Cisplatin-gemcitabine Chemotherapy Research Articles

The evolving treatment landscape of metastatic urothelial cancer.

Cisplatin-based chemotherapy is currently the first-line standard of care for patients with metastatic urothelial cancer (mUC); however, up to 50% of patients are ineligible for cisplatin, necessitating alternative treatment options. Immune checkpoint inhibitors have been shown to be effective in cisplatin-ineligible patients. However, despite advances in the first-line setting, the prognosis remains poor, and challenges persist in selecting optimal therapies, treatment sequences and combination regimens. Maintenance therapy with avelumab revealed improved overall (OS) and progression-free survival (PFS) compared with best supportive care alone in patients with platinum-responsive mUC. Antibody-drug conjugates and targeted therapy with fibroblast growth factor receptor (FGFR) inhibitors have shown promise in selected patients, particularly in patients with metastatic disease that has progressed despite platinum-based chemotherapy. At the European Society of Medical Oncology Congress in 2023, groundbreaking results were presented from two phase III trials, EV-302/KEYNOTE-A39 and CheckMate 901, focusing on previously untreated mUC. In the former, the combination of enfortumab vedotin and pembrolizumab showed significant improvements in OS, PFS and overall response rate compared with chemotherapy alone; the combination of nivolumab with gemcitabine-cisplatin chemotherapy demonstrated a significant extension in median OS, PFS and overall response rate compared with chemotherapy alone. Inaddition, erdafitinib therapy resulted in significantly longer OS than chemotherapy among patients with mUC and FGFR alterations after previous treatment with immune checkpoint inhibitors. This comprehensive summary of the current treatment landscape for mUC incorporates clinical trial evidence and discussion of agents that are currently under investigation to provide support for clinical decision making and understanding of future therapeutic approaches.

Abstract 4025: A phase II trial of neoadjuvant gemcitabine, cisplatin plus tislelizumab followed by concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: Clinical efficacy, safety and the biomarker analysis

Abstract Immune checkpoint inhibitors (ICIs) have been widely used in recurrent or metastatic nasopharyngeal carcinoma (NPC), but the addition of ICIs to chemoradiotherapy in locoregionally advanced (LA) NPC requires further investigation. We conducted a phase II, single-arm trial to evaluate the efficacy and safety of neoadjuvant gemcitabine, cisplatin (GP) plus tislelizumab followed by concurrent chemoradiotherapy (CCRT) in LA-NPC. All participants received 3 cycles of GP chemotherapy plus tislelizumab (200 mg) followed by 3 cycles of cisplatin-based CCRT. The primary endpoint was the clinical complete response rate (CR) after neoadjuvant chemoimmunotherapy (NAT). The secondary endpoints include pathological CR rate, progression-free survival (PFS), overall survival (OS), locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), etc. Pretreatment blood samples and paired (pre-/post-NAT) tissue biopsies were collected to perform full-spectrum peripheral T-cell profiling, PD-L1 and tertiary lymphoid structures (TLS) staining. Among all 63 participants, the CR rate after NAT reached 41.3% (95% CI, 28.8%-53.8%), far exceeding our hypothesized CR rate of 22%. The objective response rate (ORR) and pCR rate after NAT were 88.9% (95% CI, 80.9% to 96.9%) and 74.6% (95% CI, 62.1% to 84.7%), respectively. As of July 15th, 2023, after the median follow-up of 25 months, the 2-year PFS and OS were 98.4% and 100%. The incidence of grade 3-4 immunotherapy-related adverse events was 1.6%. The compliance of CCRT was not compromised. Patients who achieved CR had significantly more circulating CD4+ and CD8+ effector memory T cells (Tem), regulatory T cells (Treg) and follicular helper T cells (Tfh). The peripheral abundance of LAG3+ Tem and Tfh were independently predictive of NAT response. The number and maturation of TLS significantly increased after NAT in the CR group, but not in the Non-CR group. GP chemotherapy plus tislelizumab followed by CCRT was highly therapeutic and safe in treating LA-NPC, further randomized phase III studies are awaited. Citation Format: Xiao-Yun Li, Si-Yi Xie, Qiu-Yan Chen, Hai-Qiang Mai, Lin-Quan Tang. A phase II trial of neoadjuvant gemcitabine, cisplatin plus tislelizumab followed by concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: Clinical efficacy, safety and the biomarker analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4025.

