Tislelizumab plus cisplatin/carboplatin and gemcitabine versus placebo plus cisplatin/carboplatin and gemcitabine in Chinese patients with advanced urothelial carcinoma: A phase III trial in progress.

TPS588 Background: Platinum-based chemotherapy is standard first-line treatment for patients with advanced urothelial carcinoma (UC). Checkpoint inhibitors (ie, anti-PD-1 antibodies) are first-line treatment options for cisplatin-ineligible patients. Combining anti-PD-1 treatment with chemotherapy may have synergistic effects and has demonstrated antitumor activity in a variety of tumor types. Tislelizumab, an investigational monoclonal antibody with high affinity and specificity for PD-1, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports showed tislelizumab, as a single agent or combined with chemotherapy, was generally well tolerated and had antitumor activity in patients with advanced UC. Methods: This phase 3, randomized, double-blind, placebo-controlled study (NCT03967977) will compare the efficacy and safety/tolerability of tislelizumab vs placebo, both in combination with cisplatin/carboplatin and gemcitabine. Adult Chinese patients (n≈420) with histologically confirmed, inoperable, locally advanced/metastatic UC who are eligible for (but have not received) systemic anticancer therapy for advanced UC, therapies targeting PD-1/L1, or other antibody/drug targeting T-cell costimulation or checkpoint pathways, will be randomized 1:1 to receive tislelizumab (200 mg Q3W) or placebo (Q3W) plus gemcitabine (1000 mg/m2 administered on Day 1 and 8 of each 3-week cycle) and cisplatin (70 mg/m2) or carboplatin (AUC 4.5) administered on Day 1 or 2 of each 3-week cycle. Patients must provide a fresh biopsy or archival tissue for central assessment of PD-L1 expression. Overall survival (OS) is the primary endpoint. Investigator-assessed overall response rate (RECIST v1.1), duration of response, progression-free survival, and OS rates at Year 1 and 2 are secondary endpoints. Safety/tolerability, assessed by monitoring incidence and severity of adverse events, and health-related quality-of-life measures will also be evaluated. Clinical trial information: NCT03967977.

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Gemcitabine and docetaxel as first-line treatment for advanced urothelial carcinoma: A phase II study

Urologic Oncology Seminars and Original Investigations ◽

10.1016/j.urolonc.2005.06.013 ◽

2005 ◽

Vol 23 (5) ◽

pp. 381-382

Author(s):

Donald L. Trump

Keyword(s):

Urothelial Carcinoma ◽

Phase Ii ◽

Phase Ii Study ◽

Line Treatment ◽

First Line ◽

Advanced Urothelial Carcinoma ◽

First Line Treatment

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First-line chemotherapy with gemcitabine, etoposide, and cisplatin in combined-multimodality treatment for patients with advanced urothelial carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.262 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 262-262

Author(s):

Shinji Urakami ◽

Junji Yonese ◽

Yasuhisa Fujii ◽

Shinya Yamamoto ◽

Takeshi Yuasa ◽

...

Keyword(s):

Prognostic Factors ◽

Bone Metastasis ◽

Urothelial Carcinoma ◽

Multimodality Treatment ◽

Cancer Site ◽

Line Treatment ◽

First Line ◽

Advanced Urothelial Carcinoma ◽

Line Chemotherapy ◽

First Line Treatment

262 Background: We had previously reported the phase I/II study of a combination regimen of gemcitabine, etoposide, and cisplatin (GEP) in second-line treatment for patients with advanced UC. This study sought to examine the combination chemotherapy of GEP as first-line treatment for advanced urothelial carcinoma (UC) to assess efficacy, feasibility, prognostic factors, and the impact of postchemotherapy surgery on outcomes. Methods: Forty-two patients were treated with GEP as first-line treatment for metastatic or unresectable locally advanced UC. GEP was recycled every 4 weeks. Etoposide and cisplatin were given on days 1 through 3 at doses of 60 mg/m2 and 20 mg/m2, respectively, and gemcitabine was given on days 1, 8, and 15 at a dose of 800 mg/m2. Results: The median patient age was 64 years. Twenty-three male patients and 19 female patients were included. The primary cancer site is urinary bladder in 21 patients, and upper urinary tract in 21 patients. Nineteen had visceral/bone metastases, 16 had disease restricted to lymph nodes, and the remaining 7 had unresectable disease at primary site. The median number of GEP courses was 4. Thirty of 42 assessable patients (71.4%) demonstrated objective responses. At a median follow-up of 14.6 months, the median overall survival time (OS) was 16.2 months. Twenty-four of 30 responders underwent postchemotherapy surgeries. Median OS in the patients with postchemotherapy surgery was 25.4 months. In the multivariable analysis, anemia and visceral/bone metastasis were significant pretreatment prognostic factors for OS. In addition, being male and anemic were independent poor prognostic factors in patients with postchemotherapy surgery. Grade 3-4 neutropenia, anemia and thrombocytopenia occurred in 84%, 73% and 57%. There were no treatment-related deaths. Conclusions: GEP as first-line chemotherapy in combined-multimodality treatment is active and moderately tolerable for advanced UC. Postchemotherapy surgery may yield favorable outcomes in patients who achieved objective responses. Anemia and visceral/bone metastasis were independent pretreatment predictors for OS.

