ICML 2019: Randomized phase III study of lenalidomide/R-CHOP (R2-CHOP) vs placebo/R-CHOP in previously untreated ABC-type DLBCL

On Wednesday 19 June at the International Conference on Malignant Lymphoma, Lugano, CH, Professor Umberto Vitolo, presented the first report of the global ROBUST phase III randomized trial (NCT02285062) of lenalidomide/R-CHOP (R2-CHOP) vs placebo/R-CHOP in previously untreated CD20+ activated B-cell (ABC)-type diffuse large B-cell lymphoma (DLBCL).

In the double-blind trial, investigators sought to determine whether the addition of lenalidomide to R-CHOP could improve outcomes compared with R-CHOP in 570 patients with ABC-type DLBCL. The study did not meet its primary endpoint of progression-free survival (PFS)   for R2-CHOP versus placebo/ R-CHOP as frontline therapy in patients with ABC-type DLBCL.

Patient characteristics and methods

• N = 570 patients with ABC‐DLBCL
• Primary endpoint: PFS by central review (per 2014 IWG)
• Secondary endpoints included complete response (CR) rate, duration of response, time to next lymphoma treatment, objective response rate (ORR), event-free survival (EFS), overall survival (OS), and health-related quality of life
• Histologically confirmed CD20+ DLBCL, ABC subtyping by NanoString, PS <=2
• Baseline characteristics were generally similar between groups and the stratification factors were balanced (Table 1)
• Median time from diagnosis to treatment: 31 days (both groups)

Table 1. Patient demographics and baseline characteristics (ITT population)

N (%)

 

R2-CHOP
(n =285)

Placebo/R2-CHOP
(n = 285)

International Prognostic Index  (IPI) score

 

2

121 (42)

120 (42)

≥3

164 (58)

165 (58)

Bulky disease

≥7 cm*

97 (34)

99 (35)

Median age, y (range)

≥ 65 y*

 

65 (21–82)

147 (52)

65 (28–83)

148 (52)

Male/female

 

164 (58)/121 (42)

143 (50)/142 (50)

ECOG performance status

0

129 (45)

111 (39)

1

104 (36)

118 (41)

2

52 (18)

56 (20)

Ann Arbor disease stage

II

37 (13)

33 (12)†

III

80 (28)

98 (34)

IV

168 (59)

154 (54)

Elevated LDH (> 234 U/L)

 

177 (62)

176 (62)

Geographic distribution

Europe

124 (44)

150 (53)

Asia-Pacific

111 (39)

92 (33)

North America

24 (8)

23 (8)

Other

26 (9)

20 (7)

Figure 1: Robust study design

Results

• Median follow-up: 27.1 months (range 0–47)
• PFS (primary endpoint) was not met: HR = 0.85 (89% CI, 0.63–1.14), P = 0.29 (median PFS not reached for either arm)
• ORR was 91% for both arms: 69% vs 65% CR for R2‐CHOP vs placebo/R‐CHOP
• In a subgroup analysis of PFS, a positive trend supporting R2‐CHOP over placebo/R‐CHOP was observed in patients with: IPI score ≥ 3 (HR = 0.74 [95% CI, 0.53‐1.05] P = 0.09)
• 2-year OS was 79% for R2‐CHOP and 80% for placebo/R‐CHOP (median OS not reached for either arm)
• Non-statistically significant trends favoring R2-CHOP were observed in subgroups of patients with disease stage III/IV (HR 0.81; 95% CI, 0.60–10)
• The most common grade 3/4 AEs occurring in ≥10% of patients for R2-CHOP vs placebo/R‐CHOP were:
  • Neutropenia (60% vs 48%)]
  • Anemia (22% vs 14%)
  • Thrombocytopenia (17% vs 11%)
  • Leukopenia (14% vs 15%)
  • Febrile neutropenia (14% vs 9%), and
  • Lymphopenia (11% vs 8%)

Conclusion

The ROBUST trial was the first study to compare R2-CHOP with placebo/R‐CHOP in patients with previously untreated, prospectively selected, CD20+ ABC‐type DLBCL. Prof Vitolo concluded that overall, the ROBUST trial did not meet the PFS primary or key secondary endpoint for R2-CHOP vs placebo/R-CHOP. However, an encouraging trend for PFS supporting R2-CHOP was observed in patients with higher risk IPI ≥ 3. Prof Vitolo emphasized that analyses of ROBUST are still ongoing and future analyses will include the evaluation of pharmacokinetics/dosing, molecular classification, and mutational status.

Future clinical trials will investigate next-generation immunomodulatory agents for DLBCL.