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Results from the OAsis phase I/II trial on ibrutinib, venetoclax plus obinutuzumab in patients with newly diagnosed mantle cell lymphoma

Jul 23, 2020
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During the 2020 European Hematology Association (EHA) Annual Congress, Steven Le Gouill presented data from Cohort C of the OAsis phase I/II study (NCT02558816), investigating the safety and efficacy of ibrutinib, venetoclax plus obinutuzumab in patients with newly diagnosed mantle cell lymphoma (MCL).

The aim of this non-randomized trial was to identify the maximum tolerated dose of venetoclax when combined to fixed doses of ibrutinib and obinutuzumab. Secondary endpoints included safety, efficacy, response rates, progression-free survival, and overall survival.

Study design

The study included three cohorts:

  • Cohort A (n = 9): patients with relapsed/refractory (R/R) MCL receiving ibrutinib and obinutuzumab
  • Cohort B (n = 24): patients with R/R MCL receiving ibrutinib, venetoclax plus obinutuzumab
  • Cohort C (n = 15): patients with newly diagnosed untreated MCL receiving ibrutinib, venetoclax plus obinutuzumab
    • The treatment schedule is reported in Figure 1

Inclusion criteria for cohort C:

  • Age ≥ 18 for French patients, age ≥ 16 for English patients
  • Untreated patients with histologically confirmed MCL in need of treatment
  • Disease stage II─IV
  • Eastern Cooperative Oncology Group Performance Status 0─2

Figure 1. Treatment schedule1

C, cycle; D, day; W, week

Patient characteristics

Patient characteristics are reported in Table 1. Patients were rather young with quite an aggressive disease.

Table 1. Patient characteristics1

BM, bone marrow; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IGHV, immunoglobulin heavy chain variable region; MIPI, mantle cell lymphoma International Prognostic Index; NGS, next-generation sequencing; TP53, tumor protein 53

 

Characteristic

Patients

(n = 15)

Median age, years (range)

65 (51─77)

Female/Male, n (%)

9 (60)/ 6 (40)

Stage III–IV, n (%)

15 (100)

BM involvement, n (%)

8 (53)

Pleomorphic, n (%)

1 (7)

Tumor size ˃ 5 cm, n (%)

6 (40)

ECOG PS < 2, n (%)

15 (100)

MIPI high risk, n (%)

4 (27)

MIPI intermediate risk, n (%)

11 (73)

Cytogenetic and molecular features, n (%)

TP53 mutated (NGS)

17p deletion

IGHV mutated (NGS)

 

2 (13)

6 (40)

2 (13)

Results

Safety

The triplet was well tolerated in patients who have never been exposed before to chemotherapeutic agents. The most common Grade 3 and 4 adverse events/serious adverse events, observed from Cycle 1 to Cycle 6, are reported in Table 2.

Table 2. Adverse events and serious adverse events from Cycle 1 to Cycle 61

ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase

Events

Grade 3

Grade 4

Adverse events, n (%)

All adverse events

Neutropenia

Lymphopenia

Rash

ALAT increased

ASAT increased

Hepatic cytolysis

Hyperlymphocytosis

 

5 (33)

2 (13)

1 (7)

1 (7)

0

1 (7)

0

1 (7)

 

3 (20)

1 (7)

0

0

1 (7)

0

1 (7)

0

Serious adverse events

All serious adverse events

Appendicitis

 

1 (7)

1 (7)

 

0

0

Efficacy

The triplet induced very high complete remission (CR)/unconfirmed CR (CRu) rate very early. According to Cheson et al. (1999) criteria:2

  • After Cycle 2
    • Eight patients (53%) were in CR/CRu and seven (47%) in partial remission (PR)
  • After Cycle 4
    • 12 patients (80%) were in CR/CRu and two (13%) in PR
  • After Cycle 6
    • 12 patients (80%) were in CR/CRu and two (13%) in PR

According to the Lugano (2014) criteria:3

  • After Cycle 6
    • 13 patients (86%) were in CR/CRu and one (7%) in PR

After a median follow-up of 14 months (range, 5─19), only one patient progressed (not TP53 mutated nor 17p deleted) and 14 patients remained in CR and under treatment.

Measurable residual disease (MRD) was assessed in all evaluable patients:

  • At the end of Cycle 3 and at the end of Cycle 6, all the evaluable patients (n = 12, and n = 11, respectively) were MRD negative in peripheral blood
  • At the end of Cycle 6 all evaluable patients (n = 10) were MRD negative in the bone marrow
  • In comparison with Cohort A and Cohort B, which consisted of R/R MCL patients, the MRD negativity rate was higher in Cohort C (after Cycle 3, 66.5 % vs 78.6% vs 100.0%, and after Cycle 6, 66.5 % vs 77.0% vs 100.0%, respectively). This suggested that the efficacy of the therapy is better if given early in the course of the disease.

The progression-free survival at 1 year was 93.3% (95% confidence interval, 81.5─100.0%) and the overall survival was 100% at 1 and 2 years.

Conclusion

The triplet therapy was well tolerated and effective in untreated patients with MCL, with all evaluable patients remaining MRD negative at the end of Cycle 6 in both blood and bone marrow. These results will be further validated by a larger phase II trial (OAsis II) that is due to start at the end of 2020. This study will compare ibrutinib, venetoclax plus anti-CD20 antibody vs ibrutinib, and anti-CD20 antibody therapy as frontline for adult patients with newly diagnosed MCL.

  1. Le Gouill S, Morschhauser F, Boua K, et al. Ibrutinib, venetoclax plus obinutuzumab in newly diagnosed mantle cell lymphoma patients. Oral presentation #S228. 25th EHA Annual Congress; Jun 11─21, 2020. Virtual.
  2. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17(4):1244. DOI: 10.1200/JCO.1999.17.4.1244
  3. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068. DOI: 10.1200/JCO.2013.54.8800

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