Clinical and economic effectiveness of using immunotherapeutic drugs in patients with urothelial carcinoma in the healthcare system of the Russian Federation

Aim. To perform pharmacoeconomic evaluation of chemotherapy schemes GC (gemcitabine, cisplatin) and GemCarbo (gemcitabine, carboplatin) in comparison with immunotherapy drugs atezolizumab, pembrolizumab or avelumab in patients with locally advanced or metastatic urothelial carcinoma.Materials and methods. Pharmacoeconomic cost–effectiveness analysis, sensitivity analysis in context of changes of initial model parameters were performed.Results. Literature data analysis allows to make a conclusion of better clinical effectiveness and safety of immunotherapy drugs compared to chemotherapy in patients with urothelial carcinoma. Cost of medications was significantly lower for platinum-based chemotherapy (103,625.61 rubles for GC and 88,733.63 rubles for GemCarbo) compared to a course of immunotherapy (950,092.39 rubles for atezolizumab, 953,340.21 rubles for pembrolizumab, 1,328,999.43 rubles for GC + avelumab). However, the cost of treatment of complications arising during platinum-based chemotherapy was more than 20-fold higher than cost of treatment of immunotherapy complications: 578,853.02 rubles versus 15,336.78– 26,994.52 rubles). Cost–effectiveness analysis favored atezolizumab for which cost–effectiveness ratio was 53,230.69 rubles for 1 month of patient’s life. Atezolizumab had better value than standard 1st line GC chemotherapy by 10,671.80 rubles, as well as immunotherapy courses using pembrolizumab by 9,697.57 rubles and GC + avelumab by 10,824.66 rubles. The highest costs were observed for GemCarbo chemotherapy course: it is 18,522.82 rubles more expensive than atezolizumab course. Sensitivity analysis performed for the cost–effectiveness ratio showed stability of the developed model in regards to increased cost of atezolizumab course up to +18 % and decrease in overall survival with this course up to –15 %.Conclusion. Atezolizumab is a clinically effective and economically justified option for treatment of adults with locally advanced or metastatic urothelial carcinoma and PD-L1 expression ≥5 % in the healthcare system of the Russian Federation.

Mutation-based therapies for intrahepatic cholangiocarcinoma: new options on the horizon

Intrahepatic cholangiocarcinoma (ICC), a rare but rising global malignancy originating from the bile ducts, poses significant challenges in terms of effective treatment and patient outcomes. While surgical excision remains the curative option, its limited efficacy necessitates more therapeutic strategies, including systemic therapies. The management of ICC involves a multidisciplinary approach, with treatment decisions guided by patient-specific and tumor-specific factors. Gemcitabine-cisplatin (GEMCIS) chemotherapy has been a standard first-line therapy, but recent advancements in immunotherapy, particularly the introduction of durvalumab, have provided new hope. Additionally, gene mutation-based therapies, targeting fibroblast growth factor receptors (FGFRs), isocitrate dehydrogenase-1 (IDH1), human epidermal growth factor receptor-2 (HER2), and B-RAF proto-oncogene (BRAF), offer promising prospects for personalized treatment. High-throughput genomic profiling technologies have facilitated the identification of actionable targets and the development of innovative therapeutic approaches. This review summarizes the mutation-based therapies in ICC, including FDA-approved targeted drugs and ongoing clinical trials, highlighting the evolving landscape of ICC treatment.

Targetable Molecular Alterations in the Treatment of Biliary Tract Cancers: An Overview of the Available Treatments.

Biliary tract cancers (BTCs) are rare tumours, most often diagnosed at an unresectable stage, associated with poor prognosis, with a 5-year survival rate not exceeding 10%. Only first- and second-line treatments are well codified with the combination of cisplatin-gemcitabine chemotherapy and immunotherapy followed by 5-FU and oxaliplatin chemotherapy, respectively. Many studies have shown that BTC, and more particularly intrahepatic cholangiocarcinoma (iCCA), have a high rate of targetable somatic alteration. To date, the FDA has approved several drugs. Ivosidenib targeting IDH1 mutations, as well as futibatinib and pemigatinib targeting FGFR2 fusions, are approved for pre-treated advanced CCA. The combination of dabrafenib and trametinib are approved for BRAFV600E mutated advanced tumours, NTRK inhibitors entrectinib and larotrectinib for tumours bearing NTRK fusion and prembrolizumab for MSI-H advanced tumours, involving a small percentage of BTC in these three settings. Several other potentially targetable alterations are found in BTC, such as HER2 mutations or amplifications or KRASG12C mutations and mutations in genes involved in DNA repair mechanisms. This review aims to clarify the specific diagnostic modalities for gene alterations and to summarize the results of the main trials and developments underway for the management of advanced BTC with targetable alterations.

2 years short-term outcomes of radical surgery after nab-paclitaxel plus gemcitabine-cisplatin chemotherapy in patients with locally advanced perihilar cholangiocarcinoma

2 years short-term outcomes of radical surgery after nab-paclitaxel plus gemcitabine-cisplatin chemotherapy in patients with locally advanced perihilar cholangiocarcinoma

Final overall survival analysis of JUPITER-02: A phase 3 study of toripalimab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC).

