Tisotumab vedotin versus investigator’s choice chemotherapy in second- or third-line recurrent or metastatic cervical cancer (innovaTV 301/ENGOT-cx12/GOG 3057, trial in progress).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5596-TPS5596
Author(s):  
Ignace Vergote ◽  
Bradley J. Monk ◽  
Robert L. Coleman ◽  
Leslie M. Randall ◽  
Keiichi Fujiwara ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Cervical Cancer ◽  
Cell Death ◽  
Disease Progression ◽  
Treatment Options ◽  
Human Monoclonal Antibody ◽  
Objective Response ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

TPS5596 Background: Doublet chemotherapy (paclitaxel plus either platinum or topotecan) with bevacizumab (if eligible) is recommended for first-line treatment of recurrent (not amenable to curative therapy) or metastatic cervical cancer (r/mCC; Tewari 2014). In the second-line setting, there are limited data for currently available treatment options. Tisotumab vedotin (TV) is an investigational antibody-drug conjugate (ADC) composed of a tissue factor (TF)-directed human monoclonal antibody covalently linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. TV is directed to cells expressing TF and releases MMAE upon internalization, resulting in cell cycle arrest and apoptotic cell death. TV has anti-tumor activity on multiple tumor types and kills tumor cells by direct cytotoxicity, bystander cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and in a manner consistent with immunogenic cell death. In a recent phase 2 pivotal trial (innovaTV 204), TV demonstrated a clinically meaningful objective response rate (ORR) of 24% and median duration of response (DOR) of 8.3 months, as well as a manageable and tolerable safety profile with most adverse events being mild to moderate, in r/mCC patients with disease progression on or after chemotherapy. These findings support further investigation of TV in patients with r/mCC who progress on available first-line treatment options. Methods: The innovaTV 301 trial (NCT04697628) is a global, randomized, open-label, phase 3 clinical trial evaluating the efficacy and safety of TV in patients with previously treated r/mCC. Eligible patients must be ≥18 years, have r/mCC, and have experienced disease progression after receiving 1-2 prior lines of therapy (either standard of care systemic chemotherapy doublet or platinum-based therapy [if eligible; paclitaxel+cisplatin+bevacizumab, paclitaxel+carboplatin+bevacizumab, or paclitaxel+topotecan/nogitecan+bevacizumab]). Approximately 482 patients will be randomized 1:1 to receive 21-day cycles of either TV (2.0 mg/kg IV once every 3 weeks) or investigator’s choice of chemotherapy: topotecan (1 or 1.25 mg/m2 IV; Day 1 [D1] to D5 of each cycle), vinorelbine (30 mg/m2 IV; D1 and D8 of each cycle), gemcitabine (1000 mg/m2 IV; D1 and D8 of each cycle), irinotecan (100 or 125 mg/m2 IV; weekly for 28days, then every 42 days), or pemetrexed (500 mg/m2 IV, D1 of each cycle). The primary endpoint of this trial is overall survival. Key secondary endpoints are progression-free survival, ORR, time to response, DOR, safety, and quality of life outcomes. The study is currently enrolling and will have sites open in the US, EU, Japan, Latin America, Taiwan, Singapore, and South Korea. Clinical trial information: NCT04697628.

Anlotinib combined with pemetrexed and carboplatin as first-line treatment in advanced nonsquamous non-small cell lung cancer (NSCLC): ALTER L012.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21040-e21040
Author(s):  
Qiming Wang ◽  
Xiuli Yang ◽  
Tianjiang Ma ◽  
Qiumin Yang ◽  
Chenghui Zhang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Treatment Naïve ◽  
Nsclc Patients ◽  
First Line Treatment

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.

Cetuximab metastatic colorectal cancer strategy (ERMES) study: A phase III randomized two arm study with FOLFIRI + cetuximab until disease progression compared to FOLFIRI + cetuximab for 8 cycles followed by cetuximab alone until disease progression in first-line treatment of patients with RAS and BRAF wild type metastatic colorectal cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. TPS810-TPS810 ◽  
Author(s):  
Carmine Pinto ◽  
Nicola Normanno ◽  
Armando Orlandi ◽  
Evaristo Maiello ◽  
Domenico Bilancia ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Disease Progression ◽  
Objective Response ◽  
Phase Iii ◽  
Type I ◽  
Line Treatment ◽  
First Line ◽  
Primary Endpoints ◽  
First Line Treatment

