In the PIVOT-CLL trial, time-limited pirtobrutinib, venetoclax, and obinutuzumab produced deep, durable molecular remissions in treatment-naive CLL.
Time-limited pirtobrutinib (Jaypirca) plus venetoclax (Venclexta) and obinutuzumab (Gazyva) produced high rates of undetectable measurable residual disease (U-MRD) in patients with treatment-naive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to findings from the investigator-initiated phase 2 PIVOT-CLL trial (NCT05536349) presented at the
By the end of cycle 7, 92% of 77 total patients were U-MRD at or above a threshold of 10–4 (U-MRD4) in peripheral blood, and 88% of patients were U-MRD4 in bone marrow. By the end of cycle 13 (approximately 1 year of therapy), 100% of evaluable patients (n = 77) were U-MRD4 in peripheral blood, and 96% of patients were U-MRD4 in bone marrow, with 86% and 74% of patients achieving the deeper U-MRD threshold of 10–6 (U-MRD6) in blood and marrow, respectively. At a median follow-up of 30.9 months (range, 2.0-42.5), the 2-year progression-free survival rate was 99% (95% CI, 96%-100%), and the 2-year overall survival rate was 99% (95% (CI, 96%-100%). Eighty-six percent of evaluable patients met protocol criteria to discontinue all therapy after cycle 13, with 45 in complete remission and 21 in partial remission after the first year.
The trial investigators noted that additional treatment beyond that point did not appear to deepen remissions further.
“Best response seems to occur within the first year with this triplet therapy,” Nitin Jain, MD, stated in a presentation of the data.
Jain is a professor of leukemia in the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.
Jain explained that covalent BTK inhibitor–plus–BCL-2 inhibitor combinations, with or without a CD20 antibody, have already produced high rates of U-MRD in CLL across multiple doublet and triplet regimens in clinical trials. The efficacy of pirtobrutinib, a noncovalent BTK inhibitor that was
Eligible patients for PIVOT-CLL were treatment naive with CLL or SLL meeting 2018 International Workshop on CLL treatment criteria, at least 18 years of age, and had an ECOG performance status of 0 to 2 and adequate organ function.1
Treatment began with pirtobrutinib (at 200 mg daily) and obinutuzumab (at 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15) alone in cycle 1 for debulking, followed by the addition of venetoclax weekly ramp-up doses in cycle 2. Obinutuzumab dosing at 1000 mg was continued on day 1 of each cycle through cycle 6, along with pirtobrutinib at 200 mg daily and venetoclax at 400 mg daily. Then, the pirtobrutinib/venetoclax doublet was continued through cycle 13, with an option to continue pirtobrutinib plus venetoclax for an additional 12 cycles in patients with residual MRD levels at or above the 10⁻⁵ threshold.
PIVOT-CLL Trial: Key Takeaways
Among the 80 enrolled patients, the median age was 63 years (range, 38-78), 79% had unmutated IGHV, 49% had Rai stage III/IV disease, and 13% had 17p deletions/TP53-mutated disease.
A single cycle of obinutuzumab-based debulking downgraded tumor lysis syndrome risk category in 90% of high-risk and 86% of medium-risk patients before venetoclax initiation.
Moreover, serial peripheral blood testing showed a climb from a 40% U-MRD6 rate at the end of cycle 4 to a rate of 86% at the end of cycle 13.
Among the 66 patients who discontinued all therapy per protocol, the median follow-up off treatment was 18.9 months (range, 7.8-30.4). Two patients had MRD4 recurrence in peripheral blood. One patient (with unmutated IGHV, 11q deletion, and a NOTCH1 mutation) progressed 13.6 months after stopping therapy, with imaging and biopsy findings consistent with accelerated CLL. One patient died of infection 8.7 months after treatment completion while still in U-MRD6 remission. The 18-month MRD4-free survival rate among the patients who discontinued therapy was 93% (95% CI, 87%-100%).
Eleven of 77 patients (14%) who had residual MRD at a sensitivity of at least 10⁻⁵ in blood or marrow at the end of cycle 13 were eligible to receive a second year of pirtobrutinib plus venetoclax; this subgroup was enriched for high-risk features, including unmutated IGHV in 8 of 11 patients and TP53 aberrations in 3 of 11 patients. Nine patients completed the extension protocol, but additional treatment produced only modest further deepening of response, with just 1 of 9 patients with marrow-positive disease and 1 of 5 patients with blood-positive disease reaching U-MRD6 after the second year.
Grade 3/4 neutropenia and thrombocytopenia occurred in 69% and 17% of patients, respectively, and 63% of patients required granulocyte colony-stimulating factor support. Additionally, neutropenic fever occurred in 5% of patients. Venetoclax and pirtobrutinib doses were reduced in 36% and 21% of patients, respectively, most commonly because of neutropenia, and atrial fibrillation occurred in 2 patients.
“Grade 3/4 neutropenia is common and is in line with [findings from] some of the other CLL triplet trials,” Jain concluded.
PIVOT-CLL trial enrollment has since completed with 160 total first-line patients following a cohort expansion, with long-term safety and efficacy follow-up ongoing.
