The rapid growth in treatment options for chronic lymphocytic leukaemia (CLL) is allowing clinicians to tailor treatment strategies in an attempt to balance efficacy with toxicity and tolerability considerations.¹ The second-generation bruton tyrosine kinase (BTK) inhibitor acalabrutinib (Calquence) – developed to avoid off-target effects of earlier drugs in its class – is now available on the PBS² for the treatment of relapsed or refractory chronic lymphocytic leukaemia (R/R CLL) or small lymphocytic lymphoma (SLL). We spoke to Associate Professor Phillip Campbell, Director of Cancer Services at Barwon Health in Geelong, Victoria, about where the second generation BTK inhibitor fits into the treatment landscape.

Off-target effects of first-generation BTK inhibitors

BTK inhibitors have been described as revolutionising treatment for CLL,^3,4 demonstrating an improvement in progression-free survival (PFS) and overall survival (OS) –  including in patients with high-risk disease.⁴

Associate Professor Phillip Campbell, who has experience with BTK inhibitors both in the clinic and in the context of clinical trials to treat R/R CLL, explains that the chronic nature of BTK inhibitor therapy makes tolerability an important consideration in its use. “Ibrutinib, a first-in-class BTK inhibitor has served us very well for a number of years. It is a very effective form of oral therapy, but minimising toxicity for a drug that is taken indefinitely takes on an added importance. One of the concerns surrounding ibrutinib is its potential off-target effects,” he says. Treatment-related toxicities thought to be due in part to off-target activity include bleeding, arthralgia, rash, diarrhoea and atrial fibrillation.^5,6

In a real-world analysis of toxicities and outcomes in 616 ibrutinib-treated patients in the United States, toxicity was the most common reason for discontinuation of ibrutinib.⁷ The authors say, “Among the patients treated front-line with ibrutinib, the three most common toxicities leading to discontinuation were arthralgia (41.6%), atrial fibrillation (25%), and rash (16.7%).⁷

Minimising off-target effects to improve tolerability

Acalabrutinib (Calquence) was developed to achieve similar therapeutic outcomes to ibrutinib in patients with CLL without the off-target effects on other kinases such as EGFR, ITK and Tec-family.⁴ It has been shown in pivotal trials to improve progression free survival (PFS) in both the first-line⁸ and R/R⁹ CLL settings and is indicated for the treatment of CLL as monotherapy or in combination with obinutuzumab.¹⁰

“Acalabrutinib is a more selective and potent BTK inhibitor,” explains Associate Professor Campbell. “If you look at a kinase inhibition map, you can see much tighter inhibition of BTK with acalabrutinib than with ibrutinib. Based on this kinase inhibition profile, researchers postulated that this may potentially result in a reduced toxicity profile,” he says.

Associate Professor Campbell was an investigator in the international ASCEND study⁹ assessing the efficacy and safety of acalabrutinib in R/R CLL. “Our experience in the ASCEND trial was that the toxicity observed with acalabrutinib compared very favourably with what we have seen previously with ibrutinib,” Associate Professor Campbell said.

ASCEND: improved PFS with acalabrutinib versus standard of care in R/R CLL

The ASCEND study⁹ was the first randomised study to directly compare a BTK inhibitor as monotherapy with standard chemoimmunotherapy or idelalisib and rituximab combinations.  It found that acalabrutinib significantly improved PFS compared with current standard of care therapy combinations in patients with R/R CLL.⁹

The randomised, open-label phase-III study compared acalabrutinib monotherapy (n=155) to the investigator’s choice of either idelalisib plus rituximab (I-R; n=119) or bendamustine plus rituximab (B-R; n=36).

After a median follow-up of 16.1 months, median PFS (primary end point) was not reached with acalabrutinib; PFS with investigator’s choice was 16.5 months (95% CI, 14.0 to 17.1 months); hazard ratio 0.31 (95% CI, 0.20 to 0.49; P<0.0001). Estimated 12-month PFS was 88% (95% CI, 81 to 92%) for acalabrutinib and 68% (95% CI, 59% to 75%) for investigator’s choice.

Pre-specified subgroup analyses showed a consistent PFS benefit with acalabrutinib monotherapy, including in patients with high-risk features. In addition, acalabrutinib monotherapy was associated with improved PFS regardless of age, Rai stage, or bulky disease.

Serious adverse events (SAEs) occurred in 29% of patients treated with acalabrutinib monotherapy, 56% with I-R, and 26% with B-R. SAEs occurring in two or more patients receiving acalabrutinib were pneumonia (n=8) and atrial fibrillation (n=3). Deaths occurred in 10% of patients on acalabrutinib monotherapy, 11% on I-R and 14% on B-R.

“Our experience in the ASCEND study was that acalabrutinib was very well tolerated and very few patients had to discontinue treatment due to toxicity,” said Associate Professor Campbell. Adverse events led to discontinuation in 11% of patients (n = 17) receiving acalabrutinib (compared with 47% [n = 56] patients receiving idelalisib plus rituximab).

“The most common non-haematologic side effect is headache,” says Associate Professor Campbell. “It tends to be of early onset, usually responds well to simple analgesia and caffeine-containing drinks and dissipates with time.”