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Tislelizumab, an investigational anti-PD-1 antibody, combined with chemotherapy as first-line treatment for lung cancer in Chinese patients.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14067 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14067-e14067 ◽

Cited By ~ 1

Author(s):

Jie Wang ◽

Jun Zhao ◽

Zhijie Wang ◽

Zhiyong Ma ◽

Jiuwei Cui ◽

...

Keyword(s):

Lung Cancer ◽

Clinical Trial ◽

Antitumor Activity ◽

Standard Of Care ◽

Chinese Patients ◽

Advanced Lung Cancer ◽

Line Treatment ◽

First Line ◽

Cell Clearance ◽

First Line Treatment

e14067 Background: Tislelizumab, an investigational anti-PD-1 antibody, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports showed tislelizumab was generally well tolerated and had antitumor activity in patients (pts) with advanced solid tumors; 200 mg IV Q3W was established as the RP2D. Methods: This phase 2 clinical trial (NCT03432598) assessed tislelizumab (200 mg Q3W) with platinum (plt)-based chemotherapy (Q3W) as first-line treatment for Chinese pts with advanced lung cancer. All pts received tislelizumab + plt doublet (4–6 cycles) until disease progression. Nonsquamous (nsq) NSCLC pts received pemetrexed (PMX) + plt (4 cycles) followed by PMX maintenance; squamous (sq) NSCLC pts received A) paclitaxel (PXL) + plt or B) gemcitabine + plt; SCLC pts received etoposide + plt. Tumor response (RECIST v1.1) and safety/tolerability were evaluated. PD-L1 expression was retrospectively assessed with the VENTANA PD-L1 (SP263) assay. Results: As of 15 Oct 2018, 54 pts (median age 61 yr; 74% male; 72% current/former smokers; 31% with ≥10% PD-L1 expression on tumor cells) received tislelizumab; 24 pts remain on treatment. Confirmed PR was observed in 36 pts and most occurred within the first 2 assessments. Other efficacy estimates (eg, PFS) are maturing. Grade ≥3 AEs occurring in > 15% of pts were decreased neutrophil counts (n = 25) and anemia (n = 9); immune-related AEs occurring in ≥2 pts were decreased triiodothyronine, hyperthyroidism, hypothyroidism, and pyrexia (n = 2 each). One sq-NSCLC pt ( A) experienced fatal myocarditis/myositis after 1 cycle; other AEs resolved with tislelizumab interruption (n = 30), discontinuation (n = 4), or other appropriate treatment. Conclusions: Tislelizumab in combination with standard of care plt-based chemotherapy was generally well tolerated and demonstrated antitumor activity. Clinical trial information: NCT03432598. [Table: see text]

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ENGOT-OV43/KEYLYNK-001: A phase III, randomized, double-blind, active- and placebo-controlled study of pembrolizumab plus chemotherapy with olaparib maintenance for first-line treatment of BRCA-nonmutated advanced epithelial ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.tps5603 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. TPS5603-TPS5603 ◽

Cited By ~ 1

Author(s):

Ignace Vergote ◽

Jalid Sehouli ◽

Vanda Salutari ◽

Paolo Zola ◽

Radoslaw Madry ◽

...

Keyword(s):

