groups. For potential immune-oncology (IO) biomarkers, RB1 Mut+ NEPC featured significantly greater frequency of positive PD-L1 expression and lower frequencies of MDM2 and CDK12 GA. CD274 ( PD-L1) amplification, MSI-high status and cases with TMB ≥10 mut/Mb were uncommon in both groups. gLOH was higher in RB1 mut+ than RB1 mut- (P =.005). There were more cases of non-European ancestry in the RB1 mut- group. APC I1307K mut were found in 3/162 (1.9%) RB1 mut- NEPC only. Conclusions: In NEPC, the presence of RB1 mutation is associated with various GA that may have clinical relevance. Further study of RB1 status as a guide in trial designs on therapy selection for men with NEPC appears warranted. [Table: see text]
Overall survival (OS) and biomarker results from combat: A phase 2 study of bipolar androgen therapy (BAT) plus nivolumab for patients with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Markowski Mark Christopher , Taplin Mary-Ellen , Aggarwal Rahul Raj , Sena Laura , Wang Hao , Lalji Aliya , Meyers Jennifer , Skaist Alyza , Gupta Anuj , Gomes-Alexandre Carolina , Jones Tracy , Hicks Jessica , Kachhap Sushant , Yegnasubramanian Srinivasan , De Marzo Angelo M , Denmeade Samuel R. , Antonarakis Emmanuel S.
Published: June 2022

5064

Background: During BAT, intramuscular (IM) administration of testosterone (T) results in rapid cycling of serum T from supraphysiologic to near-castrate levels in men with mCRPC. In a retrospective study, clinical responses to immune checkpoint blockade (ICB) in mCRPC patients (pts) previously treated with BAT were observed. Here, we report the OS and biomarker results of a Phase 2 study in mCRPC pts treated with BAT in combination with nivolumab (COMBAT; NCT03554317). Methods: This was a multi-center, single arm, open label Phase 2 study in mCRPC pts who received T cypionate 400mg IM (BAT) every 28 days plus nivolumab 480mg IV every 28 days. Pts initially received BAT alone for a 12-week period, prior to the addition of nivolumab. Eligible pts were those with asymptomatic mCRPC who had soft tissue metastases amenable to biopsy, and who progressed on at least one prior novel AR targeted therapy (and up to one prior chemo for mCRPC). The primary endpoint was confirmed PSA50 response. OS and radiographic progression free survival (rPFS) were key secondary endpoints. All pts underwent baseline metastatic biopsies, and 24 had a second biopsy after 12 weeks of BAT. Semi-quantitative IHC (for AR, Ki67, MYC, PTEN, TP53, RB1) was performed on 24 paired biopsies, of which 15 pairs were also evaluable for RNA (whole transcriptome) sequencing. Results: 45 pts were enrolled. As previously reported, the PSA50 response was 40% (18/45, 95% CI: 26-56%, P=0.02 against the 25% null hypothesis), and median rPFS was 5.6 (95% CI: 4.4–6.0) months. After a median follow-up of 17.8 months, the median OS was 27.8 (95%% CI: 17.6–NR) months. In 24 pts with paired biopsies prior to administration of nivolumab, BAT significantly decreased median MYC (P=0.046) and Ki-67 (P=0.030) expression by IHC. 71% (17/24) of pts had any decrease in MYC following BAT, with 29% (7/24) having a >50% decrease. A >50% MYC protein decline was associated with longer rPFS (HR 0.33, 95%CI 0.14–0.78, P=0.005) and a nonsignificant association towards longer OS (HR 0.78, 95%CI 0.24–2.48, P=0.679). MYC protein and mRNA levels were tightly intercorrelated (r=0.65, P<0.001). Both rPFS and OS were numerically longer in pts with >50% declines in MYC mRNA levels (P>0.1 for both). Conclusions: BAT combined with nivolumab led to a median overall survival of >2 years in heavily pretreated mCRPC pts. BAT attenuated MYC expression, correlating with better outcomes. Clinical trial information: NCT03554317.
Pembrolizumab + chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer: Subgroup analysis of KEYNOTE-826.
Authors: Tewari Krishnansu Sujata , Colombo Nicoletta , Monk Bradley J. , Dubot Coraline , Cáceres M. Valeria , Hasegawa Kosei , Shapira-Frommer Ronnie , Salman Pamela , Yañez Eduardo , Gumus Mahmut , Olivera Hurtado de Mendoza Mivael , Samouëlian Vanessa , Castonguay Vincent , Arkhipov Alexander , Tekin Cumhur , Li Kan , Toker Sarper , Keefe Stephen Michael , Lorusso Domenica
Published: June 2022

