Pertuzumab Pharmacokinetics and Safety in Combination with Trastuzumab and Chemotherapy in Patients with Her2-Positive Advanced Gastric Cancer (Agc)

Abstract

Background: HER2 is overexpressed in 15-20% of aGC or gastro-oesophageal junction (GEJ) cancers, where trastuzumab plus chemotherapy significantly improved overall survival compared with chemotherapy alone (Bang Lancet 2010). The combination of pertuzumab, trastuzumab and docetaxel demonstrated significantly improved progression-free survival (Baselga NEJM 2012) and overall survival (Swain SABCS 2012) compared with trastuzumab plus docetaxel in HER2-positive first-line metastatic breast cancer (mBC). The combination of pertuzumab, trastuzumab and chemotherapy has the potential to improve survival outcomes in HER2-positive aGC. To identify the pertuzumab dose for clinical studies in HER2-positive gastric and GEJ cancer in the same manner used to select the dose of pertuzumab for studies in HER2-positive breast cancer, we conducted a Phase IIa study to investigate the pharmacokinetics and safety of pertuzumab in combination with trastuzumab and chemotherapy in HER2-positive aGC. Methods: JOSHUA was a randomised, open-label, multi-centre study evaluating the pharmacokinetics of two different doses of pertuzumab in the first-line treatment of HER2-positive aGC/GEJ cancer. Patients received pertuzumab 840 mg for Cycle 1 and 420 mg q3w for Cycles 2-6 (Arm A) or pertuzumab 840 mg q3w for all 6 cycles (Arm B). Six cycles of trastuzumab, cisplatin and capecitabine were given, then trastuzumab q3w until disease progression or unmanageable toxicity. Primary endpoints were pertuzumab trough concentrations (Cmin) at Day 43 (to identify the pertuzumab dose giving a steady-state Cmin of ≥20 μg/mL in ≥90% of patients) and safety. A bootstrap analysis was conducted to estimate the percentage of patients at or above the target Cmin. Results: Of 15 patients randomised to each arm, 15 and 13 were evaluable for pertuzumab Cmin at Day 43 in Arms A and B respectively. The mean Cmin was higher in patients in Arm B than Arm A at Day 43 (57.9 μg/mL [CV 56.5%] versus 40.0 μg/ mL [CV 43.2%]). The estimated proportion of patients with Cmin ≥20 μg/mL was 91.6% (95% CI 78.3-99.2) in Arm A and 98.3% (95% CI 91.4-99.97) in Arm B. The mean pertuzumab trough concentration in Arm A was ∼37% lower than that observed in a previous mBC trial using the 840/420 mg dose; the mean pertuzumab trough concentration in Arm B was similar to that observed in the previous mBC trial. At this interim safety assessment, the most common (≥13%) grade ≥3 adverse events were diarrhoea, neutropenia, anaemia, decreased appetite, fatigue, decreased neutrophil count, febrile neutropenia, hyponatremia and stomatitis. Overall, there was no difference in the adverse event profile between arms. Conclusion: Based on the pharmacokinetic and safety data from JOSHUA, a pertuzumab dose of 840 mg q3w was selected for the Phase III trial of pertuzumab in HER2-positive metastatic GEJ and GC. This dose is more likely to achieve the pharmacokinetic target of ≥20 μg/mL in >90% of aGC patients and provide trough concentrations similar to those observed in mBC clinical studies.