Polatuzumab or pinatuzumab vedotin plus rituximab for R/R NHL: Results from the ROMULUS phase II trial

On 29 March 2019, Frank Morschhauserfrom the CHRU of Lille University, Lille, FR and colleagues, published in the Lancet Haematology results from the phase II clinical trial ROMULUS ( NCT01691898). This multicenter, open-label, randomized study compared the efficacy of polatuzumab vedotin plus rituximab (R-pola) to pinatuzumab vedotin plus rituximab (R-pina) in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or R/R follicular lymphoma (FL). The primary endpoints of the trial were safety, tolerability, and anti-tumor response.

Study design & baseline characteristics

• N = 123 patients with R/R NHL:
  • DLBCL: n = 81 patients
  • FL (Grade 1−3a): n = 42 patients
• Patients were randomly 1:1 assigned to either:
  • R-pola (n = 49; [DLBCL, n = 39; FL, n = 20]):
    • R: 375 mg/m ²intravenously
    • Pola: 2.4 mg/kg intravenously
    • Treatment was received every 21 days until disease progression (PD) or unacceptable toxicity up to one year
  • R-pina (n = 63 [DLBCL, n = 42; FL, n = 21]):
    • R: 375 mg/m ²intravenously
    • Pina: 2.4 mg/kg intravenously
    • Treatment was received every 21 days until disease progression (PD) or unacceptable toxicity up to one year
  • DLBCL patients received a median of seven cycles of R-pina and a median of six cycles of R-pola
  • FL patients received a median of seven cycles of R-pina and a median of ten and a half cycles of R-pola
  • Patients with sufficient recovery from any treatment-emergent toxicity from the initial regimen (pina or pola) were eligible to receive crossover treatment consisting of the alternative alone or combined with rituximab, as per the intention-to-treat principle. Safety and efficacy endpoints were reported for the original treatment each patient received

Key findings

DLBCL patients

• Objective overall response (ORR):
  • R-pina (n = 42): 60% (95% CI, 43−74)
  • R-pola (n = 39): 54% (95% CI, 37−70)
• Complete response (CR):
  • R-pina (n = 42): 26% (95% CI, 14−42)
  • R-pola (n = 39): 21% (95% CI, 9−36)
• Median progression-free survival (PFS):
  • R-pina (n = 42): 5.4 months (95% CI, 3.9−6)
  • R-pola (n = 39): 5.6 months (95% CI, 4.3−8
• Median duration of response (DoR):
  • R-pina (n = 42): 6.2 months (95% CI,3.6−4)
  • R-pola (n = 39): 13.4 months (95% CI, 6.5−2)
• Median overall survival (OS):
  • R-pina (n = 42): 16.5 months (95% CI, 7.5−5)
  • R-pola (n = 39): 20.1 months (95% CI, 10.4−6)
• Median OS among patients who were refractory to their previous therapy:
  • R-pina (n = 42): 11.9 months (95% CI, 6.3−0)
  • R-pola (n = 39): 11.7 months (95% CI, 5.3−9)

FL patients

• ORR:
  • R-pina (n = 21): 62% (95% CI, 38−82)
  • R-pola (n = 20): 70% (95% CI, 46−88)
• CR:
  • R-pina (n = 21): 5% (95% CI, 0.1−24)
  • R-pola (n = 20): 45% (95% CI, 23−68)
• Median PFS:
  • R-pina (n = 21): 12.7 months (95% CI, 8.9−5)
  • R-pola (n = 20): 15.3 months (95% CI, 12.2−1)
• Median DoR:
  • R-pina (n = 21): 6.5 months (95% CI,6.0−1)
  • R-pola (n = 20): 9.4 months (95% CI, 7.2−not estimable)
• Median OS:
  • R-pina (n = 21): not reached
  • R-pola (n = 20): not reached

Full cohort

• Two-year OS among all patients (DLBCL + FL):
• R-pina: 90.5% (95% CI, 77.9−100.0)
• R-pola: 87.8% (95% CI, 72.0−100.0)
• Six patients with PD received crossover treatment with R-pina or R-pola accordingly (5 DLBCL, 1 FL):
  • Five out of six PD patients progressed further after crossover
  • One patient died after receiving one cycle of crossover treatment

Safety

• The most common treatment-emergent adverse events (TEAEs) for both R-pina and R-pola groups were:
  • Fatigue
  • Diarrhea
  • Peripheral neuropathy
  • Nausea
  • Neutropenia
• Pina was discontinued in 79% of patients with DLBCL and in 91% of patients with FL
• Pola was discontinued in 80% of patients with DLBCL and in 85% of patients with FL
• The most common reasons for treatment discontinuation were PD (38%) in patients with DLBCL and AEs (62%) in patients with FL
• Neutropenia was the most common Grade 3−4 AE and led to treatment discontinuation in only one patient treated with R-pina in each of the DLBCL and FL patient groups
• Febrile neutropenia was reported in 2% of DLBCL patients in the R-pina group (Grade 4) and in 5% of DLBCL patients in the R-pola group (Grade 3). It was also reported in 5% of FL patients in the R-pina arm (Grade 3)

Conclusions

• R-pina and R-pola are potential treatment options for patients with R/R DLBCL or R/R FL
• Pola is currently under further investigation for NHL due to its longer DoR when compared to pina, and overall benefit–risk of R-pola