GALEN trial phase II results: obinutuzumab + lenalidomide for relapsed/refractory follicular lymphoma

There is currently no standard-of-care treatment for patients with relapsed/refractory (R/R) follicular lymphoma (FL), although therapeutic options include rituximab, rituximab plus chemotherapy and autologous stem cell transplant. Therefore, there is an unmet need to provide efficacious new treatment options.¹

Rituximab is a type I chimeric IgG1 anti-CD20 monoclonal antibody (mAb) which, in combination with the immunomodulatory agent, lenalidomide, has proven efficacy in patients with R/R FL. This chemotherapy-free regimen, termed R², was approved by the United States (US) Food & Drug Administration in May 2019 for patients with previously treated FL and marginal zone lymphoma (MZL).²

Obinutuzumab (GA101), a type II humanized IgG1 anti-CD20 mAb, displays greater antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis, as well as B-cell killing effects compared to rituximab.³ Studies in patients with previously untreated FL comparing rituximab to obinutuzumab, have shown that obinutuzumab prolongs progression-free survival (PFS), regardless of the chemotherapy backbone it is combined with.⁴ It was, therefore, hypothesized that obinutuzumab in combination with lenalidomide (GALEN) could improve the outcome of patients with R/R FL.¹

The phase Ib results of the GALEN study were previously published in Blood in 2018. The investigators established the recommended phase II doses of lenalidomide (20mg), and obinutuzumab (1000mg fixed dose), and showed GALEN had a satisfactory safety profile.⁵ Furthermore, Frank Morschhauser, University of Lille, Lille, FR, and colleagues, recently published the results of the phase II portion of the GALEN study (NCT01582776) in Lancet Hematology, which investigated the efficacy and safety of GALEN in patients with R/R FL.¹

Study design and patient characteristics

• Multicenter, single-arm, phase II study in France
• Adult patients had CD20⁺ R/R FL (N= 89) and had:
  • World Health Organization (WHO) grade 1, 2 or 3a disease
  • An Eastern Cooperative Oncology Group (ECOG) score of 0–2
  • ≥ one lesion by CT scan
  • A life expectancy ≥ three months
  • Received a prior rituximab-containing therapy
  • No other efficacious treatment options available

Table 1. Administration of study drugs * Patients achieving a partial response (PR) or greater after six months of induction were eligible for the maintenance portion of the trial

 

Administration

Dose

Day administered per cycle

Given until

N

Induction therapy: six 28-day cycles

 

88

Lenalidomide

Oral

Creatinine clearance (CrCl) ≥ 50 mL/min: 20mg

CrCL 30–50 mL/min: 10mg

Cycle 1: 1–21

Cycles 2–6: 2–22

 

-

Obinutuzumab

Intravenous (IV)

1000mg

Cycle 1: 8, 15 and 22

Cycles 2–6: 1

 

-

Maintenance therapy year one: 12 28-day cycles*

 

75

Lenalidomide

Oral

10mg

All cycles: 2–22

Maximum of 12 cycles

-

Obinutuzumab

IV

1000mg

Alternate cycles: 1

As tolerated until disease progression (PD)

-

Maintenance therapy year two: six 56-day cycles

 

56

Obinutuzumab

IV

1000mg

All cycles: 1

 

-

• A percentage of planned doses taken (total dose taken [mg] x 100 / total dose expected [mg]) was calculated (given as lenalidomide versus obinutuzumab):
  • During induction: 61% vs 84%
  • At least 90% of doses taken, by end of year one maintenance: 70% vs 95%
  • At least 90% of doses taken, by end of year two maintenance (obinutuzumab): 77%

Patient characteristics of the safety population (n= 88) are shown in Table 2.