TPS810 Background: The optimal duration and content of first-line therapy in mCRC pts once they have achieved objective response is controversial. In the FIRE-3 trial, ETS was significantly associated with PFS and OS. Based on this evidence it can be hypothesized that once this goal has been achieved, further exposure to combined antineoplastic treatment may not result in improvement or preservation of such result but only in an increase of toxicity. We designed a strategy study to compare FOLFIRI + cetuximab until PD to FOLFIRI + cetuximab for 8 cycles followed by cetuximab alone until PD in first line treatment of RAS/BRAF WT mCRC pts. Methods: This is a multicenter, open-label, randomized phase III trial. Untreated and unresecteble RAS/BRAF WT mCRC pts were randomized 1:1 to receive Cetuximab (400 mg/mq w1 and then 250 mg/mq weekly) + FOLFIRI until PD (standard arm) or Cetuximab (400 mg/mq week 1 and then 250 mg/mq weekly) + FOLFIRI for 8 cycles followed by Cetuximab monotherapy until PD (experimental arm). Tumor assessment is planned every 8 weeks. The objective of the study is to demonstrate a not inferior efficacy and a better toxicity profile for the experimental treatment compared to the standard treatment. The co-primary endpoints are PFS and incidence of G 3-4 AEs. Secondary endpoints are OS, ORR, ETS (8 weeks) and safety. A prospective multiple gene mutation analysis by NGS of both tumor tissue and blood will be performed to find potential predictive factors and surrogate markers of treatment efficacy. The two co-primary endpoints will be compared between the two arms using a fixed-sequence testing procedure to control for the family-wise type I error rate of 0.05 in a strong sense. This sequence considers that a reduction of grade 3-4 AEs is only of relevance, if non-inferiority is shown regarding PFS. 600 evaluable pts will be enrolled and randomized. Study recruitment started on January 2015, currently 139 pts have been randomized. Clinical trial information: NCT02484833.

Apatinib in combination with S-1 as first-line treatment in patients with advanced gastric cancer: A phase II clinical trial.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 71-71
Author(s):  
Chuantao Zhang ◽  
Zimin Liu ◽  
Na Zhou ◽  
Jianli Zhang ◽  
Jingjuan Zhu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Clinical Trial ◽  
Advanced Gastric Cancer ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Line Treatment ◽  
Efficacy And Safety ◽  
First Line ◽  
First Line Treatment

71 Background: Apatinib is a standard therapy for advanced gastric cancer in third-line setting. However, the efficacy and safety of apatinib plus S-1 as first-line therapy is unknown. Here, we conducted a single center study to evaluate the efficacy and safety of it. Methods: In this phase II trial, chemotherapy-naive patients with advanced gastric cancer were enrolled between August 24, 2016 and Sept 25, 2017, at a single centers in P.R. China. The patients enrolled were assigned to S-1 plus apatinib, S-1 (40 mg m-2 depending on patient's body surface area) was given orally, twice daily for 2 consecutive weeks, followed by a 1-week rest period, and apatinib 500 mg was given once daily, every 3-week cycle. The primary endpoint was overall survival(OS). Secondary endpoints were progression-free survival(PFS), time to progress (TTP), objective response rate (ORR) and safety. On disease progression, patients had the option to receive single-agent apatinib every 3 weeks.This trial is registered with ClinicalTrials.gov , number NCT02525237. Results: Thirty eligible patients, median age 63 years (range 40-76) and median performance status 1 (ECOG 0-2) ,were enrolled, 9 patients have no evaluation or withdrew consent. Therefore, of the 21 patients the median PFS and TTP were 5.34±1.83 months [1.76–8.92] and 1.34±0.08 months[1.18–1.51], respectively. Additionally, one(4.76%) patient had a complete response, one (4.76%)patients had partial responses, 11 patients had stable disease, and 9 patients had progress of disease. The objective response rate(ORR)and the disease control rate(DCR) were 9.52%(2/21) and 57.14%(12/21),respectively. Until Sept 25.2017,the primary endpoint(OS) had not been reached. We recorded grade 3 or 4 adverse events including elevated bilirubin and/or transaminase, fatigue, abdominal pain, thrombocytopenia,et al. There were no treatment-related deaths. Conclusions: First-line chemotherapy with S-1 plus apatinib in patients with advanced gastric cancer did not reach its primary objective. However, it holds promise of becoming a standard first-line treatment for patients with advanced gastric cancer. Clinical trial information: NCT02525237.

scholarly journals KEYNOTE-826: A phase 3, randomized, double-blind, placebo-controlled study of pembrolizumab plus chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5595-TPS5595 ◽  
Author(s):  
Ronnie Shapira-Frommer ◽  
Jerome Alexandre ◽  
Bradley Monk ◽  
Tanja N. Fehm ◽  
Nicoletta Colombo ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Cell ◽  
Objective Response ◽  
Controlled Study ◽  
Line Treatment ◽  
First Line ◽  
Phase 3 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
First Line Treatment

