CLL Research: Phase 2 CAPTIVATE Study Suggests Role for Fixed-Duration Treatment of CLL/SLL

Ibrutinib (Imbruvica®) is a Bruton’s Tyrosine Kinase (BTK) inhibitor. Ibrutinib binds to BTK and shuts down this proliferation signaling protein which plays a part in the rapid growth of malignant cells. BTK occurs downstream of the B-cell receptor signaling pathway and is over-expressed in malignant cells. The U.S. Food and Drug Administration approved the use of ibrutinib for relapsed/refractory (R/R) CLL in February 2014. It is now a recommended drug for the treatment of both treatment naïve and R/R patients. Ibrutinib is the only once daily BTKi, and it has shown significant overall survival (OS) benefit as front-line therapy in the randomized Phase 3 RESONATE-2 and ECOG1912 clinical trials. Ibrutinib is effective in patients who have historically been considered high-risk, including those patients with deletion 17p and TP53 mutations. The U.S. FDA has approved two generic versions of ibrutinib in recent months, but they are not yet available for distribution. These generics from manufacturers in India will likely reduce the cost of treatment once they enter distribution.

This study builds upon the Phase 2 CAPTIVATE study that enrolled 149 patients under age 70 who had not received any prior treatment for their CLL. These patients received three months of ibrutinib monotherapy followed by 12 months of both ibrutinib plus venetoclax. The three months of ibrutinib monotherapy served to debulk the disease-burden and reduce the risk of tumor lysis syndrome (TLS) before starting venetoclax.
uMRD, defined as 100% uMRD in peripheral blood and bone marrow serially over three or more treatment cycles (28-days), was found in 75% of patients’ blood and 72% of patients’ bone marrow.
This data begins to answer the question, is fixed-duration treatment possible and effective? The next step was to determine if patients can come off therapy after reaching uMRD through a fixed-duration treatment?

After completing the fifteen-month fixed duration treatment portion of the CAPTIVATE study, 86 patients with confirmed uMRD were randomized 1:1 to receive ibrutinib or placebo. This study segment was double-blinded, so neither investigators nor patients knew a patient was receiving ibrutinib or a placebo. Those patients who did not meet the definition of uMRD were randomized 1:1 to take open-label ibrutinib or to continue with the combination of ibrutinib and venetoclax.

The primary end-point or goal for this study was 1-year Disease-Free Survival (DFS). DFS is defined as survival with no clinical progression or a change from uMRD status. The secondary end-points were to assess rates of uMRD (less than one malignant cell in 10,000) via flow cytometry), responses according to the International Workshop on CLL (iwCLL) guidelines, progression-free survival (PFS), and adverse events (AEs).

The uMRD cohort consisted of 86 patients with confirmed uMRD who were randomized to ibrutinib (n=43) or place (n=43). The 63 patients who did not meet the definition of confirmed uMRD given above were randomly assigned to receive ibrutinib (n=31) or ibrutinib plus venetoclax (n=32).

In the confirmed uMRD group, the one-year DFS was not statistically different for patients randomized to placebo (95.3%) versus 100% for those who continued on ibrutinib.

The data in the uMRD cohort of this trial suggest that fixed-duration therapy is feasible in patients who achieve undetectable MRD (uMRD) status. The selection of durations for these clinical trials can be arbitrary. Investigators hope that the follow up of patients who did not achieve uMRD within the initial fifteen months may show that longer “MRD-guided” courses of treatment can result in a better understanding of what is the optimal treatment duration with combination therapy of ibrutinib plus venetoclax. Investigators hope to publish this data at future conferences.

There are several reasons to look for fixed-duration treatments. Providers like fixed durations because they limit exposure to drugs which can impact side effects or toxicities. Further, investigators theorize that if you are not on continuous treatment, you reduce the chance of resistance developing to a drug and increase the potential to re-treat using this same agent. (See article in Recent Articles Section of our website that features an article by Dr. Meghan Thompson on successful retreatment with venetoclax.)

The question remains as to the advisability of stopping all therapy upon attainment of uMRD. This study begins to answer this question with 1-year DFS data that indicates little difference in outcomes for those who continue on ibrutinib versus those who stopped treatment because they received placebo. I personally am affected by this research as I was able to attain uMRD seven months after adding venetoclax to the ibrutinib I had taken for more than three years. My specialist and I agreed that there is still not enough long-term data for a high risk patient such as me to cease some form of therapy. It will be interesting to see data after longer follow-up in this clinical trial.

This is exciting early data that hopefully bring us closer to determining the efficacy of fixed-duration treatments in attaining uMRD and hopefully be able to withhold treatment for a significant period of time without relapse. There are many studies of different combinations being conducted world-wide to attempt to find the best combination of drugs with the lowest side effect profiles. In the past, the only fixed-duration treatments were chemoimmunotherapy which can have long-term toxic effects on our bodies, and raise our risk of infection and secondary cancers above levels associated with the disease itself.