Ibrutinib Extends PFS in Patients with TP53-Mutated Chronic Lymphocytic Leukemia

John N. Allan, MD

For patients with chronic lymphocytic leukemia (CLL), the presence of a TP53 mutation is a strong negative predictor of survival and first-line chemotherapy is often sub-optimal for this patient population, with a progression-free survival (PFS) of 18% and an overall survival (OS) of 38%. However, a pooled analysis presented during the 62nd American Society of Hematology Annual Meeting and Exposition suggested that first-line treatment with ibrutinib (Imbruvica) could help improve PFS in this vulnerable patient population.

For the analysis, data was pooled from the PCYC-1122e (NCT01500733; single-agent ibrutinib; n=34), PCYC-1130 (NCT02264574; ibrutinib + obinutuzumab; n=18), ECOG1912 (NCT02048813; ibrutinib + rituximab; n=26), and RESONATE-2 (NCT01722487; single-agent ibrutinib; n=11) studies. Both ECOG1912 and RESONATE-2 excluded patients with del(17p) but did not exclude patients with TP53 mutations. PFS, OS, and safety were reported in each study.

According to the analysis, 89 patients were included. The median age of the patients was 65 and 69% of patients were male. At baseline, 53% had Rai stage III/IV and 38% had bulky disease. Additionally, 69% had unmutated IGHV. Of the 89 patients, 45 received ibrutinib as a single agent while 44 received it in combination with an anti-CD20 agent.

At the 48-month mark, the PFS was 79% and the OS was 88%. The median duration of treatment was 46 months. The most common reason for treatment discontinuation was progressive disease (20%), study closure (12%) and, adverse events (AE’s) (10%). At the current follow-8-, 46% of patients remained on ibrutinib.

In an interview with Targeted Oncology, John N. Allan, MD, a hematology oncologist at Weill Cornell Medicine, discussed how ibrutinib extends PFS in patients with CLL. He also discussed combination therapy in the future of CLL treatment.

TARGETED ONCOLOGY: Prior to this analysis, what data did we have to support BTK inhibition in this patient subset?

ALLAN: There was limited data, which is kind of the impetus for this study. Most of these clinical trials that have been done prospectively excluded subjects with some TP deletion. And there were certain subsets that did have mutations on them. But when we mined the data, there is just so few patients from any one specific study, there was no good way to understand how they are doing long term. Most of our evidence came from one of the studies that are included in this, from the NCI. Which is done as a phase 2 study enrolling subjects with 17p deletion and treated with frontline Ibrutinib (Imbruvica). But that was only 34 subjects and to date, that had some of the longest follow-up that had been reported. Given this dearth of long-term evidence and small numbers patched around the literature, that was the need to bridge this knowledge gap, which was the reason for this study of myself and the co-authors.

TARGETED ONCOLOGY: What methods were used to conduct the analysis and what 4 trials were included?

ALLAN: We took a pooled analysis of 4 clinical trials. The 4 clinical trials were the phase two NCI study that I had stated, PCYC-1122e, the ECOG1912 study, the ILLUMINATE and the RESONATE-2 study. The latter 3 are all phase 3 studies. We took these arms with the ibrutinib-based therapies and evaluated how many subjects when each of those arms had p53 disruption, defined by 17p deletion and/or TP53 mutation, and combined those subjects finding 89 total patients across those 4 clinical trials. That allowed us to have enough power and statistics to understand how this patient population may do over time.

TARGETED ONCOLOGY: What did ultimately the long-term results show?

ALLAN: The main outcomes that we're looking at were PFS, OS, response, and safety. Ultimately, we found these 89 subjects had TP53 disruption, and the median age was 65 years, and 69% of patients had unmutated IGHV. All 89 subjects had FISH analysis available, and we found that 53% of the patients included had a deletion of 17p present. Not all patients had sequencing available. But we did find that 58 of the 89 subjects did have sequencing results available and of those, 91% patients were positive for the mutation and were included in this study. When we looked at this and pooled the data, the median follow-up was for 15 months on ibrutinib.

I should note that the ILLUMINATE and the EGOG1912 studies incorporated Ibrutinib plus anti-CD20, either rituximab (Rituxan) or obinutuzumab (Gazyva). It was a mixed population in terms of the ibrutinib- based therapy. The other studies were using monotherapy only. When we looked at that, about half of the patients were treated with monotherapy, and half of the patients were treated with anti-CD20. Then when you look at the long-term outcomes, which is the whole point of doing the study, the 4-year PFS rate was 79%, and the 4-year OS rate was 88%. [The results] were rather impressive and shows that while these patients historically have done very poorly, they appear to be doing pretty well and overcoming some of this high-risk features of their disease biology.

With that said, we did find that in 20% of patients, the primary reason for ibrutinib discontinuation was progressive disease. In other studies, without these high-risk patients, it's kind of the opposite. We don't see progressive disease as a major cause of discontinuation and rather we see adverse events being a major cause of discontinuation. This leads us to believe that these patients are at risk of failure, though, they are still doing very well. There may be a subset as we tease out the data a little bit further, that we will identify that we can expect that will do well as patients without these aberrations.

TARGETED ONCOLOGY: Were there any differences in the safety profile in a specific population versus standard risk patients?

ALLAN: We did not see any new safety signals, and we didn't necessarily expect to. Ultimately, we found that safety was consistent with previous reports. We found that the most common AE's typically declined with time on the drug over the years, which has been reported in many of these ibrutinib-based studies. And ultimately, we found that 9 patients discontinued ibrutinib due to an adverse event, and 2 of those subjects were due to atrial fibrillation. So, there are the same signals that we've seen previously, but nothing new in this higher-risk patient population. These are all frontline treated patients. So, they haven't had previous therapies and technically are more fit than in relapsed/refractory settings.

TARGETED ONCOLOGY: Was there anything about the analysis that surprised you?

ALLAN: I think we were not necessarily surprised. We were somewhat expecting to see good outcomes. I do think the outcomes look really good, and maybe that's surprising in this high-risk patient population. We expected to see this based on some of the anecdotal evidence, and some of the data that's been published thus far. It’s encouraging for patients and physicians to know that we have a very good therapy for these frontline patients that seems to overcome some of the historical high-risk features of their disease.

TARGETED ONCOLOGY: In your opinion, where do you think BTK-inhibition is headed in CLL? Could it be in time limited combinations, maybe even in combination with CAR-T cell therapy?

ALLAN: If you look at the ASH abstracts from this year coming up, or that have been presented or will be presented, you'll see a large volume of studies with combination therapies. And so, I think the field is starting to move. Not necessarily away from monotherapy, but we are starting to try to understand how we can optimize responses and durability of those responses for patients. And that's, that's mostly through combinations of BTK-inhibitors, plus BCL2-inhibitors, mainly venetoclax (Venclexta), at this stage of the game, and plus or minus anti-CD20. And so, there's a lot of different strategies to use to optimize that fixed duration of just a set amount of time, response adapted treatment durations, depending on when you achieve MRD negativity, etc. Unfortunately, we don't know the best approach. There's not much evidence to guide us there. But you see, there's more and more data being generated every year with longer-term follow-up. Some of these answers I do expect will be answered over the next several years.

_REFERENCE:

_{2219 Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukemia (CLL) with 4 years of follow-up in patients with TP53 aberrations (del(17p) or TP53 Mutation): A pooled analysis from 4 clinical trials. ASH. December 6, 2020. Accessed March 29, 2021 https://bit.ly/3sDA6o2}