scholarly journals Novel HER2-Directed Treatments in Advanced Gastric Carcinoma: AnotHER Paradigm Shift?

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1664
Author(s):  
Angela Dalia Ricci ◽  
Alessandro Rizzo ◽  
Fabiola Lorena Rojas Llimpe ◽  
Francesca Di Fabio ◽  
Dario De Biase ◽  
...  
Keyword(s):  
Advanced Disease ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Future Research ◽  
Her2 Positive ◽  
Advanced Gastric Carcinoma ◽  
Primary Endpoints ◽  
Fda Approval ◽  
New Treatments

Human epidermal growth factor receptor 2 (HER2) is overexpressed and/or amplified in approximately 15–20% of gastric adenocarcinoma (GC) patients. In 2010, the landmark ToGA trial established the combination of trastuzumab plus chemotherapy as the first-line standard of care for HER2-positive GC patients with advanced disease. However, subsequent studies on HER2 targeted therapies in this setting failed to meet their primary endpoints, and not all HER2-positive GC patients benefit from targeted approaches. More recently, novel HER2-directed treatments have been investigated, including trastuzumab deruxtecan (T-Dxd); following the results of the DESTINY-Gastric01 study, T-Dxd received its first U.S. Food and Drug Administration (FDA) approval on 15 January 2021 for the treatment of adults with unresectable, locally advanced, or metastatic GC who have received a prior trastuzumab-based regimen. In this review, we discuss the current HER2-targeted treatments for GC in the advanced disease setting, mainly focusing on emerging new treatments and future research directions.

scholarly journals Biliary Tract Cancers: Molecular Heterogeneity and New Treatment Options

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3370
Author(s):  
Nicola Personeni ◽  
Ana Lleo ◽  
Tiziana Pressiani ◽  
Francesca Colapietro ◽  
Mark Robert Openshaw ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Advanced Disease ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Resistance Mechanisms ◽  
Anatomical Location ◽  
Molecular Heterogeneity ◽  
Isocitrate Dehydrogenase 1 ◽  
Tract Cancer

Most patients with biliary tract cancer (BTC) are diagnosed with advanced disease, relapse rates are high in those undergoing surgery and prognosis remains poor, while the incidence is increasing. Treatment options are limited, and chemotherapy is still the standard of care in both adjuvant and advanced disease setting. In recent years, different subtypes of BTC have been defined depending on the anatomical location and genetic and/or epigenetic aberrations. Especially for intrahepatic cholangiocarcinoma (iCCA) novel therapeutic targets have been identified, including fibroblast growth factor receptor 2 gene fusions and isocitrate dehydrogenase 1 and 2 mutations, with molecularly targeted agents having shown evidence of activity in this subgroup of patients. Additionally, other pathways are being evaluated in both iCCA and other subtypes of BTC, alongside targeting of the immune microenvironment. The growing knowledge of BTC biology and molecular heterogeneity has paved the way for the development of new therapeutic approaches that will completely change the treatment paradigm for this disease in the near future. This review provides an overview of the molecular heterogeneity of BTC and summarizes new targets and emerging therapies in development. We also discuss resistance mechanisms, open issues, and future perspectives in the management of BTC.

Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: A phase II study of the Belgian Group of Digestive Oncology.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 245-245 ◽  
Author(s):  
I. Borbath ◽  
A. Ceratti ◽  
C. Verslype ◽  
A. Demols ◽  
T. Delaunoit ◽  
...  
Keyword(s):  
Skin Rash ◽  
Phase Ii ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Skin Toxicity ◽  
Standard Of Care ◽  
Egfr Expression ◽  
Prior Systemic Therapy ◽  
Ecog Ps