6009 Background: There are currently no FDA-approved IO therapies for NPC. Toripalimab in combination with Gemcitabine-Cisplatin (GP) chemotherapy had shown significant improvement over chemotherapy alone in progression-free survival (PFS) as first-line treatment for recurrent or metastatic (r/m) NPC at the interim PFS analysis of JUPITER-02 (NCT03581786) study. The final overall survival (OS) analysis results are summarized here. Methods: Patients with r/m NPC (n = 289) were randomized (1:1) to receive toripalimab 240 mg (n = 146) or placebo (n = 143) in combination with GP once every 3 weeks (Q3W) for up to 6 cycles, followed by monotherapy with toripalimab or placebo Q3W until disease progression, intolerable toxicity, or completion of 2 years of treatment. Stratification factors were ECOG performance score (0 vs. 1) and extent of disease (recurrent vs. primary metastatic) at enrollment. The primary endpoint was PFS by an independent review committee. Secondary endpoints included OS and safety. Results: By the cutoff date of Nov 18, 2022, when 133 events were reached for the final OS analysis, the median survival follow up was 30.1 months. A significant improvement in OS was observed for the toripalimab arm over the placebo arm: HR = 0.63 (95% CI: 0.45-0.89), two-sided p = 0.0083. The median OS was not reached in the toripalimab arm and was 33.7 months in the placebo arm. The 2-year and 3-year OS rates were 78.0% vs. 65.1%, and 64.5% vs. 49.2% respectively. A consistent effect on OS, favoring the toripalimab arm, was observed in nearly all subgroups, including PD-L1 high and PD-L1 low expression subgroups. No new safety signals were identified in the toripalimab arm since the interim report. The incidence of Grade ≥3 adverse events (AEs) (89.7% vs 90.2%) and fatal AEs (3.4% vs 2.8%) were similar between two arms. However, AEs leading to discontinuation of toripalimab/placebo (11.6% vs 4.9%), immune-related (irAEs) (54.1% vs. 21.7%) and Grade ≥3 irAEs (9.6% vs. 1.4%) were more frequent in the toripalimab arm. Conclusions: The addition of toripalimab to GP chemotherapy as 1st-line treatment for r/m NPC provided clinically important and highly significant OS advantage over GP alone with a manageable safety profile. These results support the use of toripalimab with GP chemotherapy as the new standard care for this population. Clinical trial information: NCT03581786 .

Clinical feasibility of curative surgery after nab-paclitaxel plus gemcitabine-cisplatin chemotherapy in patients with locally advanced cholangiocarcinoma

BackgroundThis study was conducted to evaluate the clinical feasibility of nab-paclitaxel plus gemcitabine-cisplatin triplet chemotherapy in patients with locally advanced cholangiocarcinoma in real-world practice. MethodsWe retrospectively reviewed patients with locally advanced cholangiocarcinoma who were treated with nab-paclitaxel plus gemcitabine-cisplatin between October 2019 and August 2021 at a single institution. The initial diagnosis of cholangiocarcinoma was histologically confirmed. ResultsOne hundred twenty-nine patients were included in this study. Among the patients with a measurable lesion (57.4%), the objective response rate and disease control were 60.8% and 91.9%, respectively. Seventy-seven patients (59.7%) were determined as resectable after triplet chemotherapy, but 73 (56.6%) underwent subsequent curative surgery. The major postoperative complication rate was 15.1%, and there were 2 postoperative mortalities (2.7%). There were 6 complete remission cases (8.2%) in the final pathology. The R0 resection was achieved in 67 patients (91.8%). Despite the initial locally advanced cholangiocarcinoma, a pathologic T stage of less than T2 was reported in 67 patients (91.8%). Fifty-two patients (71.2%) had no lymph node metastasis. Patients who underwent surgery after triplet chemotherapy had significantly higher 12-month overall survival (95.9% vs 76.8%; P < .001) than those treated with chemotherapy alone. ConclusionNab-paclitaxel plus gemcitabine-cisplatin chemotherapy demonstrated a down-staging effect through a high response rate, indicating that this triplet chemotherapy is feasible as induction therapy in patients with locally advanced cholangiocarcinoma.

Observation on the Effect of High-Quality Nursing Intervention plus Health Education in Chemotherapy for Non-Small Cell Lung Cancer and Its Influence on the Physical and Mental Health of Patients.

Objective The objective is to analyze the effect of high-quality nursing intervention combined with health education in the chemotherapy for non-small cell lung cancer and its impact on the physical and mental health of patients. Methods The study included 136 patients with non-small cell lung cancer treated at our hospital from March 2020 to December 2021, who were divided into the observation group and the routine/control group by randomization, with 68 patients in each. All patients received the GP (gemcitabine + cisplatin) chemotherapy. The control group received routine nursing care, whereas the observation group received high-quality nursing care mixed with health education. The effect of nursing intervention, patient self-management, and the influence on the physical and mental health of the patients was compared between the two groups. Results The total efficacy rate (89.71%) of the observation group was significantly higher than that of the routine group (57.35%) (P < 0.05). The self-management level of the patients in the observation group, indicated by the Exercise of Self-Care Agency (ESCA) score, was considerably higher than that of the regular group after nursing intervention. Similarly, the observation group's quality of life, which was evaluated in terms of physical function, role function, emotional function, cognitive function, social function, and overall health status, was much better than the routine group's. Furthermore, the SAS, SDS, and overall incidence of adverse events were lower in the observation group than in the regular group. (P < 0.05). Conclusion The application of high-quality nursing intervention combined with health education in chemotherapy for non-small cell lung cancer has favorable clinical benefits, enhances patient compliance and self-management capacity, and exerts a positive influence on the patient's physical and mental health. Adverse reactions can provide a more trustworthy scientific basis for therapeutic therapy. The method should be widely used.

