Investigating Beyond the First-Generation BTK Inhibitors in CLL

CASE SUMMARY

• A 61-year-old woman reported symptoms of unintentional weight loss and increasing fatigue​.
• No significant medical history​
• Physical exam: axillary lymphadenopathy, spleen palpable ~6 cm below costal margin; chronically ill-appearing and continues only limited daily activity​
• CT of chest, abdomen, pelvis: largest node: 4.2 x 2.8 cm; all others < 3 cm ​

Laboratory results:​

• White blood cell: 47,000/mL; 76% lymphocytes​
• Absolute neutrophil count: 3,600/mm³ ​
• Hemoglobin: 8.7 g/dL ​
• Platelets: 115,000/mm3 ​
• Lactate dehydrogenase: 250 U/L ​
• β2-Microglobulin: 4.3 µg/L ​
• Comprehensive chemistry panel: within normal limits​
• Flow Cytometry: CD5+, CD20+, CD23+​
• Fluorescence in situ hybridization: del(11q) ​
• Molecular analysis: IGHV-unmutated​

Targeted Oncology: What is your thought process behind designing end points for clinical trials?

FARRUKH AWAN, MD: Nowadays, to demonstrate a survival advantage in [treatment of patients with] chronic lymphocytic leukemia [CLL], Hodgkin's disease, or even in large cell lymphoma sometimes, it's extremely hard because there's so much [therapy] crossover and everyone will end up getting the same treatment at some point in time. About 7 to 10 years ago now, when I submitted my investigational new drug application to the FDA, I had an end point of progression-free survival in an early intervention trial of ibrutinib [Imbruvica], but survival is not a valid end point [in this case].

So I asked if [I could] use a qualitative end point like quality-of-life measures, [such as] depression, sleep, anxiety, sexual function, appetite, etc, so can we do a composite of that as health-related symptoms or disease burden...and then look at the changes in patients who [had treatment] intervention early vs late. However, the FDA said that that could only be an exploratory objective, but it cannot be your primary objective. So, I think they're still in that era where you must have a measurable end point and I think they're not ready to move towards these unmeasured end points. More and more trials are being encouraged [to have quality-of-life measures as] secondary and tertiary end points, but not as the primary end point. Hopefully, at some point in time, we will do a study [looking at quality-of-life measures for this patient population].

Farrukh Awan, MD​

Professor, Department of Internal Medicine

Division of Hematology and Oncology

UT Southwestern Medical Center​

What is the primary pathway in CLL?

B-cell receptor signaling is the primary pathway through which the CLL signal gets transduced.¹ The CLL cell is perpetually on...and it signals through Bruton’s tyrosine kinase [BTK] and spleen tyrosine kinase [SYK] pathways, and you can always block those with different [treatments] as we have multiple inhibitors available. At the mitochondrial level, you can target BCL2 and cause apoptosis. There are multiple therapies and antibodies for use…and these targeted therapies that target different pathways—such as PI3K kinase inhibitors, BTK inhibitors, and SYK inhibitors—are all available.1 Bottom line is that this is a very targetable pathway and we're learning more and more about it every day.

Where does ibrutinib [Imbruvica] stand in the field of treatment for patients with CLL today?

I think for the most part, there is very little [remaining] argument to use ibrutinib anymore, but one thing we clearly know about ibrutinib is that it's a very active drug.² Nobody is doubting [it's activity in these patients]...but it’s more toxic.³ A specific problem that is a major issue with ibrutinib is that [older patients], especially in patients 70 years of age or older, have an increased risk of cardiovascular toxicity. So, the toxicity with ibrutinib has now been shown clearly to be worse as compared with the newer BTK inhibitors,3 and that's what we consistently see, which is why we most of us have moved on [from ibrutinib].

What data show the efficacy for the generation of BTK inhibitors after ibrutinib?

In terms of the BTK inhibitor [space], which is getting more crowded, there's at least 7 or 8 different BTK inhibitors that are at different stages [of development]…. Acalabrutinib [Calquence] was one of the first [BTK inhibitor's approved] right after ibrutinib,⁴ and the first important [study for this therapy] was ELEVATE-TN [NCT02475681].⁵ This study compared acalabrutinib plus obinutuzumab [Gazyva], a CD20 antibody therapy, vs acalabrutinib [alone] vs chlorambucil plus obinutuzumab. The idea [behind this trial design] was that [older patients with treatment-naive CLL] are the patients who would ordinarily not be candidates for chemotherapy, so you can combine them or you can compare them with acalabrutinib vs chemotherapy and see if the CD20 antibody adds anything to it. Now, when the study was designed, our thought process was that the CD20 antibody probably won't do much if you add it to the BTK inhibitor as was shown with ibrutinib and rituximab [Rituxan].⁶

References:

1. Burger JA, O'Brien S. Evolution of CLL treatment - from chemoimmunotherapy to targeted and individualized therapy. Nat Rev Clin Oncol. 2018;15(8):510-527. doi:10.1038/s41571-018-0037-8
2. Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6(11):3440-3450. doi:10.1182/bloodadvances.2021006434
3. Mato AR, Nabhan C, Thompson MC, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103(5):874-879. doi:10.3324/haematol.2017.182907
4. Project Orbis: FDA approves acalabrutinib for CLL and SLL. FDA. November 21, 2019. Accessed March 5, 2024. https://tinyurl.com/nhe3ccjb
5. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2
6. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443. doi:10.1056/NEJMoa1817073