Phase III, randomised trial of avelumab versus physician’s choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300

Abstract

BackgroundThere currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician’s choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC.Patients and methodsPatients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10 mg/kg by intravenous infusion every 2 weeks or physician’s choice of chemotherapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 or irinotecan 150 mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.ResultsA total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0 months; hazard ratio (HR)=1.1 [95% confidence interval (CI) 0.9–1.4]; P = 0.81} or the secondary end points of PFS [median, 1.4 versus 2.7 months; HR=1.73 (95% CI 1.4–2.2); P > 0.99] or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm.ConclusionsTreatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy.Trial registrationClinicalTrials.gov: NCT02625623.

A phase 3 study of nivolumab in previously treated advanced gastric or gastroesophageal junction cancer (ATTRACTION-2): 2-year update data

“…Currently, evidence for standard-of-care in third-or later-line therapy for patients with advanced G/GEJ cancer is limited. This includes studies such as KEYNOTE-059 [10], INTEGRATE [11], TAGS [12], JAVELIN Gastric 300 [13], and a Chinese apatinib study [14]. Most of the studies do not provide evidence of long-term efficacy in patients with G/GEJ cancer, with the exception of the phase 2 KEY-NOTE-059 study that evaluated the long-term efficacy and safety of pembrolizumab, another immune checkpoint inhibitor [15].…”

Optimal management of gastroesophageal junction cancer

“…The JAVELIN 300 study evaluated avelumab versus physician's-choice paclitaxel or irinotecan in patients who had received ≥2 lines of chemotherapy. 67 Avelumab did not improve OS versus chemotherapy, and no benefit was seen in a subgroup analysis of PD-L1-positive patients (≥1% of tumor cells). Finally, preliminary results of the phase 3 KEYNOTE-181 study evaluating second-line pembrolizumab versus physician's-choice docetaxel or irinotecan in patients with advanced esophageal/GEJ carcinoma (64% SCC) show that pembrolizumab significantly improved RR, median OS (9.3 vs 6.7 months; HR, 0.69; P = .0074), and 12-month OS (43% vs 20%) in patients whose tumors expressed PD-L1 CPS ≥10 (n = 222).…”

“…Furthermore, patients with GEJ tumors also appeared to benefit (HR, 0.61), whereas patients with gastric tumors did not. The JAVELIN 300 study evaluated avelumab versus physician’s‐choice paclitaxel or irinotecan in patients who had received ≥2 lines of chemotherapy . Avelumab did not improve OS versus chemotherapy, and no benefit was seen in a subgroup analysis of PD‐L1–positive patients (≥1% of tumor cells).…”

“…Combined, these Cancer June 15, 2019 studies suggest that pembrolizumab is not superior to chemotherapy in an unselected population. Table 2 [64][65][66][67][68][69] outlines the studies evaluating immune checkpoint inhibitors in the metastatic setting that have been completed to date.…”

Gastric Cancer: Where Are We Heading?

“…Positive results have been obtained only for anti-HER2 agent, trastuzumab, in HER2 positive GC, which may be used as first-line treatment, and for an anti-angiogenic agent, ramucirumab, which may be used in the second line of treatment, and for which no predictive factors of response have been identified [70][71][72]. The recent interest in the potential efficacy of immune check points inhibitors brought some hope, with some positive phase II and III studies [73,74], but not confirmed by other studies [75,76]. The future challenge will be to use all the available histological and molecular markers to identify the patients susceptible to benefit from specific treatments.…”