bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of the combination of lenvatinib (L) and eribulin (E) in advanced solid tumors.
Authors: Banwait Ranjit Singh , Ko Heidi Chwan , Michalek Joel , Lathrop Kate Ida , Bowhay-Carnes Elizabeth Ann , Fotopoulos Georgios , Elledge Richard M. , Karnad Anand B. , Kaklamani Virginia G. 
Published: July 2024

3158 Background: Tumor angiogenesis remains a focal point in cancer therapeutics, necessitating innovative strategies to counter resistance mechanisms. Lenvatinib, a multitargeted tyrosine kinase inhibitor, and eribulin, a microtubule inhibitor, exhibit promise in disrupting tumor vasculature. Understanding their efficacy and safety in combination therapy is crucial, especially in heavily pretreated patients with advanced solid tumors. Methods: A single-center phase II study (NCT02640508) enrolled patients with stage IV breast carcinoma, lung carcinoma, and sarcoma, evaluating the safety and efficacy of lenvatinib and eribulin combination therapy. Eribulin was given on day 1 and day 8 at 1.4 mg/m2 and lenvatinib at a dose of 20 mg starting on day 2 of a 21-day cycle. Immunohistochemistry assessed biomarkers CD31, e-cadherin, CA-9, and vimentin. Statistical analyses included multivariate modeling and Kaplan-Meier curves. The primary endpoint of the study was the overall response rate (ORR), defined per RECIST 1.1 as assessed by investigator imaging review. Secondary endpoints included safety, progression free survival (PFS) and overall survival (OS). Results: Among 29 patients enrolled, median age was 58 years, majority were female and had at least ≥3 prior lines of chemotherapy. Treatment with lenvatinib and eribulin resulted in an ORR of 24%, as seen in the table. Median PFS was 7.4 months and OS was 8.2 months. Toxicities were manageable with grade ≥3 neutropenia seen in 34.5%, febrile neutropenia in 17.2%, and hypertension in 13.8% of patients. Treatment-related adverse events leading to study-drug discontinuation occurred in 6.8% of patients. Vimentin-negative patients exhibited significantly increased OS (fold change 4.374, p<0.001) and PFS (fold change 3.395, p<0.001) after adjusting for age, CD31, and CA9. Conclusions: Lenvatinib combined with eribulin showcased promising anti-tumor activity in heavily pretreated patients with metastatic breast carcinoma, lung carcinoma, and sarcoma. Although manageable, neutropenia emerged as a notable adverse effect. These findings underscore the potential of this combination as a therapeutic strategy for advanced solid tumors, warranting further clinical investigation. The observed significant survival benefits in Vimentin-negative patients align with the biological role of Vimentin in tumor invasiveness and metastatic potential, supporting the plausibility of these results biologically. Acknowledgement: This clinical trial was supported by Eisai. Clinical trial information: NCT02640508 . [Table: see text]
Treatment outcomes of brain metastasis from primary renal cell carcinoma in United States: A National Cancer Database analysis.
Authors: Podder Vivek , Ganiyani Mohammad Arfat , Ahmad Shahzaib , Bellur Shreyas S , Khokhar Muhammad Abbas , Ayoobkhan Fathima Shehnaz , Pustake Manas , Jayram Diya K , Ozair Ahmad , Ranjan Tulika , Garje Rohan , Ahluwalia Manmeet Singh 
Published: July 2024

4561 Background: The advent of stereotactic radiosurgery (SRS) in treatment of brain metastasis (BM) has improved both clinical outcomes and survival in patients with BM. Recent studies suggest that immunotherapy presents a promising potential in the treatment of patients with BM. However, data regarding the effectiveness of combining SRS with immunotherapy for BM in metastatic renal cell carcinoma (RCC) remain largely unknown. We aim to delineate the impact of various treatment therapies including combination therapy for treatment of RCCBM. Methods: We queried the National Cancer Database (NCDB) to include patients with BM from mRCC from 2004 to 2020. We divided the patients into groups based on the treatment they received. Resultantly, 5 different treatment groups i.e., WRBT± immunotherapy, SRS± immunotherapy and immunotherapy alone were identified. We excluded patients with unknown treatment status. We analyzed survival outcomes using the Kaplan-Meier analysis and compared the effect of treatment modalities on survival with the log-rank test. Results: The NCDB yielded 6,446 patients diagnosed with BM from mRCC. In eligible cases, the median age was 63 years (range: 19-90+ years), 69.2% were male, 86.8% were White, 7.9% were Black, 41.9% had Medicare as primary payor, 27.7% had annual income >$74,063, 79.3% belonged from metropolitan areas, 39.6% were treated at academic/research program, 68.3% had Charlson-Deyo score of 0, 44.6% had an unknown grade of the primary RCC. 1,705 (43.44%) patients who were given WBRT had a median overall survival (OS) of 5.65 months, 427 (10.88%) patients were treated with SRT + immunotherapy had an OS of 19.0 months, 987 (25.15%) patients who underwent SRT only had an OS of 9.7 months, 431 (10.98%) patients who received immunotherapy only showed an OS of 12.9 months, and 375 (9.55%) patients who underwent WBRT + immunotherapy had an OS of 12.78 months (log-rank p <0.001). Conclusions: This national database analysis reveals that the combination of SRS with immunotherapy significantly increases the OS in RCCBM compared to immunotherapy, WBRT, or combination of WRBT and immunotherapy. Further prospective studies are warranted to confirm these findings. [Table: see text]
Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (aUC): Long-term outcomes from the JAVELIN Bladder 100 trial in patients (pts) with histological subtypes.