5506

Background: In KEYNOTE-826 (NCT03635567),pembrolizumab (pembro) + chemotherapy (chemo) ± bevacizumab (bev) provided statistically significant, clinically meaningful PFS and OS improvements in patients with persistent, recurrent, or metastatic cervical cancer. In the present analysis of KEYNOTE-826, we assessed outcomes in several key patient subgroups. Methods: Eligible adult patients had persistent, recurrent, or metastatic squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix not previously treated with chemo and not amenable to curative treatment; measurable disease per RECIST v1.1; ECOG PS 0–1; and a tumor sample to determine PD-L1 status. Patients were randomized 1:1 to pembro 200 mg Q3W or placebo (pbo) for up to 35 cycles + chemo (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5) ± bev 15 mg/kg. Dual primary endpoints are PFS by investigator assessment per RECIST v1.1 and OS in patients with PD-L1 CPS ≥1, all comers, and CPS ≥10. Treatment effects on PFS and OS were examined in patient subgroups defined by bev use (yes or no), histology (squamous or non-squamous [including adenocarcinoma and adenosquamous]), platinum use (carboplatin or cisplatin), and prior chemoradiation therapy (CRT). Hazard ratios (HR) and 95% CIs were based on a stratified Cox regression model. Results: 617 patients were randomized (pembro + chemo ± bev, n=308; pbo + chemo ± bev, n=309). At the May 3, 2021 data cutoff, median follow-up was 22 months. Pembro + chemo prolonged PFS and OS vs pbo + chemo in all subgroups evaluated in the all-comer population (Table). Similar benefits of pembro + chemo on PFS and OS were also seen in the protocol-specified CPS ≥1 and CPS ≥10 populations. Conclusions: Pembro + chemo ± bev prolonged PFS and OS vs pbo + chemo ± bev among the subgroups defined by bev use, histology, platinum use, and prior CRT and provided clinically meaningful benefits similar to the broader population of patients with persistent, recurrent, or metastatic cervical cancer. Clinical trial information: NCT03635567. [Table: see text]
Predominance of BRCA2 mutation and estrogen receptor-positive breast cancer among BRCA1/2 mutation carriers.
Authors: Pujol Pascal , Yauy Kévin , Coffy Amandine , Duforet-Frebourg Nicolas , Gabteni Sana , Daurès Jean-Pierre , Penault-Llorca Frederique Madeleine , Collet Laetitia , Thomas Frédéric , Turnbull Clare , Galibert Virginie , Rideau Chloé , You Benoit , Geneviève David , Hughes Kevin S. , Philippe Nicolas
Published: June 2022

551

Background: PARP inhibitor (PARPi) agents can improve progression-free survival of patients with breast cancer (BC) who carry a germline BRCA1 or BRCA2 pathogenic or likely pathogenic variant (gBRCA1/2) in both the metastatic and adjuvant setting. Therefore, we need to redefine the criteria of women and tumor phenotype that should be tested for gBRCA1/2. Methods: We studied the relative distribution of gBRCA1 and gBRCA2 in unselected populations of women with BC and in unaffected individuals. We also analyzed the proportion of estrogen receptor (ER)-positive (ER+) tumors in unselected BC patients with gBRCA1/2.We performed a meta-analysis of studies of unselected BC that analyzed the relative contribution of gBRCA1 versus gBRCA2 and ER+ tumors among gBRCA1/2 carriers. We then performed a meta-analysis of gBRCA1/2 carriage in unaffected individuals, from genome-wide population studies, the gnomAD databank, and case–control studies. Results: The BRCA2 gene was involved in 54% of BC in unselected patients with gBRCA1/2 (n=108,699) and 59% of unaffected individuals (n=238,973) as compared with 38% of gBRCA1/2 family cohorts (n=29,700). The meta-analysis showed that 1.66% (95% CI 1.08-2.54) and 1.71% (95% CI 1.33-2.2) of unselected BC patients carried a gBRCA1 and gBRCA2, respectively. In unaffected individuals, the frequency of heterozygosity for gBRCA1 and gBRCA2 was estimated at 1/434 and 1/288, respectively. Nearly 0.5% of unaffected individuals in the studied populations carried a gBRCA1/2. Carriage of a gBRCA was 2.5% for patients with ER+ tumors (95% CI 1.5-4.1) and 5.7% (95% CI 5.1-6.2) for those with ER- tumors. Overall, 58% of breast tumors occurring in women carrying a gBRCA1/2 were ER+ (n=86,870). Conclusions: This meta-analysis showed that gBRCA2 carriage is predominant in unselected BC and in unaffected individuals. ER+ tumors among women with gBRCA1/2-related BC is predominant and has been underestimated. Because PARPi agents improve progression-free survival with ER+ gBRCA1/2 BC in both the adjuvant and metastatic setting, BC should be considered regardless of ER status for BRCA1/2 screening for therapeutic purposes.
Adavosertib in combination with carboplatin in advanced TP53-mutated platinum-resistant ovarian cancer.
Authors: Embaby Alaa , Geenen Jill Jacqueline , Kutzera Joachim , Pluim Dick , Lopez-Yurda Marta I. , Beijnen Jos H. , Huitema Alwin , Witteveen Petronella , Steeghs Neeltje , van Haaften Gijs , van Vugt Marcel A.T.M. , de Ridder Jeroen , Opdam Frans
Published: June 2022

