Alvaro Alencar, MD, a hematologist/oncologist, an associate professor of clinical medicine, and associate chief medical officer in the Division of Hematology at the University of Miami Sylvester Comprehensive Cancer Center.

Alvaro Alencar, MD, discusses current unmet needs following the development of covalent BTK inhibitor resistance in CLL. 

Dr Alencar on Unmet Needs Associated With BTK Inhibitor Resistance in CLL

“The challenge is that [covalent BTK inhibitors] are extremely effective, but now we're starting to see this resistance and lack of options for these patients [with CLL]. We know that the great majority of patients will do extremely well with these classes [of drugs] and are able to have excellent disease control and very good tolerability for a very long time, but we still see more and more patients that, over time, will develop resistance and won’t have a lot of [treatment options left].”

Alvaro Alencar, MD, a hematologist/oncologist, an associate professor of clinical medicine, and associate chief medical officer in the Division of Hematology at the University of Miami Sylvester Comprehensive Cancer Center, discusses current unmet treatment needs following covalent BTK inhibitor resistance in patients with chronic lymphocytic leukemia (CLL).

Although treatment with BTK inhibitors has shown promising efficacy in patients with CLL, resistance to these drugs leaves patients with a lack of options, Alencar begins. With BTK inhibitors, patients typically have excellent disease control and tolerate the drugs well for a long time, he notes. However, higher incidences of resistance to BTK inhibitors have been seen among patients with CLL.

After resistance to covalent BTK inhibitors and BCL2 inhibitors, treatment with PI3K inhibitors is an option, although these inhibitors are now less frequently used, Alencar says. He also emphasizes that CAR T-cell therapy could be another option after patients develop resistance to BTK inhibitors. Nevertheless, he explains that there’s currently limited access to CAR T-cell therapy in the CLL setting.

An ongoing phase 1 trial (NCT05131022) presented by Alencar at the 

 demonstrated the efficacy of an additional potential treatment option beyond BTK inhibitors after patients develop resistance: the novel NX-5948 BTK degrader. An 

 that among patients evaluated for efficacy (n = 30), the overall response rate (ORR) was 75.5% (95% CI, 61.1%-86.7%), and patients with a longer follow-up demonstrated an ORR of 84.2% (95% CI, 68.7%-94.0%).

Videos

Alvaro Alencar, MD, explains the rationale of a phase 1 trial investigating NX-5948, a BTK degrader, in chronic lymphocytic leukemia. 

Dr Alencar on the Rationale of Investigating BTK Degraders in CLL

“The idea of the study [is] to develop a drug that will degrade [or] completely eliminate this receptor and therefore prohibit the scaffolding mechanism…even when [BTK] inhibitors, be it covalent and noncovalent, no longer work.”

Alvaro Alencar, MD, hematologist/oncologist, associate professor, clinical medicine; associate chief medical officer, University of Miami Sylvester Comprehensive Cancer Center, explains the rationale of the ongoing phase 1 trial (NCT05131022) evaluating the novel BTK degrader NX-5948 in chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Findings from the study were presented at the 

Alencar notes that BTK degraders play a crucial role in targeting a part of the B-cell receptor pathway that goes beyond BTK inhibitors. He explains that although BTK inhibitors also target the B-cell receptor pathway, they also completely block the receptor. Of these BTK inhibitors, there are 2 classes, Alencar says, including covalent and noncovalent BTK inhibitors. However, when these drugs are used, patients develop resistance in the receptor, he says. Alencar notes that when the receptor is completely inhibited, downstream activation is still there because the dead receptor acts as scaffolding. Alternative receptor pathways come through the dead receptor and can still activate the cell downstream, he explains.

analysis presented at the ASH Annual Meeting

 evaluated efficacy in 30 patients, who experienced an overall response rate (ORR) of 75.5% (95% CI, 61.1%-86.7%); among patients with a longer follow-up, responses deepened to an ORR of 84.2% (95% CI, 68.7%-94.0%). Regarding safety, the most common treatment-emergent adverse effects included purpura/contusion (36.7%), fatigue (26.7%), petechiae (26.7%), and neutropenia (23.3%). Grade 3 or greater neutropenia occurred in 18.3% of patients with CLL.

Alencar emphasizes that the rationale of the phase 1 study is to develop a drug that will degrade and eliminate the B-cell receptor pathway. This prohibits the scaffolding aspect of the dead receptor and maintains activity when either covalent or noncovalent BTK inhibitors no longer work, he concludes.

6366820464112

“Despite [being a] very highly pretreated population, we’ve seen this fast, prolonged, continued, and deepening response. There are a large proportion of patients with 

 mutations, which confers a lot of resistance, who still saw a response rate of [75.5%] in this population, which is very high.”

Alvaro Alencar, MD, hematologist/oncologist, associate professor of clinical medicine, associate chief medical officer, University of Miami Sylvester Comprehensive Cancer Center, discusses findings from an ongoing phase 1 trial (NCT05131022) evaluating NX-5948, a BTK degrader, in patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies.

 included 34 patients with CLL, of whom 30 were evaluable for efficacy. The overall response rate (ORR) was 75.5% (95% CI, 61.1%-86.7%), with responses deepening to 84.2% (95% CI, 68.7%-94.0%) in patients with longer follow-up. Responses were rapid, durable, and appeared to deepen over time, with some patients remaining on therapy for more than 12 months and others exceeding 18 months of treatment, Alencar explains.

Notably, the population included a significant proportion of patients with 

 mutations, a known marker of poor prognosis and resistance, yet response rates remained high at 76%, Alencar says.

Alencar noted that NX-5948 demonstrated an acceptable safety profile across B-cell malignancies, including in patients with CLL. The most common treatment-emergent adverse effects (TEAEs) included purpura/contusion (36.7%), fatigue (26.7%), petechiae (26.7%), and neutropenia (23.3%), with grade 3 or higher neutropenia occurring in 18.3% of patients.

Six TEAEs led to treatment discontinuation, including in 1 patient with CLL and 5 with non-Hodgkin lymphoma. Importantly, no new safety signals were observed with longer treatment duration or higher doses, and 2 grade 5 adverse effects—pulmonary embolism and subdural hematoma—were deemed unrelated to NX-5948.

Responses were also observed in patients with baseline 

 mutations, further supporting the activity of NX-5948 in patients with high unmet clinical needs. Durable responses were achieved in 13 patients who had sustained responses of at least 6 months, and 5 patients remained on therapy for more than 1 year.

Alencar concludes that based on NX-5948’s early efficacy in heavily pretreated CLL and B-cell malignancies with high-risk features, the phase 1b expansion of this study will be initiated to further assess its potential in addressing unmet clinical needs.

Alvaro Alencar, MD, discusses the preliminary efficacy and safety of NX-5948, a BTK degrader, in patients with chronic lymphocytic leukemia.

Alvaro Alencar, MD

Articles

Dr Alencar on Unmet Needs Associated With BTK Inhibitor Resistance in CLL

Dr Alencar on the Rationale of Investigating BTK Degraders in CLL

Dr Alencar on the Preliminary Efficacy and Safety of NX-5948 in CLL