Authors: Loriot Yohann , Gupta Shilpa , Powles Thomas , Grivas Petros , Petrylak Daniel P. , Tyroller Karin , Jacob Natalia , Hoffman Jason , Bellmunt Joaquim 
Published: July 2024

4567 Background: Results from the phase 3 JAVELIN Bladder 100 trial (NCT02603432) led international treatment guidelines to recommend avelumab 1L maintenance as a standard-of-care treatment for pts with aUC without progression after 1L platinum-based chemotherapy (PBC). Around 20% of UCs are mixed with other histological subtypes/variants; these tumors do not have specific treatment guidelines and represent an unmet treatment need. In the large real-world AVENANCE study (NCT04822350; N=594) of avelumab 1L maintenance in pts with aUC in France, outcomes in pts with histological subtypes were consistent with those in the overall population. Here, we report a post hoc analysis of long-term outcomes from JAVELIN Bladder 100 in pts with predominantly UC mixed with <50% histological subtype component. Methods: Eligible pts had unresectable locally advanced or metastatic UC without progression after 1L PBC and were randomized 1:1 to receive avelumab + best supportive care (BSC) or BSC alone. The primary endpoint was overall survival (OS) measured from randomization; secondary endpoints included progression-free survival (PFS) and safety. This post hoc analysis was conducted in all pts with histological subtypes. Results: In the avelumab + BSC and BSC alone arms, respectively, 44/350 and 57/350 pts had histological subtypes. At efficacy data cutoff (June 4, 2021), median follow-up in both arms was ≥38.0 mo. In pts with histological subtypes, OS and PFS measured from randomization were prolonged with avelumab + BSC vs BSC alone (Table). Long-term safety (cutoff, April 6, 2023) in treated pts with histological subtypes was generally consistent with the overall safety population. Treatment-related adverse events (TRAEs) of any grade occurred in 36 pts (83.7%) in the avelumab + BSC arm vs 1 pt (1.8%) in the BSC alone arm; grade ≥3 TRAEs occurred in 9 pts (20.9%) and 0 pts, respectively. Conclusions: This exploratory analysis shows the long-term efficacy and safety of avelumab 1L maintenance in pts with histological subtypes in JAVELIN Bladder 100. No new safety concerns were identified. These results were consistent with those in the overall population and support the use of avelumab 1L maintenance in pts with aUC without progression following 1L PBC, including pts with predominantly UC mixed with <50% histological subtype component. Clinical trial information: NCT02603432 . [Table: see text]
Preliminary efficacy and safety results from RC48-C017: A phase II study of neoadjuvant treatment with disitamab vedotin plus toripalimab in patients with muscle invasive bladder cancer (MIBC) with HER2 expression.