5516

Background: Ovarian cancer is globally the second most common cause of death among women with gynecologic malignancies. Despite high initial response rates, the overall prognosis of this patient population remains poor. The majority of advanced ovarian cancers will become platinum resistant defined by recurrence within six months after completion of platinum therapy. In the first part of the current phase II study, the combination of carboplatin and the Wee1 inhibitor adavosertib (AZD1775), showed to be safe and effective in patients with TP53 mutated platinum resistant ovarian cancer. The aim of this additional cohort is to gain more information about the safety and efficacy of the combination and to explore predictive biomarkers for resistance and response to adavosertib. Methods: In this additional cohort 29 evaluable were treated with carboplatin AUC 5 mg/ ml·min and adavosertib 225 mg BID for 2.5 days in a 21-day cycle. The anti-tumor activity was assessed according to RECIST 1.1. Pre-, on- and post-treatment biopsies were obtained to explore genetic determinants of drug resistance and response to adavosertib. Results: A total of 32 patients with a median age of 62 years (39-77 years) were enrolled in this cohort. All patients had carboplatin/paclitaxel as first line therapy. Six patients received a second-line non-platinum containing regimen. Median platinum free interval was 5.8 months (range 1.7 – 11.9). Twenty-nine patients were evaluable for efficacy. Grade 1-2 bone marrow toxicity, nausea, vomiting and fatigue were the most common adverse events. Dose reductions of carboplatin and/or adavosertib were made in 15/29 evaluable patients (52%). Dose delays occurred in the majority of patients (76%), mostly due to neutropenia and thrombocytopenia. Twelve patients showed PR as best response, resulting in an ORR of 38% in the intention-to-treat population (95% CI 21%-56%). The median PFS was 5.6 months (range 1.1-32 months, 95% CI 4.2-7.0) and median duration of response was 5.3 months (95% CI 0.13-10.5). Conclusions: Adavosertib 225 mg BID for 2.5 days and carboplatin AUC 5 in a 21-day cycle could be safely combined and shows promising anti-tumor efficacy in patients with platinum resistant ovarian cancer. Bone marrow toxicity remains the most common reason for dose reductions and dose delays. Translational biomarker results (CCNE1 analysis as potential predictive marker for response and resistance and WGS) to better understand the anti-tumor activity of the combination are pending. Clinical trial information: NCT01164995.
Role of cytoreductive surgery for the second ovarian cancer relapse in patients previously treated with chemotherapy alone at first relapse: A subanalysis of the DESKTOP III trial.
Authors: Sehouli Jalid , Fotopoulou Christina , Vergote Ignace , Reuss Alexander , Ferron Gwenael , Meier Werner , Greggi Stefano , Mosgaard Berit J. , Selle Frederic , Guyon Frederic , Pomel Christophe , Lecuru Fabrice , Zang Rongyu , Hellmann Kristina , Kim Jae-Weon , Romeo Margarita , Raspagliesi Francesco , Eyjólfsdóttir Brynhildur , Du Bois Andreas , Harter Philipp
Published: June 2022