245 Background: Cholangiocarcinomas (CCK) are uncommon tumors with an increasing incidence and a poor prognosis. Epidermal growth factor receptor (EGFR) expression and activation in CCK have been demonstrated. Methods: We conducted a multicenter phase II trial combining cetuximab (Ctx), an anti-EGFR chimerized IgG1 monoclonal antibody, to gemcitabine (Gem). Patients with either locally advanced (LA) or metastatic (M) CCK (excluding gallbladder) were included; no prior systemic therapy was allowed. Ctx was administrated at the initial dose of 400 mg/m2 and further injections at 250 mg/m2 every 7 days, and Gem was administrated at 1000 mg/m2 on days 1, 8, and 15 every 4 weeks. The primary endpoint was the progression-free survival (PFS) rate at 6 months. A Simon 2-stage design was used. We hypothesized that Gem/Ctx would improve 6 month-PFS rate from 20% to 40%. We needed 3 patients with PFS ≥ 6 months from the first 13 to further include a total of 43 patients. Results: Forty-four patients with advanced CCK (41% LA/59%M) were enrolled from 09/2008 to 01/2010. Median age was 61.5 years (range 40-86) and baseline ECOG PS was 0 for 68% and 1 for 32% of the patients. Forty-three percent of the patients had prior surgery. Forty-six percent of the patients were free from progression at 6 months. Median PFS was 5.8 months (95% CI, 4.4-7.4 m) and median overall survival was 11.6 months (95% CI, 8.7-14.6 m). Nine patients (20.9%) had partial response with a median duration of 5 months (range 2-10 m). Disease control rate (PR + SD > 8 weeks) was 81.4%. The most common grades 3/4 related-toxicities were haematological abnormalities (47.7%), skin rash (13.6%) and fatigue (11.3%). Due to toxicity, 6 patients discontinued study treatment; 14 and 3 patients had a Gem and Ctx dose reduction respectively. Among the nine responders, 8 experienced a skin rash of at least grade 2, suggesting a relationship between skin toxicity and efficacy. Conclusions: Our study met its endpoint, i.e., a PFS rate of 46% at 6 months, suggesting that Gem-Ctx combination had promising activity with a manageable toxicity profile in advanced CCK. Adding Ctx to the new standard of care Gem-cisplatin deserves further investigations in CCK. [Table: see text]

A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab-refractory esophagogastric (EG) cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 52-52 ◽  
Author(s):  
Yelena Yuriy Janjigian ◽  
Marinela Capanu ◽  
Tooba Imtiaz ◽  
David Paul Kelsen ◽  
Geoffrey Yuyat Ku ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Tumor Regression ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Cancer Resistance ◽  
Her2 Positive ◽  
Tumor Biopsy ◽  
Disease Stabilization ◽  
Erbb Family Blocker

52 Background: Trastuzumab (T) combined with chemotherapy has been the standard of care for pts with HER2+ EG cancer. Resistance to T is now emerging in this population. Afatinib (A), a potent ErbB Family Blocker, induced nearly complete tumor regression in MSKCC HER2+ patient derived xenografts (PDX). We report the initial results of a phase II study of afatinib in patients with T refractory EG cancer. Methods: Pts with HER2+ (IHC 3+ or FISH>2.0) EG adenocarcinoma –progressive on trastuzumab -received A 40 mg. Archival pre-T tissue, tumor biopsy after progression on T and after 1 week on A mandated on protocol. The primary endpoint-overall clinical benefit at 4 months: stable disease (SD) or partial response (PR). Results: 14 pts treated with A; median duration 5.1 mos (1.7 to 12.1 mos). Median age 62, KPS 80, median 2 (1 to 4) prior T containing regimens, 64% of tumors IHC3+; 36% IHC2+/FISH>2.2. Adverse events included: diarrhea (Grade 1/2:69%), fatigue (Grade 1/2:54%), rash (Grade 1/2:54%), mucositis (Grade 1:23%), paronychia (Grade 1/2:15%). To date, 13 pts evaluable for response, 3 of 13 pts (23%) had disease stabilization (PR or SD); 1 pt with confirmed PR - a durable 75% regression of biopsy proven metastases. Median OS 6.6 mos (1.9 to NR). PDXs established from biopsies of T refractory tumors of 5 pts. Next generation sequencing of matched pre-T and post-T progression tumors from 6 pts was performed and results will be reported. Conclusions: Afatinib shows clinical efficacy in patients with T refractory EG cancer. The study has been expanded to accrue additional patients. Efforts to elucidate the mechanisms of T resistance including validation of potential drivers of T resistance using HER2+ PDXs are ongoing. Updated molecular and clinical data will be presented. Clinical trial information: NCT01522768.