Ovarian Cancer ◽

Residual Tumor ◽

Phase Iii ◽

Controlled Study ◽

Concomitant Treatment ◽

Line Treatment ◽

First Line ◽

Double Blind ◽

Recist 1.1 ◽

First Line Treatment

TPS5603 Background: There is a significant unmet need to develop new regimens for BRCA1/2-nonmutated advanced ovarian cancer (OC). The PARP inhibitor olaparib is approved for women with platinum-sensitive, recurrent OC regardless of BRCA1/2 status and, more recently, for newly diagnosed women with BRCA-mutated OC. In the TOPACIO/KEYNOTE-162 study, the combination of the PD-1–blocking antibody pembrolizumab (pembro) and niraparib demonstrated efficacy in platinum-resistant relapsed OCirrespective of BRCA1/2 status. ENGOT-OV43/KEYLYNK-001 (ClinicalTrials.gov, NCT03740165) is a phase 3, randomized, double-blind, active- and placebo-controlled study of pembro plus paclitaxel-carboplatin chemotherapy (CT) followed by olaparib maintenance for first-line treatment of patients with BRCA1/2-nonmutated advanced epithelial OC (EOC). Methods: Patients with stage III or IV BRCA-nonmutated EOC, primary peritoneal cancer, or fallopian tube cancer will be stratified by surgery status (no residual tumor after primary debulking surgery [PDS], residual tumor after PDS, or planned interval debulking), bevacizumab use, and PD-L1 status (combined positive score < 10 or ≥10). After one lead-in cycle of CT, patients will be randomized 1:1:1 to receive: CT + pembro followed by olaparib maintenance; CT + pembro followed by placebo; or CT + placebo followed by placebo. The CT regimen will be administered for 5 cycles, and pembro 200 mg Q3W will be administered for 35 infusions. Olaparib 300 mg BID maintenance therapy will start after the end of CT as concomitant treatment with pembro until discontinuation or for 2 years if the patient has a complete response. Bevacizumab use is permitted at investigator’s discretion and determined prerandomization. Primary endpoints are investigator-assessed progression-free survival (PFS) per RECIST 1.1 criteria and overall survival. Key secondary endpoints are PFS per RECIST 1.1 assessed by blinded independent central review, PFS after next-line treatment, and safety. Enrollment is currently ongoing. Clinical trial information: NCT03740165.

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Clinical evidence for the first-line treatment of advanced urothelial carcinoma: Current paradigms and emerging treatment options

Cancer Treatment Reviews ◽

10.1016/j.ctrv.2020.102072 ◽

2020 ◽

Vol 89 ◽

pp. 102072 ◽

Cited By ~ 1

Author(s):

Maria Koufopoulou ◽

Paulo A.P. Miranda ◽

Paulina Kazmierska ◽

Sohan Deshpande ◽

Priyanka Gaitonde

Keyword(s):

Urothelial Carcinoma ◽

Clinical Evidence ◽

Treatment Options ◽

Line Treatment ◽

First Line ◽

Advanced Urothelial Carcinoma ◽

First Line Treatment

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Bevacizumab biosimilar LY01008 compared with bevacizumab (Avastin) as first‐line treatment for Chinese patients with unresectable, metastatic, or recurrent non‐squamous non–small‐cell lung cancer: A multicenter, randomized, double‐blinded, phase III trial

Cancer Communications ◽

10.1002/cac2.12179 ◽

2021 ◽

Author(s):

Yuankai Shi ◽

Kaijian Lei ◽

Yuming Jia ◽

Bingqiang Ni ◽

Zhiyong He ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell ◽

Phase Iii ◽

Chinese Patients ◽

Line Treatment ◽

Small Cell Lung ◽

First Line ◽

Phase Iii Trial ◽

Double Blinded ◽

First Line Treatment

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Lapatinib as first-line treatment for muscle-invasive urothelial carcinoma in dogs

Scientific Reports ◽

10.1038/s41598-021-04229-0 ◽

2022 ◽

Vol 12 (1) ◽

Author(s):

Shingo Maeda ◽

Kosei Sakai ◽

Kenjiro Kaji ◽

Aki Iio ◽

Maho Nakazawa ◽

...

Keyword(s):

Urothelial Carcinoma ◽

Kinase Inhibitor ◽

Phase Iii ◽

Her2 Overexpression ◽

Line Treatment ◽

First Line ◽

Her2 Positive ◽

Durable Response ◽

Muscle Invasive ◽

First Line Treatment

AbstractEpidermal growth factor receptors 1 and 2 (EGFR and HER2) are frequently overexpressed in various malignancies. Lapatinib is a dual tyrosine kinase inhibitor that inhibits both EGFR and HER2. Although a phase III trial failed to show the survival benefits of lapatinib treatment after first-line chemotherapy in patients with EGFR/HER2-positive metastatic urothelial carcinoma, the efficacy of lapatinib for untreated urothelial carcinoma is not well defined. Here, we describe the therapeutic efficacy of lapatinib as a first-line treatment in a canine model of muscle-invasive urothelial carcinoma. In this non-randomized clinical trial, we compared 44 dogs with naturally occurring urothelial carcinoma who received lapatinib and piroxicam, with 42 age-, sex-, and tumor stage-matched dogs that received piroxicam alone. Compared to the dogs treated with piroxicam alone, those administered the lapatinib/piroxicam treatment had a greater reduction in the size of the primary tumor and improved survival. Exploratory analyses showed that HER2 overexpression was associated with response and survival in dogs treated with lapatinib. Our study suggests that lapatinib showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use for untreated advanced urothelial carcinoma in dogs. The use of lapatinib as a first-line treatment may be investigated further in human patients with urothelial carcinoma.

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