Acalabrutinib shows improved PFS in the first-line setting

Acalabrutinib has also shown PFS benefits in the first-line CLL treatment.⁸ ELEVATE-TN found that acalabrutinib, either in combination with obinutuzumab or as monotherapy, significantly improved PFS compared to obinutuzumab-chorambucil chemoimmunotherapy.

This was a multicenter, open-label study in patients with treatment-naïve CLL in which patients were randomly assigned to receive either acalabrutinib and obinutuzumab (n=179), acalabrutinib monotherapy (n=179), or obinutuzumab and oral chlorambucil (n=177). The primary endpoint was PFS between the two combination arms. Crossover to acalabrutinib was allowed in patients who progressed on obinutuzimab-chlorambucil.

At a median follow-up of 28.3 months, median PFS was longer with acalabrutinib-obinutuzumab and acalabrutinib monotherapy, compared with obinutuzumab-chlorambucil (median not reached with acalabrutinib plus obinutuzumab versus 22.6 months with obinutuzumab, HR 0.1, 95% CI 0.06 – 0.17, p<0001; median not reached acalabrutinib monotherapy vs 22.6 months with obinutuzimab, 0.20; 0.13 – 0.3, p<0.0001).

Estimated PFS at 24 months was 93% with acalabrutinib-obinutuzumab (95% CI 87–96%), 87% with acalabrutinib monotherapy (81–92%), and 47% with obinutuzumab-chlorambucil (39–55%).

The authors noted, “Efficacy improvements were consistently observed across prespecified patient subgroups with acalabrutinib-obinutuzumab and acalabrutinib monotherapy versus obinutuzumab-chlorambucil, including age and high-risk genomic features such as del(17)(p13.1), unmutated IGHV, and complex karyotype, in which outcomes are often worse with chemoimmunotherapy.”⁸

The most common grade 3 or higher adverse events across the groups was neutropenia (30% in the acalabrutinib-obinutuzumab group, 9% in the acalabrutinib monotherapy group, and 41% in the obinutuzumab-chorambucil group). All-grade infusion reactions were less frequent with acalabrutinib-obinutuzumab (13%) than with obinutuzumab-chlorambucil (40%). Grade 3 or higher infections occurred in 21% patients given acalabrutinib-obinutuzumab, 14% patients given acalabrutinib monotherapy, and 8% of patients given obinutuzumab-chorambucil. Deaths occurred in 4% of patients given acalabrutinib-obinutuzumab, 7% of patients given acalabrutinib, and 9% of patients given obinutuzumab-chlorambucil.

 Treatment choices in CLL continue to evolve

Associate Professor Campbell is optimistic that CLL treatment will continue to evolve as further data becomes available. “In an Australian treatment context, most of the sequencing data supports starting with frontline chemoimmunotherapy, then a BTK inhibitor, followed by B-cell lymphoma 2 (Bcl-2) inhibitor-based treatment,” he explains. “However emerging data suggests patients may still respond to a BTK inhibitor after progressing on a Bcl-2 inhibitor. As this data matures and becomes more compelling, physicians will have greater choice when considering treatment options for their patients, and may not need to worry about using a BTK inhibitor later in the treatment course,” he says.

References

1. Brander D et al. Tailored treatment strategies for chronic lymphocytic leukemia in a rapidly changing era. 2019 ASCO Educational Book https://doi.org/10.1200/EDBK_238735
2. Pharmaceutical Benefits Scheme Authority Listing: acalabrutinib https://www.pbs.gov.au/medicine/item/12117R
3. Molica S et al. Emerging bruton tyrosine kinase inhibitors for chronic lymphocytic leukaemia: one step ahead ibrutinib. Expert Opin on Emerg Drugs 2020;25(1):25–35. https://www.tandfonline.com/doi/abs/10.1080/14728214.2020.1724282
4. Isaac K, Mato AR. Acalabrutinib and Its Therapeutic Potential in the Treatment of Chronic Lymphocytic Leukemia: A Short Review on Emerging Data Cancer Manag Res 2020 Mar 19;12:2079-2085.doi: 10.2147/CMAR.S219570. https://pubmed.ncbi.nlm.nih.gov/32256115/
5. Wu J et al. Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol 2016;9:80 https://pubmed.ncbi.nlm.nih.gov/27590878/
6. Bond DA, Woyach JA. Targeting BTK in CLL: Beyond Ibrutinib. Curr Hematol Malig Rep. 2019;14(3):197-205. doi:10.1007/s11899-019-00512 https://pubmed.ncbi.nlm.nih.gov/31028669/
7. Mato AR et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica 2018;103(5):874 – 879 https://www.haematologica.org/article/view/8458
8. Sharman JP et al. Acalabrutinibwith or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE-TN): a randomised, controlled, phase 3 trial. 2020 Apr 18;395(10232):1278-1291. doi: 10.1016/S0140-6736(20)30262-2. https://pubmed.ncbi.nlm.nih.gov/32305093/
9. Ghia P et al. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia J Clin Oncol. 2020 May 27:JCO1903355. doi: 10.1200/JCO.19.03355. https://pubmed.ncbi.nlm.nih.gov/32459600/
10. Calquence Australian Approved Product Information https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2019-PI-02285-1&d=202009281016933