RAINFALL Washes Away First-Line Ramucirumab Plus Chemotherapy For Metastatic Gastric Cancer

Adding ramucirumab to cisplatin and fluoropyrimidine chemotherapy does not improve survival for patients with metastatic HER2-negative gastric or gastro-oesophageal junction adenocarcinoma

medwireNews: RAINFALL trial findings do not support the first-line use of the antiangiogenic agent ramucirumab alongside chemotherapy for patients with metastatic HER2-negative gastric or gastro-oesophageal junction cancer. 

The study’s primary endpoint of investigator-assessed progression-free survival (PFS) was statistically significantly better for the 326 patients who were randomly assigned to receive ramucirumab 8 mg/kg on days 1 and 8 of a 21-day cycle, alongside cisplatin and capecitabine, than for the 319 patients who instead received placebo plus chemotherapy. 

However, the difference in median PFS between the treatment arms was just 0.3 months (5.7 vs 5.4 months, hazard ratio=0.75) and “therefore not clinically significantly”, report Charles Fuchs, from Yale School of Medicine in New Haven, Connecticut, USA, and fellow RAINFALL investigators. 

Furthermore, sensitivity analysis of radiological images for 458 patients that underwent central independent review failed to confirm a significant difference between the two groups. 

And overall survival (OS) did not significantly differ between the ramucirumab and placebo trial arms, at a median of 11.2 and 10.7 months, respectively. 

“On the basis of these efficacy results, ramucirumab in combination with cisplatin-fluoropyrimidine cannot be recommended for first-line treatment”, the researchers conclude in The Lancet Oncology.

The study follows earlier phase II results showing no benefit with first-line ramucirumab given with a modified FOLFOX6 regimen to patients with advanced gastric and gastro-oesophageal adenocarcinoma, as well as negative results for the AVAGAST and AVATAR trials of first-line bevacizumab with chemotherapy.  

The author of a linked comment observes that these negative results are in contrast to positive findings for ramucirumab given alone (REGARD study) and in combination with paclitaxel (RAINBOW study) in the second-line setting. 

“The authors hypothesise that the angiogenic pathway might promote tumour growth mainly in metastatic gastric cancer, or that a natural selection of angiogenic sensitive tumours occurs after systemic treatment”, writes Annemieke Cats, from the Netherlands Cancer Institute in Amsterdam. 

Alternatively, the chemotherapy backbone of cisplatin and fluoropyrimidine may affect antiangiogenic therapy, she suggests, continuing that “[i]n this context, the results of the ongoing RAMSES trial (NCT02661971) in which ramucirumab is combined perioperatively with FLOT chemotherapy in patients with resectable gastric cancer, are eagerly awaited”. 

Annemieke Cats concludes: “The RAINFALL trial once again shows that understanding the evolutionary biology of gastric cancer against the background of patients’ genetic make-up, and the effect these factors have on the complex interaction between anti-cancer drugs and the tumour and vascular microenvironment, is crucial for the personalisation of future gastric cancer treatment.” 



Fuchs CS, Shitara K, Di Bartolomeo M, et al. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised , placebo-controlled, phase 3 trial . Lancet Oncol; Advance online publication 1 February 2019. http://dx.doi.org/10.1016/S1470-2045(18)30791-5

Cats A. No clear role for angiogenesis inhibitors in first-line therapy for stomach cancer . Lancet Oncol; Advance online publication 1 February 2019. http://dx.doi.org/10.1016/S1470-2045(18)30892-1

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