Adding Ramucirumab to Frontline Chemo Does Not Improve Survival in Gastric Cancer

Charles S. Fuchs, MD

Adding ramucirumab (Cyramza) to standard first-line chemotherapy significantly improved investigator-assessed progression-free survival (PFS) compared with chemotherapy plus placebo in treatment-naïve patients with HER2-negative gastric cancer. However, the addition of ramucirumab did not improve overall survival (OS), a secondary endpoint of the study, in the phase III RAINFALL study.¹

In the final intent to treat study population, median PFS was 5.85 months in patients randomized to ramucirumab in addition to cisplatin plus either capecitabine (or IV 5-fluorouracil for those patients unable to swallow capecitabine) compared with 5.55 months in those randomized to chemotherapy plus placebo (HR, 0.75; P = .0024). Median OS was 11.17 months in the ramucirumab arm and 10.74 months in the placebo arm (HR, 0.96; P = .68).

Given the data, ramucirumab should “not supplant existing standard of care in first line,” lead study author Charles S. Fuchs, MD, director of the Yale Cancer Center said at the 2018 Gastrointestinal Cancers Symposium. “I don’t think the data support that.” The sentiment was echoed by the invited discussant Stephen Leong, MD, who noted the total drug cost for 9 treatments of ramucirumab for a 70-kg man to be $67,000 to induce a median improvement in PFS of 9 days.

Ramucirumab did significantly improve median OS in the second-line setting in 2 previous randomized placebo-controlled studies (REGARD² and RAINBOW³) of patients with advanced gastric or gastroesophageal junction adenocarcinoma. On that basis, RAINFALL randomized in a 1:1 ratio 645 patients with HER2-negative gastric cancer and an ECOG performance status of 0 or 1 to placebo plus cisplatin plus capecitabine every 3 weeks or the same chemotherapy regimen with the addition of ramucirumab, 8 mg/kg on day 1 and 8 of the cycle. Treatments were continued until disease progression or intolerable toxicity.

As of the data cutoff of November 6, 2017, study drug was discontinued in 96% of the ramucirumab arm and 97% of the placebo arm, the most common reason being progressive disease (60% and 70% in the 2 arms, respectively).

Treatment arms were well balanced for age, sex, ethnicity, performance status, and primary tumor location. The median age of patients was 60 years in the ramucirumab arm and 62 in the placebo arm. Thirty-five percent of patients in the placebo arm had weight loss ≥10% during the 3 months prior to study entry, compared with 27% in the ramucirumab arm. About three-fourths in each arm had 2 or fewer metastatic sites. Peritoneal metastases were present in 40% of the ramucirumab group and 35% of the placebo group.

Investigator-assessed PFS among the first 508 patients enrolled, the study’s primary endpoint, was a median of 5.72 months in the ramucirumab arm and 5.39 months in the placebo arm (HR, 0.75; P = .011); this improvement in PFS persisted in the full 645-patient cohort. The effect of treatment on PFS or OS did not differ by patient or disease characteristics.

The objective response rate was similar between the 2 groups at 41% in the ramucirumab arm and 36% in the placebo arm (P = .17). The disease control rate was also similar, 82% and 77%, respectively (P = .10).

There was no difference between groups in exposure of chemotherapy agents. The median number of treatment cycles was 6 in each arm, the duration of therapy was 19.0 and 18.8 weeks in ramucirumab- and placebo-treated patients, respectively, and the relative dose intensity exceeded 90% in each arm.

The rate of deaths due to adverse events was similar in both arms at 5.6% in those randomized to ramucirumab and 4.8% in the placebo group. Treatment-emergent adverse events were similar between arms, with more hand-foot syndrome (31% vs 20%), thrombocytopenia (34% vs 19%), and decreased appetite (41% vs 32%) in the ramucirumab arm. The rate of febrile neutropenia was modestly higher in the placebo arm (5.1% vs 3.7%).

As expected, adverse events related to VEGF inhibition occurred at a higher rate in the ramucirumab arm, including grade ≥3 hypertension (9.9% vs 1.6%).

Use of post-study anticancer therapy was similar between groups, 46% in the ramucirumab arm and 51% in the placebo arm. Ramucirumab post-study was used by 12% of the ramucirumab arm and 17% of the placebo arm. In an exploratory analysis of the impact of post-study ramucirumab on OS, as measured from the start of first-line therapy, “patients who received post-study ramucirumab appeared to experience longer survival. Specifically patients who were randomized to first-line ramucirumab who then continued on post-study ramucirumab had a median OS of 16.2 months, whereas patients randomized to placebo who did not receive post-study ramucirumab experienced a median OS of 13.0 months,” said Fuchs.

When measured from the start of second-line therapy, patients who received post-study ramucirumab-based therapy had a median OS time of 7.7 to 8.8 months, compared with 6.5 to 6.7 months in those whose post-study treatment did not include ramucirumab.

Besides financial implications, another consideration from the RAINFALL data is whether to continue ramucirumab in the second-line setting if ramucirumab is used as first line, said Leong, director, Developmental Therapeutics Clinical (Phase I) Program at the University of Colorado Cancer Center. In addition, quality-of-life data have not yet been reported. He indicated that ramucirumab plus chemotherapy will not replace the current standard of a doublet or triplet with a 5-FU or platinum backbone in the first-line setting and that an indication for ramucirumab as first-line treatment is not being sought.

References

1. Fuchs CS, Shitara K, Di Bartolomeo M, et al. RAINFALL: A randomized, double-blind, placebo-controlled phase III study of cisplatin (Cis) plus capecitabine (Cape) or 5FU with or without ramucirumab (RAM) as first-line therapy in patients with metastatic gastric or gastroesophageal junction (G-GEJ) adenocarcinoma. Presented at: 2018 Gastrointestinal Cancers Symposium; January 18-20, 2018; San Francisco, Calif. Abstract 5.
2. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31-39.
3. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224-1235.

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