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

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Shingo Maeda ◽  
Kosei Sakai ◽  
Kenjiro Kaji ◽  
Aki Iio ◽  
Maho Nakazawa ◽  
...  

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.

Author(s):  
Rupert Bartsch

SummaryOne year into the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic, the 2020 San Antonio Breast Cancer Symposium (SABCS) was another large congress held in a virtual format. Despite these circumstances, clinically relevant data were presented, and this short review focuses on developments in the fields of triple-negative breast cancer (TNBC) and metastatic HER2-positive breast cancer. A quality-of-life (QoL) analysis from IMPassion031 showed that adding atezolizumab to neoadjuvant chemotherapy was not associated with a detrimental effect on QoL, while the burden of treatment-induced side effects increased with each cycle of neoadjuvant therapy in both treatment arms. KEYNOTE-355 evaluated the addition of pembrolizumab to chemotherapy as first-line treatment in metastatic TNBC (mTNBC); a significant improvement of progression-free survival (PFS) was reported in the pembrolizumab arm. At the 2020 SABCS, results with respect to different chemotherapy backbones were reported and the benefit of pembrolizumab was maintained irrespective of the type of taxane. Disappointingly, the phase III IPATunity130 study could not confirm a PFS improvement with the AKT inhibitor ipatasertib when added to paclitaxel as first-line treatment in mTNBC. A biomarker analysis from the phase III ASCENT study showed that the antibody–drug conjugate sacituzumab govitecan was superior to chemotherapy by investigator’s choice independent of Trop‑2 expression and BRCA mutation status. In HER2-positive breast cancer, the PRECIOUS trial suggested a small albeit significant benefit with reinduction of pertuzumab in later treatment lines in patients progressing on prior dual HER2-blockade in the first- or second-line setting. The HER2-specific tyrosine kinase inhibitor tucatinib when added to trastuzumab and capecitabine was shown to improve PFS and overall survival (OS) over trastuzumab and capecitabine alone in pretreated patients in the randomized HER2CLIMB trial; this benefit was apparently independent of hormone-receptor expression. An update from the DESTINY-Breast01 trial reported a median PFS of 19.4 months with trastuzumab deruxtecan in heavily pretreated patients. Finally, an analysis from the PERTAIN trial with > 6 years median follow-up showed excellent OS in patients with luminal B/HER2-positive receiving first-line trastuzumab/pertuzumab in combination with endocrine therapy suggesting that chemotherapy-free treatment is an option in highly selected patients.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21040-e21040
Author(s):  
Qiming Wang ◽  
Xiuli Yang ◽  
Tianjiang Ma ◽  
Qiumin Yang ◽  
Chenghui Zhang ◽  
...  

e21040 Background: The anti-angiogenic drug bevacizumab combined with chemotherapy has achieved positive results in previous studies. In particular, the median progression-free survival (PFS) for EGFR-negative patients was increased to 8.3 months in the BEYOND study. Unlike bevacizumab, anlotinib is a novel multitarget tyrosine kinase inhibitor and can be conveniently orally administered. In the phase III trial ALTER 0303, anlotinib significantly improved overall survival (OS) and PFS in advanced NSCLC patients. This exploratory study aims to establish the efficacy and safety of anlotinib in combination with pemetrexed and carboplatin as first-line treatment in advanced non-squamous NSCLC. Methods: This is a multi-center, single-arm clinical trial. Adults with treatment-naive, histologically confirmed stage IIIB-IV non-squamous NSCLC, ECOG 0-1, and without known sensitizing EGFR/ALK alterations are included. Patients received anlotinib (12 mg p.o., QD, d1 to 14, 21 days per cycle) combined with pemetrexed (500 mg/m2, iv, d15-21, Q3W) + carboplatin (AUC = 5, iv, d15-21, Q3W) for 4 cycles followed by anlotinib and pemetrexed maintenance until disease progression (PD). The primary endpoint was PFS. Secondary endpoints were OS, objective response rate (ORR), disease control rate (DCR) and safety. Results: Between Mar 2019 and Dec 2020, 40 patients were enrolled in six centers and 31 of them have received at least one tumor assessment. Median age was 62 (33, 75); 66.7% male, 11.1% brain metastasis. At data cutoff (Dec 31, 2020), patients were followed up for a median of 8.26 months. Median PFS was 10.5 months (95% CI: NE, NE); ORR was 67.7% (0 CR, 21 PR), DCR was 96.8% (0 CR, 21 PR, 9 SD) and median OS was NE. The most common Grade ≥ 3 AEs were hypertension 22.2%, neutropenia 19.44%, myelosuppression 11.1%, thrombocytopenia 8.33%, leukopenia 5.56%, hand-foot syndrome 5.56% and there were no Grade 5 toxicities. Conclusions: This study finds that anlotinib plus pemetrexed and carboplatin can significantly improve PFS and ORR compared to standard chemotherapy for treatment-naive non-squamous NSCLC patients. The combination was well tolerated, and the AEs were manageable. The follow-up time is not sufficient, and the OS outcomes need further evaluation. Clinical trial information: NCT03790228.