Abstract CT226: Final progression-free survival analysis of JUPITER-02, a randomized, double-blind, phase 3 study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma

Abstract Background: Gemcitabine-Cisplatin (GP) chemotherapy is the standard first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). Toripalimab, a humanized IgG4K monoclonal antibody specific for PD-1, in combination with GP chemotherapy showed significant improvement in progression-free survival (PFS) as first-line treatment for RM-NPC at the interim analysis of the JUPITER-02 study (NCT03581786), a randomized, placebo-controlled, double-blinded international Phase III trial. Here we report the results of the final PFS analysis and the interim overall survival (OS) analysis. Methods: Patients (n=289) with advanced NPC with no prior chemotherapy in the recurrent or metastatic setting were randomized (1:1) to receive toripalimab 240 mg (n=146) or placebo (n=143) in combination with gemcitabine and cisplatin every 3 weeks (Q3W) for up to 6 cycles, followed by monotherapy with toripalimab or placebo Q3W until disease progression, intolerable toxicity, or completion of 2 years of treatment. Stratification factors were ECOG PS (0 vs. 1) and extent of disease (recurrent vs. primary metastatic) at enrollment. Tumor response was assessed by a blinded independent review committee (BIRC) per RECIST v1.1. The primary endpoint was PFS by BIRC in the intention-to-treat population. Secondary end points included PFS by investigator, OS, objective response rate (ORR), duration of response (DOR) and safety. Results: At the final PFS analysis, the median follow-up time was 22.1 months for the toripalimab arm and 21.4 months for the placebo arm by the cut-off date of June 8, 2021. The toripalimab arm had a significantly longer PFS than the placebo arm as assessed by BIRC: median PFS 21.4 vs. 8.2 months, HR=0.52 (95% CI: 0.37-0.73), two-sided p&amp;lt;0.0001. The 1-year PFS rates were 59.0% vs. 32.9%. The ORR was 78.8% vs. 67.1% (P=0.022) and the median DOR was 18.0 vs. 6.0 months, HR= 0.49 (95% CI: 0.33-0.72). Consistently, PFS as assessed by investigator was also significantly longer in the toripalimab arm than the placebo arm: median PFS 17.3 vs. 8.1 months, HR=0.43 (95% CI: 0.31-0.58), P&amp;lt;0.0001. As of June 8, 2021, the median OS was not reached in either arm, with a trend favoring the toripalimab arm, HR=0.59 (95% CI: 0.37-0.94), P=0.024. The improvements of PFS and OS in the toripalimab arm were observed across key subgroups, including PD-L1 expression subgroups. Notably, dynamic decrease of plasma Epstein-Barr Virus DNA copy number from baseline was associated with favorable response. No new safety signal was identified. The incidence of Grade ≥3 adverse events (AEs) (89.7% vs 90.2%) and fatal AEs (2.7% vs 2.8%) were similar between the two arms; however, investigator-determined immune-related AEs (irAEs) (53.4% vs. 21.7%) and Grade ≥3 irAEs (8.9% vs. 1.4%) were more frequent in the toripalimab arm. Conclusions: The addition of toripalimab to GP chemotherapy as first-line treatment for advanced NPC had a manageable safety profile and provided superior PFS with a favorable trend in overall survival than chemotherapy alone. Citation Format: Hai-Qiang Mai, Qiu-Yan Chen, Dongping Chen, Chaosu Hu, Kunyu Yang, Jiyu Wen, Jingao Li, Yingrui Shi, Feng Jin, Ruilian Xu, Jianji Pan, Shenhong Qu, Ping Li, Chunhong Hu, Yi-Chun Liu, Yi Jiang, Xia He, Hung-Ming Wang, Wan-Teck Lim, Rui-Hua Xu, Coherus Biosciences and Shanghai Junshi Biosciences. Final progression-free survival analysis of JUPITER-02, a randomized, double-blind, phase 3 study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT226.

Neoadjuvant Chemotherapy in Elderly Patients With Upper Tract Urothelial Cancer: Oncologic Outcomes From a Multicenter Study.

