Long-term Follow-up of Patients with Relapsed or Refractory Non-Hodgkin Lymphoma Treated with Venetoclax in a Phase I, First-in-Human Study.

PURPOSE: We previously reported a 44% overall response rate (ORR) with the oral BCL-2 inhibitor venetoclax in a phase I study of relapsed/refractory non-Hodgkin lymphoma (NHL). Complete response (CR) was observed in patients with mantle cell lymphoma [(MCL), 21%, n = 6/28] and follicular lymphoma [(FL), 17%, n = 5/29], and partial response (PR) noted in several patients with Waldenström macroglobulinemia (WM), and marginal zone lymphoma (MZL). Here, we report the long-term outcomes of these four cohorts. PATIENTS AND METHODS: All patients (n = 106) received venetoclax monotherapy in dose cohorts of 200 to 1,200 mg daily until disease progression or unacceptable toxicity. ORR, progression-free survival (PFS), duration of response (DoR), and adverse events (AEs) were evaluated. RESULTS: At a median follow-up of 38.5 months (range, 30.0-46.5), the median PFS for all 106 patients was 5.4 [95% confidence interval (CI), 3.5-8.4] months (FL, 10.8; MCL, 11.3; MZL, 21.2; and WM, 30.4). The median DoR was 14.9 (95% CI, 9.7-27.6) months (FL, 26.6; MCL, 15.7; MZL, 20.1; and WM, 25.3). Achievement of CR versus PR predicted longer DoR in both MCL (31.5 vs. 10.1 months) and FL (37.6 vs. 9.7 months). All grade hematologic AEs were infrequent: neutropenia (19%), anemia (19%), and thrombocytopenia (17%), with no new cytopenias after 2 years on therapy. Nonhematologic AEs included nausea (49%), diarrhea (46%), fatigue (44%), with decreased incidence after 1 year. CONCLUSIONS: Venetoclax monotherapy has a manageable safety profile and achieves durable responses in a subset of patients with FL, MCL, WM, and MZL, particularly in those who achieve CR. Further research is warranted on combination strategies to enhance the durability of response to venetoclax.

Efficacy of venetoclax plus rituximab for relapsed CLL: 5-year follow-up of continuous or limited- duration therapy.

We report long-term follow-up of the phase 1b study of venetoclax and rituximab (VenR) in patients with relapsed chronic lymphocytic leukemia (CLL), including outcomes with continuous or limited-duration therapy. Patients received venetoclax daily (200-600 mg) and rituximab over 6 months and then received venetoclax monotherapy. Patients achieving complete response (CR), CR with incomplete marrow recovery (CRi), or undetectable minimal residual disease (uMRD) assessed by flow cytometry (<10-4 cutoff) were allowed, but not required, to discontinue therapy, while remaining in the study and could be retreated with VenR upon progression. Median follow-up for all patients (N = 49) was 5.3 years. Five-year rates (95% CI) for overall survival, progression-free survival, and duration of response were 86% (72-94), 56% (40-70), and 58% (40-73), respectively. Of the 33 deep responders (CR/CRi or uMRD), 14 remained on venetoclax monotherapy (continuous therapy), and 19 stopped venetoclax therapy (limited-duration therapy) after a median of 1.4 years. Five-year estimates of ongoing response were similar between continuous (71%; 95% CI, 39-88) or limited-duration therapy (79% [49-93]). Six of 19 patients in the latter group had subsequent disease progression, all >2 years off venetoclax (range, 2.1-6.4). Four patients were retreated with VenR, with partial responses observed in the 3 evaluable to date. VenR induced deep responses that were highly durable with either continuous or limited-duration therapy. Retreatment with VenR induced responses in patients with CLL progression after discontinuing therapy. Continuous exposure to venetoclax in deep responders does not appear to provide incremental benefit.

Addition of rituximab in relapsed/refractory chronic lymphocytic leukemia after progression on venetoclax monotherapy.

Venetoclax is approved as monotherapy and in combination with rituximab for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Two Phase 1 studies (M12-175 [NCT01328626]; M13-365 [NCT01682616]) were conducted in which patients who initially responded and then progressed on venetoclax monotherapy could receive added rituximab. Ten patients were evaluated (M12-175, n = 8; M13-365, n = 2), and five (50%) responded again upon addition of rituximab, including three complete and two partial responses. Responses were ongoing after 5-10 months of follow-up. Addition of rituximab was well tolerated. These findings indicate potential clinical benefit with rituximab added to venetoclax post-progression in some patients with R/R CLL.

Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial.

