Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma

Background:

Ibrutinib (I) and venetoclax (V) have each demonstrated modest single-agent activity in relapsed/refractory follicular lymphoma (FL) (Gopal A, JCO 2018; Davids M, JCO 2017). Preclinical data have shown synergy with these agents in B‐cell cell lines (Kuo H, Mol Cancer Ther 2017). Based on these observations, we proposed the first trial to combine I and V in FL. Results from the phase Ib portion of this multi-institutional investigator-initiated trial are presented here (NCT02956382).

Methods:

This phase Ib/II trial is open at Georgetown/Lombardi CCC, Hackensack/John Theurer CC, and University of Washington/Fred Hutchinson/Seattle Cancer Care Alliance. Eligibility criteria include WHO grade 1‐3a FL, >1 prior systemic therapy, measurable disease warranting therapy by standard criteria or physician discretion, ECOG performance status < 2, adequate marrow, hepatic, renal function. Patients (pts) were enrolled in a standard phase I 3+3 design at a starting dose level (DL) of I 420 mg daily, V 400 mg daily (DL0). The highest initially planned dose level was DL3: I 560 mg daily, V 800 mg daily. There was no dose ramp up of V based on monotherapy experience in FL. Pts at high risk for tumor lysis syndrome (TLS), defined as node ≥ 8 cm and/or significant lymphocytosis, were hospitalized for initial dose. Pts received study drugs until progression or unacceptable toxicity. Response was assessed by PET-CT and bone marrow biopsy (if marrow involvement present at time of enrollment).

Results:

Sixteen pts were enrolled between November 2017 - May 2020. Median age was 66 years (range 50-87); 75% were male; 75% were Stage III/IV, 94% had WHO grade 1/2 FL (Table 1). FLIPI score at enrollment was 25% low risk, 44% intermediate risk, 31% high risk. Two pts were considered high risk for TLS. Pts received a median of 2 prior therapies (range 1-8); 19% were refractory to last line of therapy. Cohort enrollment was: DL0 (n=3), DL1 (n=6), DL2 (n=6), DL3 (n=1). The protocol was amended to close DL3 based on pharmacokinetic data from DL2 indicating a 1.8-fold higher mean steady-state ibrutinib plasma exposure compared to ibrutinib 560 mg monotherapy and concern for potential toxicity.

Grade 3 adverse events (AE) included neutropenia (25%), thrombocytopenia (13%), lung infection (13%), upper respiratory infection (6%), neutropenic fever (6%), atrial fibrillation (6%), ALT/AST elevations (6%), mucositis (6%), failure to thrive in setting of progression (6%), abdominal pain (6%). There were no grade 4/5 AE. Grade 1/2 AE occurring in > 20% of pts included diarrhea (75%), nausea (63%), bruising (38%), rash (31%), headache (31%), constipation (25%), fatigue (25%). There was no evidence of clinical TLS; 19% had grade 1 hyperuricemia. The pt enrolled at DL3 had grade 1 diarrhea, grade 1 neutropenia. One dose limiting toxicity (DLT) occurred at DL1 (I 560 mg, V 400 mg): grade 3 neutropenia with fever and infection. There were no other DLTs. Therefore, DL2 (I 560 mg, V 600 mg) was determined to be the recommended phase 2 dose (RP2D).

The ORR was 69% (0.413, 0.890); CR 25% (0.073, 0.524). The ORR at the RP2D was 83% (CR 33%). Responses by dose level are listed in Table 2. The regimen demonstrated activity in the bone marrow; 2 pts had eradication of involvement and 1 had a decrease from 60% to 0.5% by flow cytometry. Response by lines of prior therapy: 1 (86%, 6/7), > 2 (56%, 5/9). Most pts (91%) had a response by time of first assessment (12 weeks).

The median progression-free survival (PFS) was 8.3 months (5.6 months, NA) (Figure 1). Of note, 2 responding pts chose to withdraw from study due to travel and were censored in the PFS analysis at time of discontinuation. One remained in a CR at least 9 months after study withdrawal as documented by PET-CT performed off protocol. No pts discontinued due to toxicity.

Conclusion:

In the first clinical trial to combine a BTK inhibitor and a BCL-2 inhibitor in relapsed/refractory FL, we found the I-V doublet to demonstrate a toxicity profile similar to that seen in mantle cell lymphoma and CLL. While our sample size is small, there was no evidence of clinical TLS, despite omission of the V ramp up. Preliminary results of anti-tumor activity are encouraging and further evaluation at the RP2D (I 560 mg, V 600 mg) is ongoing in the phase II trial. The combination of ibrutinib and venetoclax may provide an effective option for FL, utilizing a targeted approach distinct from other novel agents currently approved for this malignancy.