Angiogenic and immunomodulatory biomarkers in axitinib-treated patients with advanced renal cell carcinoma

Aim: Immunomodulatory mechanisms contributing to angiogenic inhibition in renal tumors are not well characterized. We report associations between efficacy and tumor-associated immune cells and mRNA/miRNA expression in patients from AXIS. Materials & methods: Immunohistochemistry (n = 52) and mRNA/miRNA expression analyses (n = 72) were performed on tumor samples. Results: In axitinib-treated patients, higher CXCR4 and TLR3 expression, respectively, was associated with longer progression-free survival (hazard ratio; 95% CI: 0.3; 0.1–0.8 and 0.4; 0.2–0.9) and showed interaction with treatment (p = 0.029 and p < 0.001); lower CCR7 expression was associated with objective response (odds ratio: 0.1; 95% CI: 0.01–1.0) and longer overall survival (hazard ratio: 3.9; 95% CI: 1.4–10.3). Conclusion: CCR7, CXCR4 and TLR3 expression levels may be prognostic/predictive of clinical benefit with axitinib. Clinical trial identifier: ClinicalTrials.gov NCT00678392.

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Outcomes in Clinically Relevant Patient Subgroups From the EMBRACA Study: Talazoparib vs Physician’s Choice Standard-of-Care Chemotherapy

JNCI Cancer Spectrum ◽

10.1093/jncics/pkz085 ◽

2019 ◽

Vol 4 (1) ◽

Cited By ~ 1

Author(s):

Hope S Rugo ◽

Johannes Ettl ◽

Sara A Hurvitz ◽

Anthony Gonçalves ◽

Kyung-Hun Lee ◽

...

Keyword(s):

Breast Cancer ◽

Confidence Interval ◽

Clinical Benefit ◽

Odds Ratio ◽

Objective Response ◽

Progression Free Survival ◽

Hazard Ratio ◽

Free Survival ◽

Duration Of Response ◽

Patient Subgroups

Abstract Background Talazoparib is a poly(adenosine diphosphate-ribose) polymerase inhibitor that causes death in cells with breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations. Methods EMBRACA (NCT01945775) was a randomized phase III study comparing efficacy, safety, and patient-reported outcomes (PROs) of talazoparib (1 mg) with physician’s choice of chemotherapy (PCT: capecitabine, eribulin, gemcitabine, vinorelbine) in locally advanced or metastatic breast cancer with a germline BRCA1/2 (gBRCA1/2) mutation. Prespecified patient subgroups were analyzed for progression-free survival, objective response, clinical benefit, duration of response, and safety. PROs were evaluated in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) or triple-negative breast cancer (TNBC) subgroups. Results Of 431 patients, 287 were randomly assigned to talazoparib and 144 to PCT. Prespecified subgroup analyses showed prolonged progression-free survival with talazoparib (HR+/HER2−: hazard ratio = 0.47, 95% confidence interval = 0.32 to 0.71; TNBC: hazard ratio = 0.60, 95% confidence interval = 0.41 to 0.87) and greater objective response rate (odds ratio = 1.97 to 11.89), clinical benefit rate (odds ratio = 2.05 to 7.77), and duration of response with talazoparib in all subgroups. PROs in HR+/HER2− and TNBC subgroups showed consistent overall improvement and delay in time to definitive clinically meaningful deterioration with talazoparib vs PCT. Across subgroups, common adverse events included anemia, fatigue, and nausea with talazoparib and neutropenia, fatigue, and nausea with PCT. Seven patients (2.4%) receiving talazoparib had grade II alopecia and 22.7% had grade I alopecia. Conclusions Across all patient subgroups with gBRCA-mutated advanced breast cancer, talazoparib demonstrated clinically significant superiority in outcomes compared with PCT.

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Effects of apatinib dose interruptions on safety and efficacy in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of stomach or gastroesophageal junction in third- or later-line setting.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.142 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 142-142

Author(s):

Junsheng Wang ◽

Shukui Qin ◽

Jin Li ◽

Wenying Deng ◽

Lu Wen ◽

...

