HELOISE: Phase IIIb Randomized Multicenter Study Comparing Standard-of-Care and Higher-Dose Trastuzumab Regimens Combined With Chemotherapy as First-Line Therapy in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

Abstract

Purpose To compare standard-of-care (SoC) trastuzumab plus chemotherapy with higher-dose (HD) trastuzumab plus chemotherapy to investigate whether HD trastuzumab increases trastuzumab serum trough concentration (C) levels and increases overall survival (OS) in first-line human epidermal growth factor receptor 2-positive metastatic gastric or gastroesophageal junction adenocarcinoma. Patients and Methods Patients with Eastern Cooperative Oncology Group performance status 2, no prior gastrectomy, and ≥ two metastatic sites were randomly assigned at a one-to-one ratio to loading-dose trastuzumab 8 mg/kg followed by SoC trastuzumab maintenance 6 mg/kg every 3 weeks or loading-dose trastuzumab 8 mg/kg followed by HD trastuzumab maintenance 10 mg/kg every 3 weeks until progression; treatment in each arm was combined with cisplatin 80 mg/m plus capecitabine 800 mg/m twice per day in cycles 1 to 6. The primary objective was HD trastuzumab OS superiority (all randomly assigned patients [full-analysis set]). Final results are from an interim analysis for futility (boundary hazard ratio [HR] ≥ 0.95) at 125 deaths. Results At clinical cutoff, 248 patients had been randomly assigned. A marked increase in mean trastuzumab C was observed after the first HD trastuzumab cycle versus SoC trastuzumab. In the full-analysis set, median OS was 12.5 months in the SoC trastuzumab arm and 10.6 months in the HD trastuzumab arm (stratified HR, 1.24; 95% CI, 0.86 to 1.78; P = .2401). Results were similar in the per-protocol set (cycle 1 trastuzumab C < 12 µg/mL). Safety was comparable between arms. Conclusion HD trastuzumab maintenance dosing was associated with higher trastuzumab concentrations, no increased efficacy, and no new safety signals. HELOISE confirms standard-dose trastuzumab (loading dose of 8 mg/kg followed by 6 mg/kg maintenance dose every 3 weeks) with chemotherapy as the SoC for first-line treatment of human epidermal growth factor receptor 2-positive metastatic gastric or gastroesophageal junction adenocarcinoma.

Phase II clinical trial of S‐1 plus nanoparticle albumin‐bound paclitaxel in untreated patients with metastatic gastric cancer

“…The proportion of Chinese AGC patients receiving second‐line chemotherapy is not high, which is similar to that reported for European and USA patients, and lower than that for Japanese and Korean patients in the phase III trials . The same thing happened in our present study and 35.6% of patients received second‐line chemotherapy, which limits the contribution to overall survival.…”

Population Pharmacokinetics of Durvalumab in Cancer Patients and Association With Longitudinal Biomarkers of Disease Status

“…This is further complicated by the fact that disease status is evolving with time, and patients benefiting from therapy have a higher steady‐state exposure due to their decreased catabolic status and/or improved cachexia. This can provide a false impression of predictive or prognostic value of some biomarkers, or that higher doses may provide more efficacy, as exemplified by a trastuzumab case study in metastatic gastric cancer . Without a clear understanding of the degree of correlation between all these variables, incorrect conclusions could be easily drawn when analyzing data in only one dimension without accounting for potential interplays between PK and disease variables.…”

“…This can provide a false impression of predictive or prognostic value of some biomarkers, or that higher doses may provide more efficacy, as exemplified by a trastuzumab case study in metastatic gastric cancer. 17,18 Without a clear understanding of the degree of correlation between all these variables, incorrect conclusions could be easily drawn when analyzing data in only one dimension without accounting for potential interplays between PK and disease variables. The pitfalls of exposure-response without accounting for time-varying exposure in oncology are further discussed elsewhere.…”

Exposure–Response Analysis of Overall Survival for Tremelimumab in Unresectable Malignant Mesothelioma: The Confounding Effect of Disease Status

“…When the single‐dose experimental arm shows a clinically relevant benefit over standard of care, as in the case of trastuzumab in gastric cancer or trastuzumab‐DM1 in breast cancer, a post hoc analysis of E‐R was also conducted to decide whether nonresponders could have benefited from a higher dose. In both cases, this can result in further confirmatory trials with a higher dose (as in tremelimumab in mesothelioma) or in postapproval commitment trials, as exemplified by the HELOISE trial evaluating higher dose of trastuzumab and by the TH3RESA trial for trastuzumab‐DM1 . For both tremelimumab and trastuzumab, results demonstrated no additional benefit of higher doses and, thus, put into question the conclusions drawn from such E‐R post hoc analyses.…”