Although upper tract urothelial carcinoma (UTUC) is more common in the elderly, outcomes of neoadjuvant chemotherapy (NAC) in this population have never been explored. The objective of the study was to assess the impact of NAC on pathologic response and oncological outcomes stratified by age. This multicenter study included 164 patients treated with NAC and radical nephroureterectomy (RNU) for clinically non-metastatic, high-risk UTUC. The cohort was stratified into two groups according to median age. Patients received either cisplatin-based or non-cisplatin-based chemotherapies. Pathologic responses were defined as pathologic objective response (pOR; ≤ ypT1N0) and pathologic complete response (pCR; ypT0N0). Univariable and multivariable logistic and Cox regression analyses were performed to identify predictors for pathologic response and survival outcomes. The cohorts' median age was 68 years with the elderly group (> 68 years) comprising 74 patients. Neoadjuvant chemotherapy included methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) in 66 (40%), gemcitabine cisplatin (GC) in 66 (40%) and non-cisplatin chemotherapy in 32 patients (20%). Younger patients received more often MVAC (50% vs. 28%) while elderly received more GC (34% vs. 47%) or non-cisplatin chemotherapy (16% vs. 24%) (P=.02). Overall, pOR and pCR were similar across age groups (52% vs. 47%; P=.5 and 10% vs. 8%; P=.7). While GC and non-cisplatin chemotherapy showed a lower pCR of 5% and 3%, respectively, MVAC revealed a pCR of 17% (P=.03) and was independently associated with a higher pCR (OR 4.31; P=.03). Kaplan-Meier analysis showed no difference in recurrence-free and cancer-specific survival, whereas a lower rate was seen in overall survival for the elderly. Elderly patients with high-risk UTUC eligible for cisplatin-based NAC prior to RNU may benefit from this multimodal therapy equally as their younger counterparts. Cisplatin-ineligible patients undergoing non-cisplatin-based NAC appeared to have lower response rates and should be considered for immediate RNU.

TIRA study: A phase III, multicenter, randomized controlled study of toripalimab plus radical chemoradiotherapy with or without concurrent cisplatin in patients with high-risk locoregionally advanced nasopharyngeal carcinoma.

TPS6101 Background: Patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) suffer a high risk of distant metastasis and require guideline-recommended multimodality therapy. However, cisplatin-based concurrent chemotherapy leads to a high incidence of severe toxicities and low patient compliance, consequently limiting survival improvement. Toripalimab, an immune checkpoint inhibitor targeting programmed cell death 1 (PD-1), has a novel anti-cancer mechanism and mild toxicity spectrum. Robust evidence showed that given toripalimab + gemcitabine-cisplatin (GP) chemotherapy regimen, the median progression-free survival could be markedly improved in patients with recurrent and metastatic NPC. Besides, PD-1 antibody + radiotherapy is also regarded as a promising therapeutic strategy due to the synergistic effect. Therefore, we hypothesized that the de-intensification strategy using toripalimab + induction chemotherapy (IC) followed by radiotherapy alone would obtain equivalent survival and low toxicity in patients with LA-NPC compared with toripalimab + IC followed by concurrent chemoradiotherapy. Methods: TheTIRA study is a multicenter, randomized, controlled, open-label, phase III study. Since August 2021, we have been recruiting high-risk LA-NPC patients (stage III-IVa, except T3-4N0M0 &amp; T3N1M0) from 12 Chinese centers. Our target sample size is temporarily set at 494 patients with 247 for each arm. Patients will be 1:1 ratio randomized to the experimental or control arm. Patients in the experimental arm will receive induction-concurrent toripalimab (240 mg, d1, Q3W × 6 cycle) with IC (gemcitabine 1000 mg/m2, d1 &amp; d8 + cisplatin 80 mg/m2, d1, Q3W × 3 cycle) + intensity-modulated radiotherapy (IMRT, 70 Gy in 33 fractions), and thereafter adjuvant toripalimab (240 mg, d1, Q3W × 11 cycle). Patients in the controlled arm will receive an additional concurrent cisplatin (100 mg/m2, d1, Q3W × 2 cycle). The primary endpoint is the 3-year failure-free survival. Secondary endpoints include 3-year overall survival, 3-year distant metastasis-free survival, 3-year locoregional recurrence-free survival, quality-of-life assessment according to the systems of the European Organization for Research and Treatment of Cancer and the Functional Assessment of Cancer Therapy, and safety profile. Exploratory analysis will be performed for potential biomarkers of survival prediction including PD-L1 expression and tumor-infiltrating lymphocytes. Clinical trial information: NCT04907370.

Abstract No. 4 ▪ ABSTRACT OF THE YEAR Radioembolization with yttrium-90 glass microspheres as first-line treatment for unresectable intrahepatic cholangiocarcinoma: a prospective phase 2 clinical trial

For patients with unresectable intrahepatic cholangiocarcinoma (IHC), the current standard of care first-line treatment is gemcitabine with cisplatin, based on the ABC-02 trial which demonstrated a median OS of 11.7 months. This therapy is complicated by severe (grade 3-4) adverse events in 70% of patients. A recent phase 2 trial demonstrated 22 months median OS when cisplatin-gemcitabine chemotherapy was used with concomitant radioembolization as first line treatment, but 71% of patients had grades 3-4 toxicities, which were mostly related to the chemotherapy. The purpose of our trial was to evaluate the safety and efficacy of yttrium-90 (Y-90) glass microsphere radioembolization as first-line treatment without chemotherapy for unresectable IHC.

Clinical feasibility of curative surgery after nab-paclitaxel plus gemcitabine-cisplatin chemotherapy in patients with locally advanced cholangiocarcinoma.