Keyword(s):

Gastric Cancer ◽

Clinical Trial ◽

Advanced Gastric Cancer ◽

Gastroesophageal Junction ◽

Objective Response ◽

Progression Free Survival ◽

Hazard Ratio ◽

Safety And Efficacy ◽

Optimal Dosing ◽

Line Setting

142 Background: Apatinib, a small molecule VEGFR TKI, has been approved in the treatment of advanced gastric cancer in China. Due to toxicity, many pts underwent temporary interruptions during treatment. We analyzed the data from a phase IV clinical trial of Ahead-G201 to evaluate the relationship between dose interruption, drug safety and efficacy. Methods: At the cutoff date of Jul 10, 2017, Ahead-G201 study enrolled 1037 pts. The adverse events (AEs) and clinical efficacy were evaluated for pts with no, 1, 2 and ≥3 dose interruptions. Results: 336 of 1037 pts underwent dose interruptions during apatinib treatment: 1 interruption in 183 pts; 2 interruptions in 67 pts; and ≥3 interruptions in 86 pts. The toxicity and efficacy for them were listed in Table. For safety, pts with no interruption had the lowest incidence of all AEs (59.3%) and grade 3-4 AEs (30.0%). Pts with ≥3 interruptions had the highest objective response rate (ORR, 20.3%) and disease control rate (DCR, 82.6%). Moreover, these pts got median progression-free survival (mPFS) of 6.6 mos and median overall survival (mOS) of 9.4 mos, which were the longest among 4 groups. Furthermore, multivariate analysis revealed that ≥3 interruptions of apatinib bring much more efficacy benefit both in mPFS (6.6 vs 3.8 mos: hazard ratio, 0.5, 95%CI, 0.3 to 0.7) and mOS (9.4 vs 6.6 mos: hazard ratio, 0.5, 95%CI, 0.3 to 0.8) for pts, than those with no interruption. Conclusions: Current results indicated that dose interruptions are required to manage toxicity and it is necessary to explore an optimal dosing pattern of apatinib in advanced gastric cancer. Clinical trial information: NCT02426034. [Table: see text]

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Clinicopathologic and genomic correlates of tumor-infiltrating immune cells and immunotherapy efficacy in NSCLC.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9121 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9121-9121

Author(s):

Joao Victor Machado Alessi ◽

Biagio Ricciuti ◽

Mizuki Nishino ◽

Jason L. Weirather ◽

Ann-Elisabeth Le ◽

...

Keyword(s):