A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab refractory esophagogastric (EG) cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 59-59 ◽  
Author(s):  
Yelena Yuriy Janjigian ◽  
Geoffrey Yuyat Ku ◽  
David H. Ilson ◽  
Michelle S. Boyar ◽  
Marinela Capanu ◽  
...  
Keyword(s):  
Tumor Regression ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Cancer Resistance ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Tumor Biopsy ◽  
Disease Stabilization ◽  
Heavily Pretreated ◽  
Next Generation Sequencing Ngs

59 Background: Trastuzumab combined with chemotherapy is the standard of care for pts with HER2+ EG cancer. Resistance to trastuzumab clearly emerges in this population. Afatinib, a potent ErbB Family Blocker, induced tumor regression in MSKCC HER2+ patient derived xenografts (PDX). This study assesses safety and preliminary efficacy of afatinib in patients with trastuzumab refractory EG cancer. Methods: Pts with HER2+ (IHC 3+ or FISH>2.0) EG adenocarcinoma, after progression on trastuzumab, received oral afatinib 40 mg daily. Archival pre-trastuzumab tissue, tumor biopsy after progression on trastuzumab and after 1 week on afatinib is mandated on protocol for next generation sequencing (NGS), proteomics and establishment of PDX. The primary endpoint-overall clinical benefit at 4 months: stable disease (SD) or partial response (PR). Results: 20 pts treated with afatinib; median age 61, KPS 80; median 2 (1 to 4) prior trastuzumab regimens, 67% of tumors IHC3+; 33% IHC2+/FISH>2.0. Common adverse events included: rash or dry skin (Grade 1/2:80%), diarrhea (Grade 1/2:60%), nausea/vomiting (grade 1/2:40%) fatigue (grade1/2: 25%). To date, 19 pts evaluable for response, 2 PRs and 6 SD, 42% disease stabilization rate (PR+SD) at 4months (4 to 13 mos). PDXs established from biopsies of 7 pts. EGFR amplification was detected in the tumor of 2 pts with PRs and 1 of 6 pts with SD. Recurrent PIK3CA, ERBB3 and MTORmutations were observed. Conclusions: Afatinib shows clinical efficacy and is well tolerated in patients with trastuzumab refractory, heavily pretreated EG cancer. Enrollment has now begun in an afatinib + trastuzumab cohort. Efforts to elucidate the mechanisms of trastuzumab resistance including validation of potential drivers of trastuzumab resistance using HER2+ PDXs are ongoing. Updated molecular and clinical data will be presented. Clinical trial information: NCT01522768.

Long-term survival update of the Scandinavian Prostate Cancer Group 6 study: Bicalutamide 150 mg daily versus placebo in hormone-naïve, non-metastatic prostate cancer.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 2-2 ◽  
Author(s):  
Frederik Birkebæk Thomsen ◽  
Klaus Brasso ◽  
Ib Jarle Christensen ◽  
Jan-Erik Johansson ◽  
Anders Angelsen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Survival Benefit ◽  
Advanced Disease ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Cox Proportional Hazard Model ◽  
Proportional Hazard ◽  
Proportional Hazard Model ◽  
Cox Proportional Hazard ◽  
Baseline Psa