Authors: Sheng Xinan , Yang Kaiwei , Ji Yongpeng , Zhou Li , Zou Benkui , Huang Hang , Wang Yonghua , Bai Xue , Feng Dan , Yang Yong , Bian Jiasheng , Yu Zhixian , Niu Haitao , Du Peng , Fang Jianmin , He Zhisong , Guo Jun 
Published: July 2024

4568 Background: Disitamab vedotin (DV) is a novel humanized anti-HER2 antibody-drug conjugate. DV plus toripalimab (a recombinant humanized anti-PD-1 monoclonal antibody) showed promising antitumor activity in metastatic urothelial carcinoma (ASCO 2023). This study aimed to evaluate the safety and efficacy of DV plus toripalimab as neoadjuvant therapy in MIBC patients with HER2 expression. Methods: This is a prospective multicenter phase 2 trial which planned to enroll 40 pts. Primary endpoint is pathological CR (pCR) rate; secondary endpoints include pathologic response rate, safety and tolerability. Study enrolled pts who are previously untreated MIBC (cT2-T4aN0-1M0), medically fit for and agree to undergo curative intent RC+PLND. HER2 expression was required to be immunochemistry (IHC) ≥ 1+ tested locally. Pts received DV 2 mg/kg plus toripalimab 3 mg/kg every two weeks for 6 cycles, followed by RC+ PLND within 4 weeks. Here we present preliminary efficacy and safety results. Results: 44 pts were enrolled and clinical stage at diagnosis was: cT2N0 (38.6%), cT3N0 (29.5%), cT4aN0 (13.6%), cT2-4aN1 (18.2%). HER2 expression of IHC 1+, 2+ or 3+ was 11.4%, 56.8%, and 31.8%, respectively. By the data cut-off date (Feb-2024), 29 pts (65.9%) completed RC + PLND. The pCR rate was 62.1% (18/29). The pathologic response rate was 75.9% (22/29). Common treatment-related adverse events (TRAEs) were mostly Grade 1 or 2, including alopecia (36.4%), alanine aminotransferase increased (31.8%), aspartate aminotransferase increased (25.0%), rash (22.7%), gamma-glutamyl transferase increased (22.7%), peripheral sensory neuropathy (22.7%), and asthenia (20.5%). Grade 3-4 TRAEs were reported in 15.9% of pts. No deaths occurred. No surgery was cancelled due to TRAEs. Survival data are not yet mature. Conclusions: Neoadjuvant treatment with DV plus toripalimab showed promising efficacy results and was well tolerated in operable MIBC pts with HER2 expression. These results will support further investigation for DV plus toripalimab in this population. Clinical trial information: NCT05297552 .
Efficacy and safety of RP1 combined with nivolumab in patients with anti–PD-1–failed melanoma from the IGNYTE clinical trial.
Authors: Wong Michael K.K. , Sacco Joseph J , Robert Caroline , Michels Judith , Bowles Tawnya Lynn , In Gino Kim , Tsai Katy K. , Lebbe Celeste , Gaudy-Marqueste Caroline , Muñoz Couselo Eva , Middleton Mark R. , Samson Adel , Schadendorf Dirk , Beasley Georgia , Niu Jiaxin , Chmielowski Bartosz , Wise-Draper Trisha M. , Zhu Junhong , Viana Marcus , Milhem Mohammed M. 
Published: July 2024

9517 Background: Patients (pts) with melanoma who progress on anti–PD-1 therapy (anti–PD-1–failed) have limited treatment options. RP1 is an HSV-1–based oncolytic immunotherapy expressing human GM-CSF and a fusogenic protein (GALV-GP-R−). Here, we present data from pts with anti–PD-1–failed melanoma, including the initial cohort and updated data from a registration-directed (R-D) cohort, from the phase 1/2 IGNYTE study (NCT03767348). Methods: Pts had locally advanced or metastatic cutaneous melanoma with ≥1 measurable and injectable tumor (≥1 cm) and confirmed progressive disease (PD) while on therapy and received anti–PD-1 ± anti–CTLA-4 therapy for ≥8 consecutive weeks, with anti–PD-1 being the last treatment received. Pts on prior adjuvant anti–PD-1 therapy had confirmed PD while on adjuvant therapy. RP1 was initially given intratumorally at 1×106 plaque-forming units (PFU)/mL and then every 2 weeks (Q2W) at 1×107 PFU/mL for up to 8 total cycles (≤10 mL/cycle) combined with nivolumab (nivo; cycles 2–8, 240 mg IV); pts then received nivo alone (240 mg Q2W or 480 mg Q4W IV) for up to 2 years, with the option to receive additional courses of RP1 if specified criteria were met. Results: Overall, 156 pts were enrolled (initial melanoma cohort, n = 16; R-D cohort, n = 140); 46.2% of pts had been treated with prior anti–PD-1 combined with anti–CTLA-4, and 51.3% of patients had stage IVM1b-d disease. The overall objective response rate (ORR) was 31.4%, and 12.2% of pts achieved complete response (CR; Table). Responses were observed irrespective of prior anti–PD-1 therapy setting and disease stage (Table). Responses were seen in uninjected lesions and in bulky and visceral disease. The ORR for pts with primary anti–PD-1 resistance was 34.1%. In pts who failed prior ipilimumab + nivo, the ORR was 26.4% (Table). The median duration of response (time from baseline to end of response for responders) was > 24 months, with 100% of responses lasting > 6 months from baseline; 78% of responses were ongoing. Treatment-related adverse events (TRAEs) associated with RP1 + nivo were predominantly grade 1–2; there was 1 grade 5 TRAE (immune-mediated myocarditis attributed to nivo). Conclusions: The updated data from this expanded cohort show that RP1 + nivo provides durable and clinically meaningful antitumor activity in pts with anti–PD-1–failed melanoma. Responses were observed in both injected and uninjected lesions, including visceral lesions. The combination continues to be well tolerated. Clinical trial information: NCT03767348 . [Table: see text]
When to stop immunotherapy for advanced melanoma: Emulation of target trials.