Immune Cells ◽

Checkpoint Inhibitors ◽

Performance Status ◽

Recursive Partitioning ◽

Objective Response ◽

Progression Free Survival ◽

Clinicopathological Characteristics ◽

Free Survival ◽

Oncogenic Driver ◽

Optimal Cluster

9121 Background: Tumor-infiltrating immune cells and PD-L1 expression are associated with improved clinical outcomes in patients (pts) with NSCLC treated with immune checkpoint inhibitors (ICIs). However, as tumor-infiltrating immune cells are not a well-established biomarker for NSCLC, further data are needed to integrate and identify clinicopathological and genomic factors that influence the tumor microenvironment. Methods: We collected clinicopathologic and genomic data from pts with NSCLC who underwent multiplexed immunofluorescence. Uniform Manifold Approximation and Projection (UMAP) was used to identify distinct immunophenotypic clusters according to the number of intratumoral PD-1+ immune cells (ICs), CD8+, and Foxp3+ T cells, as well as PD-L1 on tumor and immune cells. An unbiased recursive partitioning (URP) algorithm was used to investigate an optimal cluster with respect to objective response rate (ORR) in the subset of pts treated with ICIs. Results: Among 304 pts, UMAP identified 5 clusters: PD-L1-high with high vs low CD8+ and PD-1+ ICs (clusters A & B, respectively); PD-L1-low with high vs low CD8+ and PD-1+ ICs (clusters C & D respectively); PD-L1-low and moderate levels of CD8+ and PD-1+ ICs (cluster E). Clinicopathological characteristics of the clusters shown in Table. URP analysis identified immune rich clusters A and C as optimal responders to ICIs. From the start of ICIs, we observed a significantly higher ORR (53.3% vs 4.3%; P<0.001), a significantly longer median progression-free survival (mPFS 25.6 vs 3.7 months; HR: 0.12 [95% CI: 0.05-0.32]; P<0.001), and longer median overall survival (mOS 45.1 vs 22.3 months; HR: 0.25 [95% CI: 0.1-0.68]; P=0.006) in clusters A + C (N=15) vs other clusters (N=23). After adjusting for other variables such as performance status, histology, presence of oncogenic driver mutation, and line of treatment, clusters A + C were significantly associated with improved mPFS (HR: 0.08 [95% CI: 0.03-0.24], P<0.001) and mOS (HR: 0.11 [95% CI: 0.03-0.40], P<0.001). Conclusions: Incorporation of multiplex immunofluorescence may improve prediction of response and resistance to immunotherapy in NSCLC.[Table: see text]

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Programmed Death-Ligand 1 Expression and Response to the Anti–Programmed Death 1 Antibody Pembrolizumab in Melanoma

Journal of Clinical Oncology ◽

10.1200/jco.2016.67.2477 ◽

2016 ◽

Vol 34 (34) ◽

pp. 4102-4109 ◽

Cited By ~ 310

Author(s):

Adil I. Daud ◽

Jedd D. Wolchok ◽

Caroline Robert ◽

Wen-Jen Hwu ◽

Jeffrey S. Weber ◽

...

Keyword(s):

Clinical Trial ◽

Objective Response Rate ◽

Response Rate ◽

Objective Response ◽

Progression Free Survival ◽

Hazard Ratio ◽

Tumor Biopsy ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

Programmed Death 1

Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti–programmed death 1 (PD-1). This study explored the relationship between anti–PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score ≥ 2 (membranous staining in ≥ 1% of cells) was considered positive. Results Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1–positive tumors. Demographic and staging variables were equally distributed among PD-L1–positive and –negative patients. An association between higher MEL score and higher response rate and longer PFS (hazard ratio, 0.76; 95% CI, 0.71 to 0.82) and OS (hazard ratio, 0.76; 95% CI, 0.69 to 0.83) was observed ( P < .001 for each). Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1–negative tumors may also achieve durable responses.

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Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance)

Journal of Clinical Oncology ◽

10.1200/jco.21.00286 ◽

2021 ◽

pp. JCO.21.00286

Author(s):

Jonathan E. Rosenberg ◽

Karla A. Ballman ◽

Susan Halabi ◽

Pamela J. Atherton ◽

Amir Mortazavi ◽

...

Keyword(s):

Urothelial Carcinoma ◽

Controlled Trial ◽

Objective Response ◽

Progression Free Survival ◽

Primary Objective ◽

Hazard Ratio ◽

Phase Iii ◽

Free Survival ◽

Metastatic Urothelial Carcinoma ◽

Gemcitabine And Cisplatin

PURPOSE The combination of gemcitabine and cisplatin (GC) is a standard therapy for metastatic urothelial carcinoma. Based on data that angiogenesis plays a role in urothelial carcinoma growth and progression, a randomized placebo-controlled trial was performed with the primary objective of testing whether patients treated with GC and bevacizumab (GCB) have superior overall survival (OS) than patients treated with GC and placebo (GCP). PATIENTS AND METHODS Between July 2009 and December 2014, 506 patients with metastatic urothelial carcinoma without prior chemotherapy for metastatic disease and no neoadjuvant or adjuvant chemotherapy within 12 months were randomly assigned to receive either GCB or GCP. The primary end point was OS, with secondary end points of progression-free survival, objective response, and toxicity. RESULTS With a median follow-up of 76.3 months among alive patients, the median OS was 14.5 months for patients treated with GCB and 14.3 months for patients treated with GCP (hazard ratio for death = 0.87; 95% CI, 0.72 to 1.05; two-sided stratified log-rank P = .14). The median progression-free survival was 8.0 months for GCB and 6.7 months for GCP (hazard ratio = 0.77; 95% CI, 0.63 to 0.95; P = .016). The proportion of patients with grade 3 or greater adverse events did not differ significantly between both arms, although increased bevacizumab-related toxicities such as hypertension and proteinuria occurred in the bevacizumab-treated arm. CONCLUSION The addition of bevacizumab to GC did not result in improved OS. The observed median OS of about 14 months is consistent with prior phase III trials of cisplatin-based chemotherapy.

