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

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

Characteristic	Patients (n = 15)
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
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.