5520

Background: The DESKTOP III trial has demonstrated a significant survival benefit in AGO-score positive patients who underwent complete cytoreduction at 1st relapse compared to those treated with chemotherapy alone. The question whether eligible patients who missed the opportunity of potentially life prolonging surgery at 1st relapse would benefit from surgery at the time of their second relapse, remains open. Methods: Patients randomized in the standard, non-surgical arm of the DESKTOP III trial who underwent cytoreductive surgery at a subsequent relapse at investigator’s discretion were separately analyzed. Results: The median progression-free survival (PFS) counted from randomization of 201 patients in the control arm of DESKTOP III was 14.0 months. 171 (85%) had progressive or relapsing disease and 32 of 171 (19%) underwent cytoreductive surgery. Patients’ median age at this subsequent surgery was 63 years (range: 46 – 78). Complete tumor resection was achieved in 19 patients (60%), while 5 (16%) had postoperative residual disease (n = 8 missing data). Sixteen patients (50%) commenced systemic treatment within 90 days from surgery, as documented. Thirty- and 90-day surgical mortality rates were 1 (3%) and 2 (6%), respectively. Within a postoperative median follow-up time of 43.8 months, 12 (38%) deaths were reported. Median overall survival after surgery (OS) was 54.0 months. One- and 2-year OS rates were 91% and 84%, respectively. Conclusions: Cytoreductive surgery for subsequent ovarian cancer relapse appears feasible and with low mortality in selected patients who received non-surgical treatment at 1st relapse despite a positive AGO-score. Surgery should be considered as an option in carefully selected patients also later in their journey within a specialized gynecological cancer setting. Clinical trial information: NCT01166737.
Phase 1 trial of first-line bintrafusp alfa in combination with other anticancer therapies in patients (pts) with locally advanced or advanced cervical cancer.
Authors: Oaknin Ana , Ghamande Sharad A. , Kasamatsu Yuka , Gil-Martin Marta , Diver Elisabeth J. , Jehl Genevieve , Gleicher Stephan A. , Chaudhary Surendra , Vugmeyster Yulia , Hasegawa Kosei
Published: June 2022

5528

Background: Until the recent FDA approval of pembrolizumab in combination with chemotherapy ± bevacizumab, there have been limited treatment options that address the underlying biology for pts with persistent, recurrent, or metastatic (P/R/M) or locally advanced (LA) cervical cancer. Persistent HPV infection is associated with 99% of cervical cancers and is linked to upregulation of TGF-β. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1, has shown promising clinical activity and manageable safety in pts with recurrent or metastatic cervical cancer. We report data from a phase 1 trial evaluating safety of first-line bintrafusp alfa plus chemotherapy ± bevacizumab for pts with P/R/M cervical cancer or bintrafusp alfa plus chemoradiotherapy for pts with LA cervical cancer (INTR@PID 046; NCT04551950). Methods: Pts with P/R/M cervical cancer who had not received prior systemic therapy received bintrafusp alfa 2400 mg Q3W plus cisplatin/carboplatin and paclitaxel with (cohort 1A) or without (cohort 1B) bevacizumab. Pts with LA cervical cancer received bintrafusp alfa 2400 mg Q3W plus concurrent weekly cisplatin and radiotherapy followed by maintenance therapy with bintrafusp alfa (cohort 2). Pts were treated until disease progression, death, unacceptable toxicity, or withdrawal. Primary endpoints were safety and tolerability of bintrafusp alfa in combination with current standard-of-care therapies in pts with P/R/M or LA cervical cancer. Results: As of November 25, 2021, 8 pts in cohort 1A, 9 in cohort 1B, and 8 in cohort 2 had received bintrafusp alfa for a median of 11.6, 10.0, and 5.6 cycles, respectively. At the time of this analysis, 11 of 25 pts remained on bintrafusp alfa therapy. Any-grade bintrafusp alfa–related adverse events (AEs) occurred in 75.0%, 100.0%, and 75.0% of pts in cohorts 1A, 1B, and 2, respectively (Table). The most-common grade ≥3 AEs were anemia and hematuria (25.0% each) in cohort 1A and vaginal hemorrhage (22.2%) in cohort 1B. One pt had grade 4 anemia and vaginal hemorrhage in cohort 1B. No treatment-related deaths occurred. AEs led to permanent discontinuation of bintrafusp alfa in 37.5%, 33.3%, and 12.5% of pts in cohorts 1A, 1B, and 2, respectively; the most common any-grade AE was vaginal hemorrhage (22.2%). Conclusions: No new safety signals were observed with first-line bintrafusp alfa plus chemotherapy ± bevacizumab or chemoradiotherapy in pts with P/R/M or LA cervical cancer. Clinical trial information: NCT04551950. [Table: see text]