The background of this study, or the rationale for the combination of these two oral agents, ibrutinib and venetoclax, is that they have distinct modes of action but these are complementary and they work synergistically. What has been seen is that these drugs, especially the BTK inhibitors like ibrutinib, can mobilise CLL cells out of lymph nodes and other protected niches and drugs like venetoclax can accelerate apoptotic cell killing through the Bcl-2 pathway. Working together the two drugs can eliminate both resting and dividing CLL cell subpopulations. Hence the study design to combine these two active agents.
What was the methodology used in this study?
At the ASCO meeting what was presented in the CAPTIVATE study was the fixed duration part of the study. In this study patients received three cycles of ibrutinib as a lead-in treatment, followed by twelve cycles of ibrutinib combined with venetoclax. There is another part to this study that was presented previously and that was the so-called MRD part of the study. That was presented at the American Society of Haematology 2020 meeting in December of 2020 by Professor William Wierda of MD Anderson Cancer Center. But, again, at the ASCO meeting just this week what was presented was the fixed duration cohorts.
What were your findings?
The primary endpoint of the study was the CR/CRi rate as assessed by the investigator in patients without deletion 17p. The analysis was also conducted in all treated patients. The study was powered to exclude a minimum CR rate of 37% with a one-sided alpha of 0.025 in patients without deletion 17p. This was based on prior data from the CLL10 study in which the FCR chemotherapy combination had a CR rate of 40%. Secondary endpoints were fairly standard, they included the overall response rate, the duration of response, undetectable MRD status, progression free survival, overall survival and reduction in tumour lysis syndrome risk category based on the lead-in part of the study with ibrutinib and finally overall safety.
The study reported data in this fixed duration cohort of 159 patients and in terms of completing the full twelve cycles of combination therapy that ended up being about 147 patients. The difference is due to patients who came off study for a variety of reasons.
In terms of the study population there were a number of patients with poor risk features, this included 56% of the study population with an unmutated immunoglobulin heavy chain variable region, 17% of the study population with either deletion 17p or TP53 mutation and 19% of the study population with a complex karyotype. In addition, about 30% of the study population had bulky disease with lymph node mass greater than or equal to 5cm.
In terms of the primary endpoint of CR/CRi assessed by the investigator, in patients without deletion 17p the overall response rate was 96%, the CR rate was 54.4% with an additional CRi rate of 1.5%. In all treated patients again the overall response rate was 96%, the CR rate was 52.2% and the CRi rate was 3.1%. So the primary endpoint of the study was met with a 56% CR/CRi rate in patients without deletion 17p.
When various characteristics were looked at and a Forest plot analysis was presented at the ASCO meeting, various variables did not affect the CR rate and these included age, stage of disease, 17p or TP53 mutation status or immunoglobulin heavy chain variable region mutation status. The only subpopulation that seemed to have an effect on CR rate was bulky disease and in patients with lymph node of 5cm or greater the CR rate was 31% whereas in patients without bulky disease the CR rate was 66%. All the other variables were around the overall study CR rate in the total population of about 55%.
Other endpoints that were looked at were the rates of undetectable minimal residual disease and the best undetectable MRD rates in peripheral blood were 76% of patients in those without deletion 17p and 77% in the entire study population. Undetectable MRD was 62% in patients without deletion 17p and 60% in the overall study population. When the combination of ibrutinib and venetoclax were looked at in terms of progression free survival and overall survival those rates were quite high and here I’ll just mention the entire study population, all treated patients, and the 24-month PFS rate was 95% and the 24-month overall survival rate was 98% for the entire study population.
When we look at just patients with deletion 17p or TP53 mutation we see actually similar results in terms of response rate. So overall response rate in the 17p population was 96% with a CR rate of 52%, CRi of 4%, so overall a CR/CRi rate of 56%, very similar to the entire study population. When we look at MRD or undetectable MRD rates in peripheral blood in the deletion 17p/TP53 population that was 81%. The bone marrow undetectable MRD rate was 41%. Then the other endpoints that I’ve mentioned previously for the whole study included the 24-month PFS rate and for the deletion 17p population that was 84% and the 24-month overall survival rate for the deletion 17p population was 96%. Of the total study population, again, these were 27 individuals.
That was the majority of data for the study. The final point I wanted to make was the three cycle ibrutinib lead-in was able to reduce the tumour burden in patients and therefore reduce their risk of tumour lysis syndrome from venetoclax. So in terms of reducing that risk at baseline about 94% of patients who had a high tumour burden category, and this was out of a total of 34 patients who had a high tumour burden category, 32% were able to reduce that high category for TLS down to either medium or low. Fewer than one in five patients of the entire study, about 18%, had an indication for hospitalisation for TLS prophylaxis or monitoring. It’s important to note that no clinical TLS occurred in the study and no patient had laboratory TLS per a very standard criteria called the Howard criteria.
How can these results impact the future treatment of CLL/SLL?
In terms of the results of the study and conclusions reached, the combination of ibrutinib and venetoclax met the primary endpoint with a CR/CRi rate of 56% and similar rates were seen in patients in the overall population and those with high risk features such as deletion 17p. The study had a favourable safety profile and 92% of the patients on study completed the entire fixed duration combination and three cycles of ibrutinib lead-in provided effective tumour debulking, as we just discussed, reducing the percentage of patients who were at high risk for tumour lysis syndrome.
Results of this fixed duration cohort were consistent with the previously presented MRD cohort that was presented at ASH in December of 2020 and these results support this combination fixed duration, all oral, once daily chemotherapy free regimen which, as we saw from the undetectable MRD data, results in deep responses and, as we saw from the 24-month PFS and overall survival data, leads to durable responses in patients.
Again I will just point out that this combination is not approved yet by any regulatory authority but it does set the stage in future for these combination oral regimens, hopefully resulting in long-term disease free survival for patients with CLL.