2 Background: The optimal timing of endocrine therapy in non-metastatic prostate cancer (PCa) is not clear. There is a need for more data from randomized trials. Methods: A randomized, double-blind, parallel-group trial comparing bicalutamide 150 mg once daily with placebo in addition to standard of care in patients with hormone-naïve, non-metastatic PCa. Kaplain-Meier analysis was used to estimate overall survival (OS) and multivariate Cox proportional hazard model was performed to analyse time-to-event (death). Results: 1,218 patients were included into the SPCG-6 study, 607 patients were randomised to bicalutamide and 611 patients to placebo. The majority (81.4%) were managed on watchful waiting. After median 14.6 years follow-up, 866 (71.1%) patients died, 428 (70.5%) in the bicalutamide arm and 438 (71.7%) in the placebo arm, p=0.87. In patients with localised disease (cT1-2, N0/Nx) survival favoured randomisation to the placebo arm (HR=1.19 (95% CI: 1.00-1.43), p=0.056). Bicalutamide significantly improved OS and reduced the risk of death by 23% relative to the placebo arm in patient with locally advanced disease (cT3-4, any N; or any cT, N+) with a median survival difference of 1.8 years (HR=0.77 (95% CI: 0.63-0.94, p=0.01). The survival benefit of bicalutamide in patients with locally advanced PCa was present throughout the study period. In multivariate Cox proportional hazard model OS was dependent on age (HR 1.55 (95% CI:1.20-1.85)), baseline PSA (localised PCa HR for 2 x increase in PSA 1.09 (95% CI:1.02-1.16), locally advanced PCa HR 1.23 (95% CI:1.14-1.33)), WHO histological grade (moderate vs. well HR 1.27 (95% CI:1.08-1.49), poor vs. well HR 1.92 (95% CI:1.51-2.45)), and randomisation to placebo in locally advanced disease (HR=0.76 (95% CI: 0.61-0.95)). Conclusions: The addition of early bicalutamide to standard of care resulted in a significant OS benefit in patients with locally advanced PCa, whereas patients with localised PCa derived no survival benefit from early bicalutamide. The survival benefit of bicalutamide therapy increased with higher baseline PSA. Clinical trial information: NCT00672282.

Halo 110-101: Early safety results of pegvorhyaluronidase alfa (PEGPH20; PVHA) + cisplatin (C) + gemcitabine (G) ± atezolizumab (ATZ) in patients (pts) with locally advanced or metastatic cholangiocarcinoma (CCA) and gallbladder cancer (GBC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 408-408
Author(s):  
Do-Youn Oh ◽  
Mann Muhsin ◽  
Andrea J. Bullock ◽  
Ghassan K. Abou-Alfa ◽  
Rachna T. Shroff ◽  
...  
Keyword(s):  
Immune Cell ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Primary Endpoints ◽  
Secondary Endpoints ◽  
Phase Clinical Trial ◽  
The Mean ◽  
The Individual ◽  
Dose Limiting Toxicity ◽  
Clinical Trial Information

408 Background: Standard of care for CCA/GBC is C-G therapy. MAbs (ATZ, pembrolizumab) targeting PD-L1 show promise in treating CCA/GBC. Hyaluronan (HA), which may impede drug and immune cell access, is high (67%) in CCA/GBC tumors. PEGPH20 enzymatically degrades HA. HALO 110-101 (NCT03267940) evaluates safety and activity of PEG-C-G-ATZ or PEG-C-G versus C-G in CCA/GBC pts. Methods: This study comprises two parts. In Run-In (RI) six pts were enrolled in PEG-C-G arm, then six pts in PEG-C-G-ATZ arm. Eight additional pts may be enrolled for tolerability. In Expansion (EX), up to 50 pts will be enrolled for efficacy. Treatment (Tx) cycle is 21 days (d). PEGPH20 dose is 3 μg/kg on d1, eight and 15 and ATZ dose is 1200 mg (one–three hours after PEGPH20) on d1 (PEG-C-G-ATZ only). C-G is dosed at 25 mg/m2 C and 1000 mg/m2 G on d2 and nine. In C-G arm (EX only), C-G is dosed on d1 and 8. Primary endpoints are ORR (RECIST v1.1), AEs (NCI CTCAE v4.03), laboratory/safety (RI only); secondary endpoints are PK; DOR, DCR, PFS; OS, OS by PD-L1 expression; ORR and DOR (imRECIST). Results: Eighteen pts have been enrolled (nine in each arm). The mean (SD) age is 57 (12.2) yrs in PEG-C-G and 69 (8.8) yrs in PEG-C-G-ATZ. 56% were men. All pts experienced ≥ 1 AE. The most common AEs are nausea, fatigue (50% each); decreased appetite (44%); anemia, constipation (39% each); thrombocytopenia, oedema peripheral, AST increased, myalgia (33% each). To date, there has been one dose-limiting toxicity (febrile neutropenia) in the PEG-C-G arm. There have been no deaths due to AEs. Conclusions: The overall safety profile of PEGPH20 + C + G ± ATZ is acceptable and consistent with safety observed for the individual components. There were no DLTs resulting in a dose reduction of PEGPH20, which is being dosed at 3 μg/kg in the EX phase. Clinical trial information: NCT03267940. [Table: see text]

scholarly journals Current and Future Management of HER2-Positive Metastatic Breast Cancer