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A Real-World Comparative Analysis of Lenvatinib and Sorafenib as a Salvage Therapy for Transarterial Treatments in Unresectable HCC

Journal of Clinical Medicine ◽

10.3390/jcm9124121 ◽

2020 ◽

Vol 9 (12) ◽

pp. 4121

Author(s):

Jaejun Lee ◽

Pil Soo Sung ◽

Hyun Yang ◽

Soon Kyu Lee ◽

Hee Chul Nam ◽

...

Keyword(s):

Confidence Interval ◽

Real World ◽

Salvage Therapy ◽

Objective Response ◽

Progression Free Survival ◽

Hazard Ratio ◽

Rank Test ◽

Multikinase Inhibitor ◽

Free Survival ◽

Sorafenib Group

Background/Aims: Lenvatinib was recently approved as a first-line oral multikinase inhibitor for unresectable hepatocellular carcinoma (HCC). In this study, we aimed to compare the efficacy and safety of lenvatinib and sorafenib for the treatment of unresectable HCC in patients with prior failure of transarterial treatment. Methods: Between January 2019 and September 2020, 98 unresectable HCC patients treated with lenvatinib or sorafenib as salvage therapy were enrolled from five Korean university-affiliated hospitals. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate were calculated to assess the antitumor response. Results: A total of 43 and 55 patients were treated with lenvatinib and sorafenib, respectively, as salvage therapy after the failure of transarterial treatments. The median PFS was 4.97 months in the lenvatinib group and 2.47 months in the sorafenib group (p = 0.001, log-rank test). The ORR was significantly higher in the lenvatinib group (25.6%) than in the sorafenib group (3.6%, p = 0.002). Use of lenvatinib over sorafenib (hazard ratio: 0.359, 95% confidence interval: 0.203–0.635, p < 0.001) was the most significant factor for a favorable PFS after the failure of transarterial treatments in all enrolled patients. For favorable OS, achieving objective response was the significant factor (hazard ratio 0.356, 95% confidence interval: 0.132–0.957, p = 0.041). There were no significant differences in the safety profile between the two groups. Conclusions: In this real-world study, lenvatinib was demonstrated to be more efficacious than sorafenib as a salvage therapy for transarterial treatments in unresectable HCC.

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Hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil, and oxaliplatin plus intravenous cetuximab (Cet) (Optiliv) after failure on one versus two or three chemotherapy protocols in patients (pts) with unresectable liver metastases from wt KRAS colorectal cancer (LM-CRC) (European phase II clinical trial NCT00852228).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3599 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3599-3599 ◽

Cited By ~ 3

Author(s):

Michel Ducreux ◽

Pasquale F. Innominato ◽

Mohamed Hebbar ◽

Denis Michel Smith ◽

Céline Lepère ◽

...

