Safety and efficacy of HER2 blockade by trastuzumab-based chemotherapy-containing combination strategies in HER2+ gastroesophageal adenocarcinoma

Abstract

Since completion of the Trastuzumab for Gastric Cancer study, trastuzumab with doublet chemotherapy (a fluoropyrimidine and a platinum) has been the gold-standard first-line therapy for patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2-positive (HER2þ) gastroesophageal adenocarcinoma (GEA). The safety and efficacy of 23 studies of first-line trastuzumab plus doublet chemotherapy, without checkpoint inhibitors (n ¼ 19) or with checkpoint inhibitors (n ¼ 4), conducted in patients with locally advanced unresectable or metastatic HER2þ GEA, including phase II/III, prospective, and retrospective observational studies, were summarized. In studies without checkpoint inhibitors, the median duration of trastuzumab treatment ranged from 19.5 to 39.0 weeks and from 15.3 to 30.0 weeks for chemotherapy. In studies with checkpoint inhibitors, the median duration of pembrolizumab/trastuzumab/chemotherapy was 30 weeks, and 18 weeks for chemotherapy. In studies without checkpoint inhibitors, treatment-emergent adverse events (TEAEs) of grade !3 ranged from 32% to 84%. Serious adverse events (SAEs) ranged from 15% to 39%. Adverse events resulting in discontinuation ranged from 0% to 30%. Treatment-related deaths occurred in 0%-9% of patients. In studies with checkpoint inhibitors, TEAEs of grade !3 were 57%. SAEs ranged from 31% to 38%. Adverse events resulting in discontinuation ranged from 5% to 24%. Treatment-related deaths occurred in 0%-3% of patients. In studies without checkpoint inhibitors, objective response rate (ORR) ranged from 39% to 82%, median progression-free survival (PFS) from 5.7 to 11.6 months, and median overall survival (OS) from 11.2 to 27.6 months. In studies with checkpoint inhibitors, ORR ranged from 39% to 86%, median PFS from 8.0 to 13.0 months, and median OS from 19.3 to 27.3 months. This review provides a historical benchmark on safety and efficacy of available first-line chemotherapy-based standard of care for patients with locally advanced unresectable or metastatic HER2þ GEA.

Margetuximab with retifanlimab as first-line therapy in HER2+/PD-L1+ unresectable or metastatic gastroesophageal adenocarcinoma: MAHOGANY cohort A

“…Evaluation by PD-L1 status at the pertinent cut-offs (CPS ≥1, ≥5, ≥10) is also awaited to determine which scenarios that immunotherapy provides the most therapeutic value. Moreover, the toxicity profiles of these chemotherapy-containing regimens 6 must be considered to determine optimal treatment strategies that can be personalized for each patient.…”

“…In summary, the chemotherapy-free regimen combining margetuximab and retifanlimab as first-line treatment in biomarker-selected patients (HER2 IHC3+, PD-L1 positive) met the prespecified boundary for antitumor activity and demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. 6 Moreover, initiating chemotherapy only if patients experienced disease progression did not appear to affect OS negatively; thus, delaying cytotoxic therapy allowed for patients to suspend experiencing chemotherapy-related toxicity, such as cumulative neuropathy. In a subset of patients with profound and durable response, this strategy may spare patients from chemotherapy exposure altogether, thus limiting overtreatment in this biomarker-selected population.…”

“…4,5 Across these three studies, objective response rate (ORR) ranged from 47% to 59%, median progression-free survival (PFS) from 5.7 to 7.0 months, and median overall survival (OS) from 12.5 to 14.2 months, with grade !3 adverse events (AEs) ranging from 60% to 73% and treatment-related mortality ranging from 2% to 3%. [3][4][5][6] Margetuximab is an Fc-engineered anti-HER2 monoclonal antibody (mAb) approved in breast cancer 7 and investigational in GEA, targeting the same epitope as trastuzumab, with increased affinity for both single-nucleotide polymorphisms of the activating Fc receptor (CD16A). [8][9][10] CD16A is expressed on natural killer cells, natural killer T cells, gd T cells, dendritic cells, macrophages, and monocytes.…”

“… 4 , 5 Across these three studies, objective response rate (ORR) ranged from 47% to 59%, median progression-free survival (PFS) from 5.7 to 7.0 months, and median overall survival (OS) from 12.5 to 14.2 months, with grade ≥3 adverse events (AEs) ranging from 60% to 73% and treatment-related mortality ranging from 2% to 3%. 3 , 4 , 5 , 6 …”

Glycans as Targets for Drug Delivery in Cancer

“…In the context of biomarker-guided precision oncology, the detection of the target antigen in individual tumor specimens is warranted to determine patient eligibility for mAb-based therapeutic regimens. Such is the case of clinically approved therapeutic mAbs trastuzumab and pembrolizumab/nivolumab, used in the treatment of multiple ErbB2- and PD-L1-expressing solid tumors, respectively [ 57 ].…”