Ramucirumab/Docetaxel Shows No Overall Survival Advantage in Advanced Urothelial Cancer

Daniel P. Petrylak, MD

Daniel P. Petrylak, MD

New data from the RANGE study have found that ramucirumab (Cyramza) combined with docetaxel confers a progression-free survival (PFS) benefit in patients with platinum-refractory advanced urothelial cancer versus placebo and docetaxel in extended follow-up, according to a recent paper inLancet Oncology.¹

At the overall survival (OS) database lock, median PFS in the ramucirumab group (n = 263) was 4.1 months (95% Confidence Interval [CI], 3.3-4.8 months). In comparison, median PFS in the placebo group (n = 267) was 2.8 months (95% CI, 2.6-2.9 months; Hazard Ratio [HR], 0.696 [95% CI, 0.573-0.845];P=0.0002).

However, median OS was 9.4 months (95% CI, 7.9-11.4 months) in the ramucirumab group versus 7.9 months (7.0-9.3 months) in the placebo group (stratified HR, 0.887 [95% CI, 0.724-1.086];P=0.25).

“Consistent with our primary progression-free survival analysis published in 2017, this updated analysis further supports that ramucirumab combined with docetaxel provides a progression-free survival benefit versus placebo and docetaxel. Moreover, this benefit occurred while safety and quality of life were maintained,” wrote the authors, led by Daniel P. Petrylak, MD, of the Yale University Cancer Center. “However, we observed no statistically significant improvement in overall survival in the intention-to-treat population. We could not statistically test the proportion of patients with an overall response because of the gated study design but this was higher in the ramucirumab and docetaxel group than in the placebo and docetaxel group.”

The current study reports the secondary endpoint of OS and updated PFS data from RANGE, a randomized, double-blind, placebo-controlled, international phase III trial. The study’s primary endpoint was PFS, and its primary publication included PFS data from the first 437 patients to be randomized.²

RANGE’s inclusion criteria included histologically or cytologically confirmed urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis of predominantly transitional cell histology. Included patients had an ECOG performance status of 0 or 1 and disease progression 14 months or less after receiving platinum-based chemotherapy. Patients could have received previous treatment with one immune checkpoint inhibitor if they had relapsed less than 24 months after completing a platinum-based regimen. Patients were excluded if they had received more than one previous systemic chemotherapy in the relapsed or metastatic setting.

The RANGE protocol consisted of intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg followed by intravenous docetaxel 75 mg/m² on day 1 of a 21-day cycle. The docetaxel dose was reduced to 60 mg/m² in Korea, Taiwan, and Japan. Treatment continued until disease progression or unacceptable toxicity. Patients could receive 6 cycles of docetaxel, with up to four additional cycles allowed. Ramucirumab or placebo was continued as monotherapy once docetaxel treatment was completed.

This trial did not include a planned crossover on disease progression. The authors allowed up to two dose-level decreases of ramucirumab or placebo, of 2 mg/kg each. No dose re-escalations were allowed. Cycles could be delayed up to 42 days in case of toxicities.

The intention-to-treat population consisted of 263 patients in the experimental group and 268 patients in the placebo group. At data cutoff in March 2018, 3 patients in each group were still receiving treatment (1% of the respective groups). Median follow-up in the intention-to-treat population was 7.4 months (range 0.1-31.1 months, Interquartile Range [IQR] 3.5-13.9 months). In the intention-to-treat population, 448 PFS events occurred. Of these, 212 (81% of 263 patients) were in the ramucirumab group and 236 (88% of 267 patients) were in the placebo group.

Notably, the stratified HR for PFS decreased with data maturity. At the primary analysis, the stratified HR was 0.757 (95% CI, 0.607-0.943;P=0.0118). In the current analysis, this HR decreased to 0.696 (95% CI, 0.573-0.845,P=0.0002). “We observed improvements in progression-free survival in the ramucirumab group versus the placebo group at landmark time points of 3 months, 6 months, 9 months, and 12 months,” wrote Petrylak et al.

Slightly fewer patients died in the ramucirumab group: 185 of 263 patients (70%) in the ramucirumab group vs 200 of 267 (75%) in the placebo group. In the ramucirumab group, median OS was 9.4 months (95% CI 7.9-11.4 months), while median OS was 7.9 months (7.0-9.3 months) in the placebo group (stratified HR, 0.887; 95% CI, 0.724-1.086;P=0.25). The authors found no statistically significant between-group differences in OS at 6 months, 9 months, 12 months, and 24 months.

Petrylak et al reported that treatment-emergent adverse events (AEs) were mostly grades 1 or 2 in severity and that both groups reported similar treatment-related AEs. Of note, febrile neutropenia was the most frequent treatment-related AE that was grade 3 or higher: 24 of 258 patients in the experimental group (9%) compared with 16 of 265 placebo-group patients (6%). Grade 3 or higher neutropenia was the second most common treatment-related AE with a large between-group variance: 17 of 258 (7%) in the ramucirumab group and 6 of 256 (2%) in the placebo group. The authors found that serious AEs occurred similarly regardless of group: 112 of 258 (43%) of patients who received ramucirumab vs 107 of 265 placebo patients (40%).

The authors also found that 8 ramucirumab patients died of treatment-related AEs, while 5 placebo-group patients did. In the ramucirumab group, fatal AEs included one each of the following: basilar artery thrombosis, cardiac arrest, enterovesical fistula, gastric hemorrhage, neutropenic sepsis, renal failure, and sepsis. In the placebo group, fatal AEs included one each of the following: asthenia, lung infection, pneumonitis, and pulmonary embolism. Additionally, one treatment-related fatality of unknown cause was reported in each group.

In discussing RANGE’s OS endpoint, Petrylak et al noted that their protocol was designed to test a 3-month improvement in overall survival from 9 months to 12 months with the addition of ramucirumab to docetaxel. “Since pembrolizumab has previously shown a statistically significant overall survival benefit in a similar population compared with taxane monotherapy or vinflunine in a randomized phase 3 trial, pembrolizumab could be accepted over ramucirumab as a preferred standard of care,” they wrote. “Given the few treatment options for platinum-refractory disease and the potential use of PD-1 and PD-L1 agents in frontline combinations, pending the results of several key phase 3 trials, our trial results are important for treatment decisions in the second-line setting.”

References

1. Petrylak DP, de Wit R, Chi KN, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial.Lancet Oncol. 2020;21:105—20. Published online
2. November 18, 2019.https://doi.org/10.1016/S1470-2045(19)30668-0
3. Petrylak DP, de Wit R, Chi KN, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial.Lancet. 2017;390:2266-2277.