2021 ◽  
pp. OP.21.00172
Author(s):  
Olga Martínez-Sáez ◽  
Aleix Prat
Keyword(s):  
Breast Cancer ◽  
Early Stage ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Standard Of Care ◽  
Trastuzumab Emtansine ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Line Setting ◽  
Future Management

Human epidermal growth factor receptor 2 (HER2) is overexpressed and/or amplified in approximately 20% of breast cancers, conferring an aggressive tumor behavior but also an opportunity for targeted therapies. In the advanced setting, the prognosis of patients suffering from this disease has greatly improved after the introduction of new anti-HER2 drugs beyond trastuzumab. For most patients, a taxane combined with trastuzumab and pertuzumab in the first-line setting, followed by trastuzumab-emtansine in second line, should be considered the standard of care today. However, chemo-free anti-HER2 strategies in hormone receptor-positive, HER2-positive breast cancer could also be considered in selected patients. In the third-line setting and beyond, several emerging anti-HER2 therapies are becoming available, including tucatinib, fam-trastuzumab deruxtecan-nxki (DS-8201a), neratinib, and margetuximab-cmkb. In addition, new compounds and combinations are showing promising results in the late-line setting. The treatment landscape of HER2-positive advanced disease is evolving constantly, active drugs such as pertuzumab and trastuzumab-emtansine are moving to early-stage, many biomarkers, including quantification of HER2 itself, are being explored to improve patient selection, and patient populations with specific needs are emerging, such as those with brain metastasis. Here, we provide an overview of the current and future management of HER2-positive advanced breast cancer.

A randomized, open-label, multicenter, adaptive phase 2/3 study of trastuzumab emtansine (T-DM1) versus a taxane (TAX) in patients (pts) with previously treated HER2-positive locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (LA/MGC/GEJC).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 5-5 ◽  
Author(s):  
Yoon-Koo Kang ◽  
Manish A. Shah ◽  
Atsushi Ohtsu ◽  
Eric Van Cutsem ◽  
Jaffer A. Ajani ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Data Monitoring Committee ◽  
Metastatic Breast ◽  
Standard Of Care ◽  
Phase 2 ◽  
Her2 Positive ◽  
Open Label ◽  
Previously Treated

5 Background: Trastuzumab (H) + capecitabine/fluorouracil + cisplatin is standard of care for 1st-line HER2-positive MGC/GEJC but there is no established HER2-targeted 2nd-line regimen. T-DM1 (H linked to DM1) is approved for HER2-positive metastatic breast cancer previously treated with H + TAX (separately or in combination). This and preclinical HER2-positive GC models provided the rationale for GATSBY (NCT01641939). Methods: GATSBY is a 3-arm randomized, adaptive, seamless phase 2/3 global study of T-DM1 vs TAX in pts with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization-positive), unresectable LA/MGC/GEJC who progressed during or after 1st-line fluoropyrimidine + platinum ± HER2-targeted therapy. Pts were initially randomized 2:2:1 to T-DM1 3.6 mg/kg every 3 weeks (q3w), T-DM1 2.4 mg/kg weekly (qw), or physician’s choice of paclitaxel 80 mg/m2 qw or docetaxel 75 mg/m2q3w. An independent data monitoring committee selected T-DM1 qw for further study and subsequent patients were randomized 2:1 to this or TAX. The primary endpoint is overall survival (OS); all T-DM1 qw data are analyzed, including dose selection. Results: At clinical cutoff, 06/30/15, 415 pts had been randomized overall: 228 to T-DM1 qw, 117 to TAX (70 T-DM1 q3w pts reported separately); 77.4% had prior HER2-targeted therapy; 29.9% prior gastrectomy; 46.1% were Asian. Efficacy/safety are tabulated. Conclusions: T-DM1 2.4 mg/kg qw did not show an efficacy benefit over TAX. Grade ≥3 AE rates were numerically lower with T-DM1 vs TAX and rates of SAEs, fatal AEs, and treatment discontinuations due to AEs were comparable between arms. Clinical trial information: NCT01641939. [Table: see text]

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