Keyword(s):

Clinical Trial ◽

Hepatic Artery ◽

Objective Response ◽

Progression Free Survival ◽

Hepatic Artery Infusion ◽

Free Survival ◽

Heavily Pretreated ◽

Unresectable Liver Metastases ◽

Grade 3 ◽

Line P

3599 Background: Optiliv allowed complete macroscopic resection (R0-R1) of previously unresectable LM-CRC in 28% of the pts, despite failure of 1-3 prior chemotherapy protocols (Lévi et al. Proc ASCO GI 2013). Purpose: To assess tolerability and efficacy of Optiliv according to previous chemotherapy exposure. Methods: Pts received iv Cet (500 mg/m²) and chronomodulated or conventional HAI of Irinotecan (180 mg/m²), 5-Fluorouracil (2800 mg/m²), and Oxaliplatin (85 mg/m²) q2 wks. Liver surgery was performed according to q6wks multidisciplinary reviews. Pts were categorized according to Optiliv as 2nd (N=29 pts) vs 3rd-4th chemotherapy line (N=35 pts). Results: Pt characteristics were similar in both groups. Overall, there were 22F and 42 M, aged 33-76 years, with good PS (0/1/2: 40/22/2) and predominantly liver lesions. LM-CRC were bilateral in 51 pts (79.7%), with a median of 10 metastases (1-50), 6 segments involved (1-8), and largest diameter of 52 mm (15-172). 61 pts (2nd line, 27; 3rd-4th line, 34) received a median of 6 courses (1-15). Grade 3-4 toxicities per pt were similar in both groups except for abdominal pain (2nd line, 15% vs 3rd-4th line, 35%, p=0.07), diarrhea (7% vs 24%, p=0.09), thrombocytopenia and febrile neutropenia (0 vs 9%, p=0.25). Four CR were achieved in 2nd line (15%) vs none in 3rd-4th line. Respective objective response rates were 63% and 38% (p=0.05). R0-R1 resections were performed in 11/27 pts (41%) on 2nd line vs 6/34 pts (18%) on 3rd-4th line (p=0.06), resulting in respective median progression-free survival (PFS) of 14.2 months [7.8 - 20.7] vs 7.3 [5.5 - 9.1] (p=0.002). Median overall survival (OS) was not reached at 3 years in the pts on Optiliv as 2nd line vs 15.2 months in the more heavily pretreated pts (p<0.001). Conclusions: Intravenous Cet and triplet hepatic artery infusion resulted in the doubling of secondary surgical resection rate of LM-CRC, PFS and OS in 2nd lineas compared to 3rd-4th line. Optiliv now deserves upfront testing. Clinical trial information: NCT00852228.

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Comparison between the outcome of metastatic RCC patients treated with sunitinib as part of clinical trials and matched nonparticipants receiving sutent as standard therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e15597 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e15597-e15597

Author(s):

Raanan Berger ◽

Maya Ish-Shalom ◽

Natalie Maimon ◽

Maya Gottfried ◽

Roberto Pili ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Standard Therapy ◽

Cox Regression ◽

Objective Response ◽

Progression Free Survival ◽

Trial Participation ◽

Clinical Trial Participation ◽

Free Survival ◽

Trial Participants

e15597 Background: Several studies have suggested the existence of a “trial effect”, in which for a given treatment, participation in a clinical trial is associated with a better outcome of cancer patients. The VEGFR inhibitor sunitinib is a standard treatment for mRCC. The effect of clinical trial participation on the outcome of sunitinib treatment in mRCC is poorly defined. Aims: To study the effect of clinical trial participation on outcome of mRCC patients treated with sunitinib. Methods: Records from 275 mRCC patients treated with sunitinib from 2004 to 2012 in 7 centers across 2 countries were reviewed. We compared the response rate, progression free survival, and overall survival, between clinical trial participants (n=49) and a matched cohort of non participants (n=49) who who received standard therapy. Each patient participating in a clinical trial was individually matched with a non participant by clinicopathologic factors. Progression free survival and overall survival were determined by Cox regression. Results: The groups were matched by age (median 64), gender (male 67%), Heng risk (favorable 24%, intermediate 60%, poor 16%), ECOG performance status (0-1 92%), prior nephrectomy (92%), renal cell carcinoma histology (clear cell 80%), sunitinib induced hypertension (56%), and sunitinib dose reduction/treatment interruption (41%). In clinical trial participants versus non participants, objective response was partial response/stable disease 80% (n=39) versus 73% (n=36), and progressive disease at first imaging evaluation within the first 3 months (mos) 20% (n=10) versus 27% (n=13) (p=0.63, OR 1.2). Median progression free survival was 10 versus 11 mos (HR=0.96, p=0.84), and median overall survival 23 versus 24 mos (HR=0.97, p=0.89). Conclusions: In mRCC patient treated with sunitinib, the outcome of clinical trial participants was similar to matched non participants who received standard therapy.