2021 ◽  
Vol 13 ◽  
pp. 175883592110196
Author(s):  
Paula Jimenez-Fonseca ◽  
Alberto Carmona-Bayonas ◽  
Alba Martinez-Torron ◽  
Maria Alsina ◽  
Ana Custodio ◽  
...  

Background: Trastuzumab combined with cisplatin and fluoropyrimidines, either capecitabine or 5-fluorouracile (XP/FP), is the standard first-line treatment for advanced, HER2-positive, gastric cancer patients based on the ToGA trial. Despite the lack of phase III trials, many clinicians administer trastuzumab with alternative regimens. One meta-analysis suggests that substituting cisplatin for oxaliplatin might lead to greater efficacy and less toxicity. Methods: 594 patients with HER2-positive gastroesophageal adenocarcinoma were recruited from the AGAMENON-SEOM registry. The objective was to evaluate the external validity of clinical trials with chemotherapy and trastuzumab. Results: The regimens used in at least 5% of the patients were XP (27%), oxaliplatin and capecitabine (CAPOX) (26%), oxaliplatin and 5-fluorouracil (FOLFOX) (14%), FP (14%), triplet with anthracycline/docetaxel (7%), and carboplatin-FU (5%). Median exposure to trastuzumab was longer with FOLFOX (11.4 months, 95% CI, 9.1–21.0) versus ToGA regimens (7.5, 6.4–8.5), p < 0.001. Patients with HER2-IHC 3+ cancers had higher response rates than those with IHC 2+/FISH+, odds-ratio 1.97 (95% CI, 1.25–3.09). The results achieved with CAPOX–trastuzumab were comparable to those attained with ToGA regimens. FOLFOX–trastuzumab was superior to ToGA schemes in terms of overall survival (OS), with a greater magnitude of effect in IHC 2+/FISH+ tumors (HR 0.47, 0.24–0.92) compared with IHC 3+ (HR 0.69, 0.49–0.96), and in diffuse (HR 0.37, 0.20–0.69) versus intestinal-type tumors (HR 0.76, 0.54–1.06). Conclusion: We have updated the external validity of clinical trials with trastuzumab in first-line treatment of gastric cancer. Our data confirm the comparable outcomes of ToGA regimens and CAPOX–trastuzumab in clinical practice and point toward a possible benefit of FOLFOX–trastuzumab, contingent on the subtypes typically less sensitive to trastuzumab, to be confirmed in clinical trials.


2012 ◽  
Vol 30 (29) ◽  
pp. 3588-3595 ◽  
Author(s):  
Hans-Joachim Schmoll ◽  
David Cunningham ◽  
Alberto Sobrero ◽  
Christos S. Karapetis ◽  
Philippe Rougier ◽  
...  

Purpose To compare the efficacy of cediranib (a vascular endothelial growth factor receptor tyrosine kinase inhibitor [VEGFR TKI]) with that of bevacizumab (anti–VEGF-A monoclonal antibody) in combination with chemotherapy as first-line treatment for advanced metastatic colorectal cancer (mCRC). Patients and Methods HORIZON III [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer] had an adaptive phase II/III design. Patients randomly assigned 1:1:1 received mFOLFOX6 [oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 intravenously followed by fluorouracil 400 mg/m2 intravenously on day 1 and then continuous infusion of 2,400 mg/m2 over the next 46 hours every 2 weeks] with cediranib (20 or 30 mg per day) or bevacizumab (5 mg/kg every 14 days). An independent end-of-phase II analysis concluded that mFOLFOX6/cediranib 20 mg met predefined criteria for continuation; subsequent patients received mFOLFOX6/cediranib 20 mg or mFOLFOX6/bevacizumab (randomly assigned 1:1). The primary objective was to compare progression-free survival (PFS). Results In all, 1,422 patients received mFOLFOX6/cediranib 20 mg (n = 709) or mFOLFOX6/bevacizumab (n = 713). Primary analysis revealed no significant difference between arms for PFS (hazard ratio [HR], 1.10; 95% CI, 0.97 to 1.25; P = .119), overall survival (OS; HR, 0.95; 95% CI, 0.82 to 1.10; P = .541), or overall response rate (46.3% v 47.3%). Median PFS and OS were 9.9 and 22.8 months for mFOLFOX6/cediranib and 10.3 and 21.3 months for mFOLFOX6/bevacizumab. The PFS upper 95% CI was outside the predefined noninferiority limit (HR < 1.2). Common adverse events with more than 5% incidence in the cediranib arm included diarrhea, neutropenia, and hypertension. Cediranib-treated patients completed fewer chemotherapy cycles than bevacizumab-treated patients (median 10 v 12 cycles). Patient-reported outcomes (PROs) were significantly less favorable in cediranib-treated versus bevacizumab-treated patients (P < .001). Conclusion Cediranib activity, in terms of PFS and OS, was comparable to that of bevacizumab when added to mFOLFOX6; however, the predefined boundary for PFS noninferiority was not met. The cediranib safety profile was consistent with previous studies but led to less favorable PROs compared with bevacizumab. Investigation of oral TKIs in CRC continues.


2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS588-TPS588
Author(s):  
Feng BI ◽  
Han-Zhong Li ◽  
Shaoxing Zhu ◽  
Qing Zou ◽  
Jia Tang ◽  
...  

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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