Table 2. Patient characteristics of note 

Characteristic

Safety population (n= 88)

Median age

64 years

Male

56 (64%)

FL grade 3a

12 (13%)

Median prior therapies

2 (1–3)

Early relapse (within 24 months of diagnosis)

24 (27%)

Refractory to rituximab-containing regimen

20 (23%)

ECOG status 0

62 (71%)

Ann Arbor stage 3–4

74 (84%)

Follicular Lymphoma International prognostic index (FLIPI) score of 3–5

36 (42%)

• Primary endpoint: overall response at induction
  • Investigator assessed using the 1999 international working group criteria
  • Hypothesis: overall response would increase from 50% to 70% after six treatment cycles
• Secondary endpoints: event-free survival (EFS), PFS, overall survival (OS) and safety
• Median follow-up: 2.6 years (interquartile range: 2.2–2.8)
• In total, 43 patients completed full maintenance therapy and 43 discontinued therapy (Table 3)

Table 3. Discontinuations and reasons during study * Two patients did not receive obinutuzumab and were not included so the causes of discontinuation are not listed here

 

Total

PD

Toxicity of treatment

Death

Insufficient response

Protocol violation

Patient decision

Induction*

13

4

4

1

1

1

0

Year 1 of maintenance

19

12

3

1

2

0

1

Year 2 of maintenance

11

5

4

1

0

0

1

Permanent discontinuations due to drug toxicity:

• Lenalidomide: 8
• Obinutuzumab: 1
• GALEN: 5

Efficacy

• Evaluated in patients who received ≥ one dose of obinutuzumab and lenalidomide (n= 86)
• Median PFS, duration of response (DOR) and OS were not reached (NR)
• Post-hoc analysis found that patients who experienced early PD within 24 months had similar responses, PFS and OS rates as those who relapsed later
• The study met the primary endpoint of overall response post-induction

Table 4. Efficacy results

 

N= 86

95% CI

Overall response rate (ORR) at end of induction

68 (79%)

69–87

EFS at two years

62%

51–72

PFS at two years

65%

54–74

DOR at two years

70%

57–79

OS at two years

87%

78–93

Best response

Complete response (CR)

23 (27%)

-

CR unconfirmed

10 (12%)

-

PR

35 (41%)

-

Stable disease

5 (6%)

-

PD

7 (8%)

-

Not evaluated

6 (7%)

-

Safety

• Evaluated in patients who received one dose of either obinutuzumab or lenalidomide (n= 88)
• Adverse events (AEs) of special interest of all grades:
  • Infusion-related reactions (IRRs): 14 (16%)
  • Serious infections: 13 (15%)
  • Secondary primary malignancy: 8 (9%)
  • Tumor flare: 2 (2%)
  • Tumor lysis syndrome: 2 (2%)
• In total, 57 serious AEs (SAEs) were reported in 30 of 88 (34%) evaluable patients
  • Twenty-eight of these were SAEs during the induction phase
• Deaths: 18 (21%)
  • Progressive lymphoma: 10
  • Infection: 4
    • Including one patient who died due to treatment-related febrile neutropenia
  • Related cancer: 1
  • Unknown cause: 3

Table 6. Most common AEs

AE

N= 88

Percentage (%)

Most common AEs of any grade

Asthenia

54

61

Neutropenia

38

43

Bronchitis

36

41

Diarrhea

35

40

Muscle spasms

34

39

Most common AEs grade ≥ 3

Neutropenia

38

44

Febrile neutropenia

4

4

Thrombocytopenia

12

14

Most common SAEs

Basal cell carcinoma

5

6

Febrile neutropenia

4

5

IRR

3

3

Conclusion

The phase II GALEN study met its primary endpoint with an ORR of 79% and showed activity in all subgroups, including those with disease progression within 24 months of diagnosis. The safety profile of GALEN was deemed to be acceptable and in line with other studies using the same combination therapies. Studies comparing GALEN, or combinations using GALEN as a backbone, versus R² are warranted.

Other ongoing trials involving GALEN include:

• GALEN + atezolizumab (NCT02631577)
• GALEN versus umbralisib + obinutuzumab versus obinutuzumab + chemotherapy (NCT03269669)