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Gemox chemotherapy in combination with anti-PD1 antibody toripalimab and lenvatinib as first-line treatment for advanced intrahepatic cholangiocarcinoma: A phase 2 clinical trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4094 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4094-4094

Author(s):

Zhou Jian ◽

Jia Fan ◽

Guo-Ming Shi ◽

Xiao-Yong Huang ◽

Dong Wu ◽

...

Keyword(s):

Clinical Trial ◽

Disease Progression ◽

Intrahepatic Cholangiocarcinoma ◽

Objective Response ◽

Locally Advanced ◽

Disease Free Survival ◽

Progression Free Survival ◽

Gastrointestinal Fistula ◽

Free Survival

4094 Background: The outcome of advanced intrahepatic cholangiocarcinoma (ICC) remains poor with current gemcitabine-based chemotherapy. This study is to evaluate the safety and efficacy of anti-PD1 agent toripalimab, lenvatinib in combination with oxaliplatin and gemcitabine (Gemox) chemotherapy. Methods: Locally advanced or metastatic ICC patients (pts) were given 240 mg toripalimab Q3W via intravenous (IV) infusion, 8 mg lenvatinib QD orally, and 1g/m² gemcitabine on Day 1 and Day 8, and 85 mg/m² oxaliplatin Q3W by IV for 6 cycles. The primary outcome was objective response rate (ORR), which was evaluated according to RECIST v1.1. Secondary outcomes included safety, progression-free survival (PFS) and overall survival (OS). Treatment would be terminated by confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. Whole exome sequencing was performed on available tumor tissues and PD-L1 expression was determined by immunohistochemistry staining. Results: From May 2019 to Oct 2019, 30 pathologically-confirmed advanced ICC pts with a mean age of 56.5 (range, 25-73) years, including 11 women (37%), were enrolled at Zhongshan Hospital, Fudan University (one pt withdrawn). At the end of last follow-up (February 1, 2021), the ORR was 80% (24/30; 95% CI: 61.4%-92.3%), and disease control rate (DCR) was 93.3% (28/30; 95% CI:77.9%-99.2%). Median follow-up was 16.6 months. One pt achieved complete response (CR). Three pts with locally advanced disease were down-staged and then underwent resection. They remained disease-free survival at the end of last follow-up. 23 pts experienced disease progression and 12 pts (including one pt withdrawn) have died. The median PFS was 10.0 months and median duration of response (DOR) was 9.8 months. The median OS have not been reached. 12-months OS rate was 73.3% (95% CI: 57.5%-89.2%). No grade 5 adverse event (AE) was observed in present study. Grade 3 or 4 neutropenia and thrombocytopenia observed in 3 (10%) and 1 (3.3%) patient, respectively. Non-hematological toxic effects were jaundice (10 %), rash (6.7 %), proteinuria (6.7 %), increased AST level (3.3%), vomiting (3.3%), upper gastrointestinal hemorrhage (3.3%), sepsis (3.3%), gastrointestinal fistula (3.3%), adrenocortical insufficiency (3.3%), interstitial pneumonia (3.3%), and hyponatremia (3.3%). High ORR was significantly associated with positive PD-L1 expression ( p= 0.048) and DNA damage repair (DDR)-related mutations ( p= 0.022) in tumor samples. Conclusions: Gemox chemotherapy in combination with Anti-PD1 antibody Toripalimab and Lenvatinib provided remarkable efficacy with reasonable tolerability in advanced ICC patients. These findings warrant further validation in a large randomized clinical trial. Clinical trial information: NCT03951597.

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