Authors: Amiot Mathilde , Mortier Laurent , Dalle Stéphane , Dereure Olivier , Dalac Sophie , Dutriaux Caroline , Leccia Marie Thérèse , Maubec Eve , Arnault Jean-Philippe , Brunet-Possenti Florence , De Quatrebarbes Julie , Granel Brocard Florence , Gaudy-Marqueste Caroline , Pagès Cécile , Stoebner Pierre-Emmanuel , Legoupil Delphine , Montaudie Henri , Oriano Bastien , Lebbe Celeste , Porcher Raphaël 
Published: July 2024

9521 Background: Immune checkpoint inhibitors (ICI) have demonstrated their effectiveness with a 7.5-year overall survival (OS) close to 50% for advanced stages. The design of clinical trials allowed treatment until progression or toxicity, or for a maximum duration of two years. Prolonged follow-up of responders after cessation shows sustained response and a low risk of relapse in the months following cessation. As of yet, the optimal duration of anti-PD-1 therapy for metastatic melanoma remains unestablished. The objective of this work was to evaluate the optimal duration of ICI. Methods: We conducted emulated trials using the cloning, weighting and censoring approach. Each emulated trial aimed at comparing the causal effect of stopping versus continuing ICI at a specific timepoint, in patients still under treatment and with disease control at that time. Results: The study comprised 1017 participants to the MELBASE cohort. Results of the 6-month discontinuation emulated trial showed a significantly lower OS if treatment was discontinued, compared to continuing treatment for at least three months. The 48-month survival difference was 37.8% (95% confidence interval [CI] 19.8 to 60.5), and the corresponding restricted mean survival time difference 8.3 months (95% CI: 4.1 to 12.7). The 12-month and 18-month discontinuation emulated trials both showed no evidence of benefit of either discontinuing or continuing ICI at any of those timepoints. The 24-month discontinuation emulated trial results were more in favor of stopping compared to continuing treatment at that decision point, with an absolute 48-month survival 10.5% higher (95% CI 4.4 to 18.1). Conclusions: These results suggest that a one-year course of immunotherapy is both necessary and sufficient for patients with advanced melanoma. Prolonged treatment beyond 2 years does not appear to be beneficial in terms of survival and could even be detrimental.[Table: see text]
Continuous intrathecal infusion of nivolumab in advanced melanoma with leptomeningeal disease.
Authors: Faillot Matthieu , Goldwirt Lauriane , Jouenne Fanelie , Kramkimel Nora , Baroudjian Barouyr , Ortiz-Carle Adrien , Nataf François , Oriano Bastien , Staquet Helene , Bacquet Raphael , Aractingi Sélim , Goutagny Stéphane , Mourah Samia , Lebbe Celeste , Decq Philippe 
Published: July 2024

9522 Background: The prognosis of melanoma patients with leptomeningeal disease (LMD) remains poor (median OS of 3.5 months). Intrathecal (IT) drug administration could bypass the blood-cerebrospinal fluid (CSF) barrier and has been explored in many cancers using chemotherapies or monoclonal antibodies. According to a recent phase I trial (PMID36997799), nivolumab IT delivery appears safe while its efficacy remains to be further investigated. Methods: We retrospectively reviewed melanoma patients with LMD treated with continuous IT administration of nivolumab (after decision in multidisciplinary tumor boards) at 2 institutions from February 2021 to October 2023. Patients received 10 to 13.5 mg/day of IT nivolumab delivered through a catheter (cath) connected to an implanted pump. Nivolumab concentrations were monitored in spinal CSF via an independent access port. All patients were enrolled in the MelBase cohort. Results: 11 patients (5 females, median age 52) were treated with continuous IT nivolumab with median (IQR) time to follow-up of 2.5 (1.1-6.3) months (m). Nivolumab was delivered through a spinal (n=10) and ventricular (n=1) cath. All patients had progressed on systemic immunotherapy (ipilimumab + nivolumab n=10, nivolumab n=1). Five patients had symptomatic LMD. All patients were ECOG 0 or 1 except one patient ECOG 3 (due to neurological deficit). Primary tumors were cutaneous (n=8), mucosal (n=1) and unknown (n=2). Tumors were BRAFV600 (n=10) and NRASQ61-mutated (n=1). All but 3 patients had stable extracranial disease. Concomitant systemic therapies were the following: corticosteroids (n=5), intravenous nivolumab (first 3 months of IT therapy) (n=1), and targeted therapies (n=4). The median duration of IT treatment was 1.5 (0.5-2.7) m. The median overall survival (OS) was 2.5 (1.1-NA) m. OS at 3, 12 and 19 m were 36.4 % (16.6-79.5), 27.3 % (10.4-71.6) and 13.6 % (10.4-71.6), respectively. Three patients had prolonged survival (19 m n=2, 12 m n=1). Treatment-related adverse events (all reversible) occurred in 5 patients: hemorrhage on cath path (n=1, grade 2), immune-mediated meningoencephalitis (n=1, grade 3), intracranial hypotension syndrome (n=3, grade 2). Steady state was obtained after 3 weeks of continuous IT infusion. Pharmacokinetics data are summarized in Table. Conclusions: Survival data are slightly inferior to those previously published. However 3 patients had prolonged survival (>=1 year). Median nivolumab concentrations in CSF were comparable to through plasma concentrations at steady state after 3mg/kg IV infusion. High plasma concentrations suggest rapid clearance of nivolumab from the CSF, possibly related to reverse transcytosis of immunoglobulins. [Table: see text]
Camrelizumab plus apatinib and temozolomide as first-line therapy for advanced acral melanoma: 2-year survival results from CAP 03.
Authors: Gu Junjie , Lian Bin , Mao Lili , Li Caili , Bai Xue , Zhou Li , Cui Chuanliang , Chi Zhihong , Sheng Xinan , Wang Xuan , Tang Bixia , Yan Xieqiao , Li Siming , Kong Yan , Dai Jie , Wei Xiaoting , Li Juan , Guo Jun , Si Lu 
Published: July 2024

9547 Background: Acral melanoma is the predominant subtype in Asia, which presents with aggressive biological behavior. First-line immunotherapy yields modest efficacy in advanced acral melanoma, suggesting the need of combination therapy. Our CAP 03 study investigated the combination of anti-PD-1 antibody plus antiangiogenic agent and chemotherapy for the first-line treatment of advanced acral melanoma, and the primary analysis has been published on JAMA Oncology in June 2023 (objective response rate [ORR], 64%; median progression-free survival [PFS], 18.4 months). Here we updated the efficacy results with a median follow-up of 30.3 months (95% CI, 28.9-32.5; reverse Kaplan-Meier method) at data cutoff date on January 8, 2024. Methods: In this single-center phase 2 trial (NCT04397770), patients with pathologically confirmed unresectable stage III or IV acral melanoma and without prior systemic therapy for advanced disease were recruited. Patients received first-line intravenous camrelizumab (200 mg once every 2 weeks) plus oral apatinib (250 mg once a day) and intravenous temozolomide (200 mg/m2 once a day on days 1-5 every 4 weeks) until disease progression or intolerable toxicity. The primary endpoint was ORR per Response Evaluation Criteria In Solid Tumors, version 1.1. Imaging assessment was performed after 4 weeks, then every 8 weeks until one year, and every 3 months thereafter. Overall survival (OS) was followed every 3 months. Results: Between May 2020 and August 2021, a total of 50 patients were enrolled. The confirmed ORR was 66.0% (33 of 50; 95% CI, 51.2%-78.8%). The median PFS was 21.2 months (95% CI, 10.1-27.1). The median OS was not reached, and the 1-year and 2-year OS rates were 88.0% (95% CI, 75.2%-94.4%) and 64.8% (95% CI, 49.5%-76.5%), respectively. Further analyses indicated comparable PFS benefit in subgroups by age (<65 years vs ≥65 years), sex (male vs female), Eastern Cooperative Oncology Group performance status (0 vs 1), NRAS status (variant vs wild-type), stage, lactic dehydrogenase (LDH) level, and PD-L1 combined positive score (<5 vs ≥5). Regarding OS, similar trends were observed in these subgroups, except that patients with normal LDH had better median OS than those with elevated LDH (not reached vs 22.6 months, log-rank nominal P=0.033). Conclusions: This first-line triplet combination shows encouraging survival benefits in patients with advanced acral melanoma, regardless of NRAS status or PD-L1 expression level. Follow-up is still ongoing to obtain mature OS data. Clinical trial information: NCT04397770 .