TPS5595 Background: Cervical cancer arises in the setting of persistent infection with high-risk human papillomavirus subtypes. Many patients with early-stage and locally advanced carcinoma can be salvaged with radical surgery and chemoradiation, respectively. However, women with recurrent/metastatic disease represent a poor prognostic group with high unmet clinical needs. Incorporation of anti-angiogenesis therapy has emerged as a therapeutic option, but the survival benefit of 3.7 months over chemotherapy (CT) alone is modest (Tewari et al. NEJM 2014). Because viral tumor antigen-specific T cells reside predominantly in programmed cell death 1–expressing T-cell compartments, checkpoint inhibition may unleash a diverse antitumor T-cell response. Based on the 14.3% objective response in KEYNOTE-158, the US FDA granted accelerated approval to pembrolizumab (pembro) in June 2018 for second-line therapy and beyond. Methods: KEYNOTE-826 is a phase 3, randomized, double-blind, placebo-controlled, multinational trial of CT with pembro or with placebo for first-line treatment of recurrent, persistent, or metastatic cervical cancer. Patients not previously treated with CT for recurrence who are not amenable to curative treatment will be randomized 1:1 to CT + pembro 200 mg or placebo every 3 weeks. The CT regimen (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5, with or without bevacizumab 15 mg/kg) will be selected by the investigator before randomization. Stratification factors include metastasis status at diagnosis, bevacizumab use (yes/no), and tumor PD-L1 status (combined positive score <1, 1 to <10, or ≥10). Treatment will continue until disease progression, unacceptable toxicity, or voluntary patient withdrawal for up to 35 cycles (~2 years). Primary endpoints are progression-free survival (PFS) per RECIST v1.1 assessed by blinded independent central review and overall survival. Secondary endpoints are objective response, duration of response, 12-month PFS, patient-reported quality of life, and safety. Enrollment is ongoing. Clinical trial information: NCT03635567.

scholarly journals Patient profiles as an aim to optimize selection in the second line setting: the role of aflibercept

2021 ◽  
Author(s):  
B. González Astorga ◽  
F. Salvà Ballabrera ◽  
E. Aranda Aguilar ◽  
E. Élez Fernández ◽  
P. García-Alfonso ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Therapeutic Option ◽  
Scientific Evidence ◽  
Treatment Options ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Effective Therapeutic Option ◽  
Line Setting ◽  
First Line Treatment

AbstractColorectal cancer is the second leading cause of cancer-related death worldwide. For metastatic colorectal cancer (mCRC) patients, it is recommended, as first-line treatment, chemotherapy (CT) based on doublet cytotoxic combinations of fluorouracil, leucovorin, and irinotecan (FOLFIRI) and fluorouracil, leucovorin, and oxaliplatin (FOLFOX). In addition to CT, biological (targeted agents) are indicated in the first-line treatment, unless contraindicated. In this context, most of mCRC patients are likely to progress and to change from first line to second line treatment when they develop resistance to first-line treatment options. It is in this second line setting where Aflibercept offers an alternative and effective therapeutic option, thought its specific mechanism of action for different patient’s profile: RAS mutant, RAS wild-type (wt), BRAF mutant, potentially resectable and elderly patients. In this paper, a panel of experienced oncologists specialized in the management of mCRC experts have reviewed and selected scientific evidence focused on Aflibercept as an alternative treatment.

scholarly journals Immune Checkpoint Inhibition in Oesophago-Gastric Carcinoma

2021 ◽  
Vol 14 (2) ◽  
pp. 151
Author(s):  
Anica Högner ◽  
Peter Thuss-Patience
Keyword(s):  
Cell Death ◽  
Gastric Carcinoma ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Disease Free Survival ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
The Usa ◽  
First Line Treatment

Immune checkpoint inhibitors enrich the therapeutic landscape in oesophago-gastric carcinoma. With regard to oesophageal squamous cell carcinoma (ESCC), the selective PD-1 (programmed cell death receptor 1)-inhibitor nivolumab improves disease-free survival in the adjuvant therapy setting (CHECKMATE-577). In first-line treatment, ESCC patients (pts) benefit in overall survival (OS) from the PD-1-inhibitor pembrolizumab in combination with chemotherapy (KEYNOTE-590). In the second-line setting, nivolumab (ATTRACTION-03) and pembrolizumab (KEYNOTE-181) demonstrate a benefit in OS compared with chemotherapy. These data resulted in the approval of nivolumab for the second-line treatment of advanced ESCC pts regardless of PD-L1 (programmed cell death ligand 1) status in Europe, Asia, and the USA, and pembrolizumab for pts with PD-L1 CPS (combined positivity score) ≥ 10 in Asia and the USA. Further approvals can be expected. In gastro-oesophageal junction and gastric cancer, the addition of nivolumab to chemotherapy in first-line treatment improves OS in pts with advanced disease with PD-L1 CPS ≥ 5 (CHECKMATE-649). Additionally, pembrolizumab was non-inferior to chemotherapy for OS in PD-L1 CPS ≥ 1 pts (KEYNOTE-062). In third-line treatment, nivolumab shows benefits in OS regardless of PD-L1 expression (ATTRACTION-02) with approval in Asia, and pembrolizumab prolonged the duration of response in PD-L1 positive pts (KEYNOTE-059) with approval in the USA. We discuss the recent results of the completed phase II and III clinical trials.

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