Polatuzumab vedotin for naive DLBCL: Results from a phase 1b-2 trial

On 14 May 2019, Professor Hervé Tilly from the University of Rouen, Rouen, FR, and colleagues, published in The Lancet Oncology¹ results from a phase Ib-II trial investigating the efficacy and safety of polatuzumab vedotin in combination with immnunochemotherapy in patients with naïve diffuse large B-cell lymphoma (DLBCL).

The current standard of care for DLBCL involves treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).² However, in high-risk DLBCL patients, R-CHOP does not always lead to successful outcomes and the prognosis of patients not responding to R-CHOP is poor.² The investigators of this trial assessed the tolerability and preliminary activity of polatuzumab vedotin together with cyclophosphamide, doxorubicin, prednisone (CHP) chemotherapy, as well as rituximab or obinutuzumab (anti-CD20 therapy), as first-line treatment for naïve DLBCL.

The primary objective of this ongoing, multicenter, open-label, non-randomized, phase Ib-II trial (NCT01992653) was treatment safety and tolerability, as well as the determination of the maximum tolerated dose of polatuzumab vedotin. Secondary endpoints included, overall response rate (ORR), complete response (CR), progression-free survival (PFS), event-free survival (EFS), and overall survival (OS).

Study design & baseline characteristics

• N = 82 evaluable patients with histologically-confirmed B-cell non-Hodgkin lymphoma (NHL), aged ≥ 18 years:
  • For the phase Ib dose escalation phase: n = 25 (patients who had previous lymphoma treatments were also allowed)
  • For the phase II expansion phase: n = 57 (only previously untreated B-cell NHL patients with an International Prognostic Index [IPI] 2–5)
    • Patient histology (phase II): 100% diffuse large B-cell lymphoma (DLBCL)
  • Dosing:
    • Polatuzumab vedotin (pola; 21-day cycles; up to 6–8 cycles):
      • Administration schedule: on Day 2 of cycle 1 and 2 and then on Day 1 of each cycle
      • Starting dose: 1.0 mg/kg
      • Planned dose escalations: < 50% of the previous dose
      • Maximum explored dose: 1.8 mg/kg
      • Method of administration: IV infusion via syringe pump over 90 minutes for the starting dose and then over 30 minutes for following doses if well-tolerated (infusions could be slowed or interrupted accordingly)
      • Premedication: oral acetaminophen or paracetamol, and prednisone or prednisolone
    • CHP chemotherapy:
      • Cyclophosphamide: 750 mg/m² intravenously (IV) on Day 1 of each cycle
      • Doxorubicin: 50 mg/m² IV on Day 1 of each cycle
      • Prednisone: 100 mg orally on Days 1–5 once daily
    • Anti CD20 therapy (one of the following):
      • Rituximab (R): 375 mg/m² IV on Day 1 of each cycle
      • Obinituzumab (G): 1000 mg IV on Days 1, 8, and 15 of cycle 1 and on Day 1 for the next cycles
    • For the phase II part, patients with naïve DLBCL were assigned to either:
      • Pola (1.8 mg/kg) + R-CHP: n = 45
      • Pola (1.8 mg/kg) + G-CHP: n = 21

Key findings

• Recommended phase II dose of pola from phase Ib data: 1.8 mg/kg
• Dose escalation led to only two dose-limiting events:
  • Grade 4 pulmonary embolism (1.8 mg/kg pola + R-CHP)
  • Grade 3 febrile neutropenia & Grade 3 thrombocytopenia (1.4 mg/kg pola + G-CHP)

	Naïve DLBCL phase II cohort (n = 66)	95% CI
ORR	89% (n = 59)
CR	77% (n = 55
12-month PFS	91%	84–98
24-month PFS	83%	73–93
12-month OS	94%	88–100
12-month EFS	80%	71–90
Proportion of ongoing responses at 12 months	95%	89–100

• No difference in PFS was observed with different number of treatment cycles (6 versus 8), anti-CD20 therapy (R versus G), or IPI categories (0–2 versus 3 or 4–5; post-hoc analysis)
• PFS was similar in patients with different molecular DLBCL subtypes (cell or origin) and in double expressor patients (MYC and BCL2)

Safety

• In the naïve DLBCL population who received the recommended phase II pola dose (1.8 mg/kg) the most common Grade 1–2 adverse events (AEs) observed, were the following:
  • Diarrhea: 48%
  • Nausea: 45%
  • Fatigue: 47%
  • Peripheral neuropathy: 38%
  • Constipation: 26%
  • Anemia: 26%
  • Pyrexia: 21%
• In the same population the most common Grade ≥ 3 AEs observed were:
  • Neutropenia: 30%
  • Febrile neutropenia: 18%
  • Thrombocytopenia: 9%
• The most common serious AEs were:
  • Febrile neutropenia: 14%
  • Neutropenia: 6%
  • Pneumonia: 6%
• In the same population, 11% of patients discontinued treatment due to AEs after receiving 1–5 cycles and 8% of patients had a pola dose reduction
• A higher incidence of neutropenia and thrombocytopenia was observed in patients receiving G-CHP than R-CHP
• Median time to resolution for all grades peripheral neuropathy (range): 2.4 (0.8–6.5) months
• Median time to resolution for Grade 2–3 peripheral neuropathy (range): 4.9 (1.0–9.1) months
• Four DLBCL patients (6%) died during the study either due to Grade 5 AEs (n = 2; atrial fibrillation, septic shock) or due to disease progression (n = 2)

Conclusions

The results of this phase Ib-II trial indicate that pola in combination with G-CHP or R-CHP has a manageable toxicity profile and leads to promising response outcomes in previously untreated patients with DLBCL