ECC 2013 Abstract#2588 (P416) - Phase 3 REGARD Study

Abstract 2588 (P416): Tolerability and Quality-of-Life (QoL) Results From the Phase 3 REGARD Study: Ramucirumab Versus Placebo in Patients With Previously Treated Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma I. Chau (United Kingdom) et al.

Background: Ramucirumab (RAM) was associated with significantly longer survival and progression-free survival (PFS) versus placebo (Fuchs et al., GI Cancer Symposium 2013). Here we present assessments of tolerability and QoL from REGARD. 

Methods: Patients (pts) with advanced gastric or GEJ adenocarcinoma who had previously been treated were randomized 2:1 to receive RAM 8 mg/kg IV or placebo every two weeks; both arms received best supportive care. Pts and investigators were blinded to treatment assignment. Pts were eligible if they had received prior fluoropyrimidine- or platinum-based combination therapy and had ECOG performance status (PS) of 0 or 1. PS was assessed prior to every cycle, at therapy discontinuation, and within 30 days after last dose. Time to PS deterioration was measured from randomization to first change in PS to ≥ 2 and evaluated with Kaplan–Meier analysis and log-rank test. Pts completed the EORTC QLQ-C30 (v3) QoL instrument at baseline and on study at cycles 4, 7, and 10. Scores were classified as improved or worsened if changed by a ≥ 10-point difference relative to baseline, otherwise stable. Adverse events (AEs) and supportive therapies were collected while pts were on study.

Results: 355 pts were randomized (238 to RAM, 117 to placebo); two pts in each arm did not receive treatment. RAM pts received a median of four cycles (interquartile [IQ] range 3–8), while placebo pts received three cycles (IQ range 2–4). Treatment discontinuation rates for AEs were 10.5% for RAM and 6.0% for placebo. Time to PS deterioration was longer for RAM (median 5.1 months vs. 2.4 months; hazard ratio = 0.59 [95% confidence interval: 0.41–0.83], P = 0.002). While on study, QoL completion rates were > 86% at all time points. Primarily due to disease progression, < 50% of RAM and < 25% of placebo pts provided post-baseline QoL data. For the randomized population, rates of improvement were 5–15% for RAM and 3–6% for placebo across the 15 QoL scales at cycle 4. Rates of stability were 16–37% for RAM and 8–19% for placebo. Rates of worsening were 4–18% for RAM and 1–9% for placebo, with 54% of RAM and 78% of placebo pts providing no data, primarily due to disease progression by six weeks. Rates of serious AEs were similar (44.9% RAM, 44.3% placebo). The highest rate of any specific grade ≥ 3 AE was < 10% in the RAM arm. Select supportive care is summarized in Table 1.

Table 1: Select Supportive Care for Treated Patients

Table 1: Select Supportive Care for Treated Patients

Conclusions: In addition to improved survival and PFS for RAM versus placebo, RAM was well tolerated. Rates of serious AEs were similar between arms; for RAM, the incidence of any individual severe toxicity was low and supportive care requirements were modest. For pts who received at least four cycles of therapy, more pts maintained their QoL with RAM. Performance status was maintained for a significantly longer time with RAM.

Gastric cancer continues to be a leading cause of cancer-related morbidity and mortality, underscoring an unmet need for more effective therapies. Ramucirumab is a fully human IgG1 monoclonal antibody that targets the VEGF-receptor 2. In the REGARD trial that was previously presented at ASCO, investigators demonstrated statistically significant overall survival (OS) and progression-free survival improvements with ramucirumab alone in metastatic gastric adenocarcinoma patients who failed first-line platinum- and/or fluoropyrimidine-containing combination therapy. Because the treatment intent is palliative, significant concerns exist about ramucirumab’s toxicity and how it might negatively affect quality of life of patients who are nearing the end of life. In the current analysis of the REGARD data, authors focused on QoL measures and revealed that ramucirumab was well tolerated with rates of serious adverse events being similar between ramucirumab and placebo. Importantly, more patients who received ramucirumab maintained their QoL and sustained their performance status for longer. While the OS and PFS benefits that were observed with ramucirumab were modest over best supportive care (only 1.4 months and 0.8 months, respectively), these should be interpreted within the context of a cancer in which prognosis is estimated to be in the range of only six months without treatment. The current QoL findings reassure clinicians that ramucirumab can be safely delivered. In the absence of severe toxicities, the modest but incremental survival advantages of ramucirumab may be clinically meaningful for selected patients. Economic analysis of the cost impact of ramucirumab must take into account the favorable QoL data.
— CARE Gastrointestinal Cancer Faculty