387 Background: In a recent phase II trial, nab-paclitaxel plus gemcitabine-cisplatin (Gem/Cis/nab-P) demonstrated prolonged survival and unprecedentedly high response rate in patients with advanced cholangiocarcinoma following treatment. We aimed to evaluate the clinical feasibility of this triplet chemotherapy as induction chemotherapy in patients with locally advanced cholangiocarcinoma. Methods: We retrospectively reviewed patients with locally advanced cholangiocarcinoma who were treated with Gem/Cis/nab-P between October 2019 to December 2020. Resectability after induction chemotherapy was evaluated by a multidisciplinary team. Treatment response and surgical pathology were reviewed. Results: Of the 85 patients were included in this study. 46 (54.1%) had measurable lesions. The objective response rate (ORR) and disease control rate in patients with measurable disease were 51.1% and 85.1%, respectively. Fifty-two (61.2%) patients were determined as resectable. Four patients that were judged to be resectable did not undergo surgery due to patient refusal or poor performance status after chemotherapy. Finally, 48 out of 85 patients (56.5%) underwent subsequent curative surgery after induction chemotherapy. There were six complete remission cases (12.5%) in the final pathology, which all reported patients with extrahepatic cholangiocarcinoma. R0 resection was achieved in 46 out of the 48 patients (95.8%). Despite the initial locally advanced cholangiocarcinoma, a pathologic T stage of less than T2 was reported in 44 (95.7%) patients. Lymph node metastasis was confirmed in 13 (27.1%) patients. The overall survival rates in patients who had chemotherapy followed by surgery was better than in those treated with chemotherapy alone ( P = 0.009). Conclusions: Gem/Cis/nab-P as induction chemotherapy showed promising efficacy and clinical feasibility before curative surgery in patients with locally advanced cholangiocarcinoma. This study showed that triplet chemotherapy using Gem/Cis/nab-P has a clear down-staging effect through a high response rate in patients with cholangiocarcinoma

P-19 A multicentred phase II clinical trial on yttrium 90-resin microspheres followed by gemcitabine-cisplatin for treatment of locally advanced intra-hepatic cholangiocarcinoma

Yttrium 90-resin microspheres (Y90-RE) has been reported to be effective in treating intra-hepatic cholangiocarcinoma (ICC). This phase II, investigator-initiated, clinical trial aims to study the efficacy and feasibility of administering Y90-RE followed by standard gemcitabine-cisplatin (GC) chemotherapy in unresectable ICC (NCT02167711).

JUPITER-02: Randomized, double-blind, phase III study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC).

LBA2 Background: Gemcitabine-cisplatin (GP) chemotherapy is the standard 1st line treatment for locally advanced, recurrent or metastatic (r/m) NPC. Toripalimab, a humanized IgG4K monoclonal antibody specific for PD-1, provided durable responses in patients (pts) with r/m NPC as monotherapy in the ≥2nd line setting (POLARIS-02 study). The results of JUPITER-02, a randomized, placebo-controlled, double-blinded Phase III trial of toripalimab in combination with GP chemotherapy as first-line treatment for r/m NPC are summarized. Methods: Pts with advanced NPC with no prior chemotherapy in the r/m setting were randomized (1:1) to receive toripalimab 240 mg or placebo d1 in combination with gemcitabine 1000 mg/m2 d1, d8 and cisplatin 80 mg/m2 d1 every 3 weeks (Q3W) for up to 6 cycles, followed by monotherapy with toripalimab or placebo Q3W until disease progression, intolerable toxicity, or completion of 2 years of treatment. Stratification factors were ECOG PS (0 vs. 1) and extent of disease (recurrent vs. primary metastatic) at enrollment. Progression-free survival (PFS) and response were assessed by independent review committee (IRC) per RECIST v1.1. The primary endpoint was PFS by IRC in the ITT population. Secondary end points included ORR, DOR and OS. There was one prespecified interim analysis of PFS at 130 PFS events with a planned final analysis at 200 PFS events. Results: 289 pts were randomized: 146 to the toripalimab arm and 143 to the placebo arm. By May 30, 2020 as the interim analysis cutoff date, the median treatment duration was 39 weeks in the toripalimab arm and 36 weeks in the placebo arm. A significant improvement in PFS was detected for the toripalimab arm compared to the placebo arm (HR = 0.52 [95% CI: 0.36-0.74] two-sided p = 0.0003), with median PFS of 11.7 vs. 8.0 months. The 1-year PFS rates were 49% and 28% respectively. An improvement in PFS was observed across relevant subgroups, including all PD-L1 subgroups. The ORR was 77.4% vs. 66.4% (P = 0.033) and the median DOR was 10.0 vs. 5.7 months (HR = 0.50 [95% CI: 0.33-0.78]). As of Jan 15, 2021, OS was not mature, with 25 deaths in the toripalimab arm and 35 in the placebo arm (HR = 0.68 [95% CI: 0.41-1.14], P = 0.14). The incidence of Grade ≥3 adverse events (AEs) (89.0% vs 89.5%); AEs leading to discontinuation of toripalimab/placebo (7.5% vs 4.9%); and fatal AEs (2.7% vs 2.8%) were similar between two arms; however, immune-related (irAEs) (39.7% vs. 18.9%) and Grade ≥3 irAEs (7.5% vs. 0.7%) were more frequent in the toripalimab arm. Conclusions: The addition of toripalimab to GP chemotherapy as 1st-line treatment for pts with advanced NPC provided superior PFS and ORR and longer DOR than GP alone with a manageable safety profile. These results support the use of toripalimab with GP chemotherapy as the new standard care for this population. Clinical trial information: NCT03581786.

