New data from the Phase II CAPTIVATE (PCYC-1142) study investigating ibrutinib in combination with venetoclax, presented a potential chemotherapy-free, fixed-duration treatment option for patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The results were presented during an oral presentation at the 2021 American Society of Clinical Oncology Annual Meeting (Abstract 7501).
CAPTIVATE is a multicenter, Phase II study of first-line ibrutinib + venetoclax (I+V) in CLL. The study followed up on results from the minimal residual disease (MRD) cohort in which undetectable MRD (uMRD) was achieved in over two-thirds of patients with 12 cycles of I+V, and 30-month progression-free survival (PFS) rates were >=95 percent irrespective of subsequent randomized treatment. Results were first presented at the 2020 American Society of Hematology Annual Meeting (Abstract 123). The new research shows results from the fixed-duration cohort.
In the ibrutinib and venetoclax fixed-duration cohort, the primary endpoint was complete response rate, including complete response with incomplete recovery. Key secondary endpoints were objective response rate, duration of response, uMRD rate (<10-4 by 8-color flow cytometry), PFS, OS, and tumor lysis syndrome (TLS) risk category reduction based on tumor burden shifted to medium- or low-risk after ibrutinib lead-in therapy and AEs.
The CAPTIVATE study evaluated 159 patients between the ages of 18 and 70 years old with CLL/SLL. Patients received 3 cycles of ibrutinib lead-in followed by 12 cycles of I+V (ibrutinib 420 mg/day PO; venetoclax ramp up to 400 mg/day PO). High-risk features included del(17p)/TP53 mutation (17%), del(11q) (18%), complex karyotype (19%), and unmutated IGHV, (56%). A total of 147 (92%) and 149 (94%) patients completed planned treatment with ibrutinib and venetoclax, respectively. Median time on study was 27.9 months (range, 0.8-33.2).
The ibrutinib and venetoclax cohort met its primary endpoint of complete response (CR) rate of 56 percent (95% CI 48-64) among patients without del(17p), 70 years old or younger, and with 27.9 months of follow-up. This rate was higher than the 37 percent minimum meaningful rate study assumption (P<0.0001). The CR rate was consistent across all patients in the study, including high-risk CLL patient groups. Furthermore, 24-month PFS and overall survival (OS) were 95 percent and 98 percent, respectively.
"What stood out to me as a participant in this study were the high complete response rates in almost all the subgroups that were looked at including various high-risk groups. Overall, the study had a 55 percent CR rate. All the subgroups, including deletion 17p, TP 53 mutant, deletion 11q, and immunoglobulin heavy chain variable region unmutated showed high CR rates. The only group that did not have a high CR rate were patients with bulky disease, 5 centimeters or greater, who had a 31 percent CR rate. Otherwise, all groups, including those with advanced stage and those with advanced age achieved that high complete response rate," said Rajat Bannerji, MD, PhD, Hematologist/Oncologist, Chief of Hematologic Malignancies, and Professor of Medicine in the Division of Blood Disorders at Rutgers Robert Wood Johnson Medical School, who is a co-author on the abstract.
"The other main observation was the very high rate of undetectable minimal residual disease, with 77 percent undetectable MRD rate in blood and 60 percent in the bone marrow across the entire study population. I think the high-level uMRD rate was pretty impressive and hopefully predicts for really good, sustained responses in these patients."
The most common Grade 3/4 adverse events were neutropenia (33%), infections (8%), hypertension (6%), and decreased neutrophil count (5%). Adverse events led to discontinuation of ibrutinib in 4 percent and venetoclax in 2 percent of patients. Overall, the safety profile of the combination was generally consistent with known adverse events for each agent and no new safety signals were identified.
One particular finding of note was that, of 34 patients with high baseline tumor lysis syndrome risk based on tumor burden, 32 (94%) shifted to medium or low risk. After ibrutinib lead-in, no tumor lysis syndrome occurred.
"I think it's really reassuring that, as a frontline therapy, this doublet combination is very active, and the ibrutinib run-in reduces the risk of tumor lysis syndrome, so it gives you confidence to treat patients with this combination in terms of tumor lysis syndrome risk. Because we know with venetoclax there is a risk of tumor lysis in patients with either a high circulating lymphocytosis, with bulky disease, or with both," said Bannerji.
"In this study, there is a 3-month run-in with ibrutinib alone before the venetoclax is added, and then there are 12 months of the combination. The 3 cycle run-in period was enough to get 94 percent of patients, or 32 out of 34, who at study entry fit the high tumor burden category, down staged, if you will, to either a medium or low tumor lysis risk category. That again lends itself to the idea that you could manage most patients entirely as an outpatient with this regimen, not having to admit them to the hospital for TLS, prophylaxis, and monitoring."
The authors concluded that the fixed-duration regimen provided deep, durable responses in patients with CLL/SLL, including those with genomic high-risk features. While the study is still in the realm of clinical trials, Bannerji said he is looking forward to seeing the implications for further research and treatment.
"I think there are going to be a lot of nuances to the study that will come out with longer follow-up. The progression-free survival is quite high, 95 percent at 2 years, and overall survival is 98 percent at 2 years. The question over time will be: Who are the patients who progress and what's going on in those patients? Is there clonal evolution of the CLL with selection of high mutations or new resistance mutations? How will patients who progress despite this very active regimen respond to future lines of therapy?" he noted.
There are other ongoing trials exploring the potential of ibrutinib and venetoclax in combination for CLL treatment, including the Phase III GLOW study. Results from this ongoing study, assessing the ibrutinib plus venetoclax combination in comparison to chlorambucil plus obinutuzumab for first-line treatment of patients with CLL or SLL (NCT03462719), were presented at the European Hematology Association 2021 Congress. Bannerji brought up more research questions that should be explored.
"Another interesting observation will be: Are there patients who will not require any further treatment? Will we see a plateau where this combination regimen might be the only treatment some patients require, and then if so, who are those patients? How can we predict for the long-term responders versus the shorter-term responders?" noted Bannerji. "For example, if we go back to the German CLL8 study, we know young, good risk patients who were treated with the FCR chemotherapy regimen, [and] there was clearly a plateau with that regimen where some patients had very long-term, progression-free survival, of whom some may have been cured."
"Again, it's going to be interesting now with these two oral novel therapies combined: Are we going to see a plateau and who are those patients? Longer follow-up is going to give us a lot of information about this regimen and there is potential for further study and further research," Bannerji concluded.
Sarah LaCorte is associate editor of Oncology Times.