Purpose Venetoclax is an orally bioavailable B-cell lymphoma 2 inhibitor. US Food and Drug Administration and European Medicines Agency approval for patients with 17p deleted relapsed/refractory chronic lymphocytic leukemia [del(17p) CLL] was based on results from 107 patients. An additional 51 patients were enrolled in a safety expansion cohort. Extended analysis of all enrolled patients, including the effect of minimal residual disease (MRD) negativity on outcome, is now reported. Patients and Methods Overall, 158 patients with relapsed/refractory or previously untreated (n = 5) del(17p) CLL received venetoclax 400 mg per day after an initial dose ramp up. Responses were based on 2008 International Workshop on Chronic Lymphocytic Leukemia criteria, with monthly physical exams and blood counts. Computed tomography scan was mandatory at week 36, after which assessment made was by clinical evaluation. Marrow biopsy was performed when complete remission was suspected. MRD was assessed by flow cytometry. Results Patients had a median of two prior therapies (range, zero to 10 therapies), 71% had TP53 mutation, and 48% had nodes that were ≥ 5 cm. Median time on venetoclax was 23.1 months (range, 0 to 44.2 months) and median time on study was 26.6 months (range, 0 to 44.2 months). For all patients, investigator-assessed objective response rate was 77% (122 of 158 patients; 20% complete remission) and estimated progression-free survival at 24 months was 54% (95% CI, 45% to 62%). For 16 patients who received prior kinase inhibitors, objective response rate was 63% (10 of 16 patients) and 24-month progression-free survival estimate was 50% (95% CI, 25% to 71%). By intent-to-treat analysis, 48 (30%) of 158 patients achieved MRD below the cutoff of 10-4 in blood. Common grade 3 and 4 adverse events were hematologic and managed with supportive care and/or dose adjustments. Conclusion Venetoclax achieves durable responses and was well tolerated in patients with del(17p) CLL. A high rate of blood MRD < 10-4 was achieved in this high-risk population.

Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with irinotecan: results of an open-label, phase 1 study.

PURPOSE: The oral Bcl-2 inhibitor navitoclax demonstrated activity in solid and hematologic malignancies as monotherapy and in combination with other cytotoxic agents in preclinical and early clinical studies. We evaluated the safety, pharmacokinetics (PK), and antitumor activity of navitoclax plus irinotecan. METHODS: In this multicenter, open-label, phase 1 dose escalation study, adults with advanced solid tumors received navitoclax (starting dose 150 mg/day) in combination with 1 of 2 irinotecan schedules during a 21-day cycle: a once-every-3-week regimen (Q3W 180, 250, or 350 mg/m(2)) or a once-weekly regimen (QW 75 or 100 mg/m(2)). Enrollment occurred until a maximum tolerated dose (MTD) and/or recommended phase 2 dose (RPTD) was reached. RESULTS: All patients (Q3W, n = 14; QW, n = 17) were evaluable for safety, PK, and efficacy. The most common adverse event in both groups was diarrhea (Q3W 92.9 %; QW 76.5 %), which was the most frequent grade 3/grade 4 adverse event (Q3W 42.9 %; QW 29.4 %). The study was amended to exclude 4 UGT1A1*28 7/7 homozygous patients due to frequent irinotecan-related grade 3/grade 4 diarrhea and/or febrile neutropenia. No apparent PK interactions between navitoclax and irinotecan were observed. The MTD of the combination was exceeded in the Q3W group at the lowest dose administered. In the QW group, the MTD and RPTD for navitoclax were 150 mg when combined with irinotecan 75 mg/m(2). One patient in each group achieved a partial response. CONCLUSION: The RPTD of navitoclax in combination with irinotecan 75 mg/m(2) QW during a 21-day cycle was 150 mg in these heavily pretreated patients.

Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with erlotinib in patients with advanced solid tumors.

PURPOSE: Navitoclax (ABT-263), a novel, oral Bcl-2 inhibitor, enhances the antitumor effects of chemotherapy in vitro by lowering the apoptotic threshold. This phase I study (NCT01009073) evaluated the safety, pharmacokinetics, and preliminary antitumor activity of navitoclax combined with erlotinib in patients with advanced solid tumors. PATIENTS AND METHODS: An open-label dose escalation study included an arm evaluating navitoclax combined with erlotinib, which included a dose escalation cohort and a planned safety expansion cohort. Patients with documented cancers for whom erlotinib therapy was appropriate received erlotinib 150 mg orally once daily plus navitoclax 150 mg orally once daily, with navitoclax dose escalation via a continuous reassessment method model. RESULTS: Eleven patients were enrolled, including six patients with nonsmall cell lung cancer. Dose-limiting toxicities, most commonly diarrhea, were observed in 4 patients. Navitoclax dosing remained at 150 mg/day because the maximum tolerated dose was exceeded at this starting dose. The planned dose escalation did not occur; no recommended phase II dose (RPTD) was identified, and there was no safety expansion cohort. The most common treatment-related adverse events were diarrhea, nausea, vomiting, and decreased appetite. Pharmacokinetic analysis showed no apparent interactions between co-administered navitoclax and erlotinib. No objective responses were observed; the disease control rate was 27 % (95 % CI, 6-61 %). CONCLUSION: At the erlotinib and navitoclax doses administered, RPTD was not reached, but the safety profile of the combination was consistent with data from monotherapy studies. There were no apparent pharmacokinetic interactions between erlotinib and navitoclax. Three patients had stable disease.