JUPITOR-02: Randomized, Double-Blind, Phase 3 Study of Toripalimab or Placebo Plus Cisplatin and Gemcitabine as First-Line Treatment for Recurrent or Metastatic Nasopharyngeal Carcinoma

Background: Gemcitabine-Cisplatin (GP) chemotherapy is the standard first-line treatment for recurrent or metastatic (RM) Nasopharyngeal Carcinoma (NPC). Toripalimab, a humanized monoclonal antibody specific for human programmed death-1 (PD-1), provided durable responses in patients with RM-NPC in the second line+ setting. Methods: In this international phase III trial, 289 patients with RM-NPC with no prior chemotherapy in the RM setting were randomized (1:1) to receive either toripalimab or placebo in combination with GP every 3 weeks for up to 6 cycles, followed by monotherapy with toripalimab or placebo until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) as assessed by a blinded independent review committee per RECIST v1.1.RESULTSAt interim analysis, a significant improvement in PFS was detected in the toripalimab arm than the placebo arm, median PFS 11.7 vs. 8.0 months, HR=0.52 (95% CI: 0.36-0.74), p=0.0003. As of February 18, 2021, a 40% reduction in risk of death was observed in the toripalimab arm than the placebo arm, HR=0.603 (95% CI: 0.364 to 0.997). The incidence of Grade ≥3 adverse events (AEs) (89.0% vs 89.5%), AEs leading to discontinuation of toripalimab/placebo (7.5% vs 4.9%), and fatal AEs (2.7% vs 2.8%) were similar between two arms; however, immune-related (irAEs) (39.7% vs. 18.9%) and Grade ≥3 irAEs (7.5% vs. 0.7%) were more frequent in the toripalimab arm. Conclusions: The addition of toripalimab to GP chemotherapy as a first-line treatment for patients with RM-NPC provided superior PFS and OS than GP alone with a manageable safety profile. Trial Registration: NCT number NCT03581786. Funding: Shanghai Junshi Biosciences Co., LTD, Shanghai, China. Declaration of Interest: Hui Feng and Sheng Yao are employed by Shanghai Junshi Bioscience and TopAlliance Biosciences. Patricia Keegan is employed by TopAlliance Biosciences. Rui-hua Xu has served in a consulting or an advisory role for Bristol-Myers Squibb, Merck Serono, Roche, Astellas, AstraZeneca. The rest of authors have no disclosures of potential conflicts of interests. Ethical Approval: This trial was conducted in full conformance with the ICH E6 guideline for Good Clinical Practice (GCP) and the principles of the Declaration of Helsinki.

Magrolimab and gemcitabine-cisplatin combination enhance phagocytic elimination of bladder cancer.

e17035 Background: CD47 is an antiphagocytic signal and macrophage checkpoint that bladder and other cancer cells over-express to evade innate immunity. Magrolimab (Hu5F9-G4) a CD47 blocking antibody, promotes phagocytosis of cancer cells by macrophages and is being tested in several clinical trials (NCT02953509, NCT03248479, NCT02953782, NCT03558139). Chemotherapies synergize with magrolimab by increasing “eat me” signals on cancer cells, and thus enhancing phagocytosis. This synergy has been shown in MDS and AML, whereby magrolimab+azacitidine has shown encouraging efficacy in pre-clinical and clinical studies. This study aimed to investigate the effect of magrolimab as monotherapy and in combination with gemcitabine-cisplatin chemotherapy in bladder cancer. Methods: Phagocytosis of urothelial bladder cancer cells (639V) was evaluated in vitro with magrolimab alone and in combination with chemotherapy (gemcitabine + cisplatin). Treatment in vivo was evaluated in a xenograft mouse model. 639V cells were transplanted into NSG mice and upon confirmation of engraftment mice were randomized into 4 treatment cohorts: control (PBS), magrolimab, chemotherapy (cisplatin + gemcitabine), and magrolimab in combination with chemotherapy. In the first experimental setup treatment was started early in small tumors and in the second experimental setup treatment was started late after tumors have grown to large size. Tumor growth was monitored by in vivo bioluminescent imaging. Metastases were evaluated postmortem. Results: Chemotherapy increased calreticulin on bladder cancer cells. Magrolimab enhanced phagocytosis of bladder cancer cells in vitro and combination of magrolimab with chemotherapy further increased phagocytosis compared to either therapy alone. Magrolimab and chemotherapy, each alone decreased tumor growth in vivo but only combination of magrolimab with chemotherapy showed a strong inhibition of tumor growth, resulting in a significantly prolonged survival compared to all other treatment cohorts. This was shown for both, small tumors and large tumors. Metastases formation in liver and lungs was completely inhibited by treatment with magrolimab, whereas mice treated with chemotherapy alone or PBS control showed metastases in these organs. Conclusions: Magrolimab treatment in combination with chemotherapy was efficacious in preclinical in vitro and in vivo studies in bladder cancer and provides a novel treatment opportunity for patients with bladder cancer and other solid tumors.

A phase III study of futibatinib (TAS-120) versus gemcitabine-cisplatin (gem-cis) chemotherapy as first-line (1L) treatment for patients (pts) with advanced (adv) cholangiocarcinoma (CCA) harboring fibroblast growth factor receptor 2 (FGFR2) gene rearrangements (FOENIX-CCA3).

TPS600 Background: Pts with adv CCA have poor survival outcomes, and chemotherapy offers limited survival benefit (5-year survival rates, 5–10%; median overall survival [OS], 8–12 months). FGFR2 gene rearrangements are known to be early drivers of oncogenesis in ~15% of pts with intrahepatic (i) CCA. Futibatinib, an oral, highly selective, irreversible FGFR1-4 inhibitor has shown antitumor activity against a broad spectrum of FGFR-deregulated tumors in preclinical studies. In a previous study, futibatinib demonstrated clinical activity and tolerability in heavily pretreated pts with adv CCA harboring FGFR2 gene rearrangements. This phase 3 trial (FOENIX-CCA3) is designed to evaluate futibatinib vs gem-cis as 1L therapy for pts with adv iCCA harboring FGFR2 rearrangements. Methods: FOENIX-CCA3 is a multicenter, open-label, randomized phase 3 study that will be conducted in pts with metastatic or unresectable iCCA harboring FGFR2 rearrangements (assessed at screening by a central laboratory). Pts must have an ECOG performance status of 0 or 1 and should not have received previous systemic anticancer therapy for adv disease (adjuvant/neoadjuvant therapy ≥6 mo prior to randomization is permissible). Pts with clinically-significant alterations in calcium-phosphorus homeostasis or ectopic mineralization/calcification will be excluded. Approximately 216 pts will be randomized (1:1 ratio) to receive 20 mg futibatinib once daily until disease progression or other discontinuation criteria are met or gem-cis (on days 1 and 8 of a 21-day cycle) for 8 cycles or until disease progression, whichever occurs first. Pts will be stratified by prior surgical excision (yes vs no), geographic region, and locally adv vs metastatic disease. The primary endpoint is progression-free survival (PFS) assessed by independent central review (ICR). Secondary endpoints include objective response rate and disease control rate based on ICR, OS, PFS per investigator assessment, and safety. The anticipated start date is in April, 2020.

Advanced Intrahepatic Cholangiocarcinoma: Post Hoc Analysis of the ABC-01, -02, and -03 Clinical Trials.

The incidence of intrahepatic cholangiocarcinoma (iCCA) is increasing. The aim of the study was to provide reference survival data for patients with advanced iCCA treated with first-line cisplatin-gemcitabine chemotherapy (current standard of care). Individual data from patients with iCCA recruited into the prospective, random assignment Advanced Biliary Tract Cancer (ABC)-01, -02, and -03 studies were retrieved. The prevalence and survival of liver-only iCCA was also assessed. Survival analysis was performed using univariate and multivariable Cox regression. All statistical tests were two-sided. Of 534 patients recruited into the ABC-01, -02, and -03 studies, 109 (20.4%) had iCCA. Most patients (n = 86, 78.9%) had metastatic disease at the time of recruitment; 52 patients (47.7%) had liver-only disease. Following random assignment, 66 (60.6%) iCCA patients received cisplatin and gemcitabine. The median progression-free and overall survival (OS) were 8.4 months (95% confidence interval [CI] = 5.9 to 8.9 months) and 15.4 months (95% CI = 11.1 to 17.9 months), respectively. Of these 66 patients, 34 patients (51.5%) had liver-only disease. Following chemotherapy, 30 (45.5%) and 21 (31.8%) were progression-free at 3 and 6 months from chemotherapy commencement, respectively. The median OS for patients with liver-only iCCA at diagnosis and after 3 and 6 months of chemotherapy was 16.7 months (95% CI = 8.7 to 20.2 months), 17.9 months (95% CI = 11.7 to 20.9 months), and 18.9 months (95% CI = 16.7 to 25.9 months), respectively. Multivariable analysis confirmed that iCCA had a longer OS compared with other non-iCCA biliary tract cancers (hazard ratio = 0.58, 95% CI = 0.35 to 0.95, P value = .03); liver-only iCCA patients also showed longer OS even though findings did not reach statistical significance (hazard ratio = 0.65, 95% CI = 0.36 to 1.19, P value = .16). Patients diagnosed with advanced iCCA have a better OS compared with other biliary tract cancers; a similar trend was identified for patients diagnosed with liver-only iCCA. These findings are to be considered for future clinical trial design.