Second-Generation BTK Inhibitors Hit the Treatment Bullseye With Fewer Off-Target Effects

https://doi.org/10.37765/ajmc.2020.88475

Once known as a paradigm changing class of precision oncology, or targeted, drugs,¹ Bruton tyrosine kinase (BTK) inhibitors are now well established as treatment for several hematological malignancies. They are named for Lt Col Ogden C. Bruton, MD, chief of pediatrics at Walter Reed Army Medical Center in the 1950s, who in 1951 discovered the first host immunodeficiency in humans, X-linked agammaglobulinemia^.2,3

The BTK protein is essential to helping B cells develop and mature into functional and specialized white blood cells; these are part of the adaptive immune response in producing antibodies, or immunoglobulins.⁴ But mutations in the BTK gene, more than 600 of which have been identified, can lead to a sizeable reduction in the number of circulating B cells, along with reduced ability to fight infection, absence of the BTK protein, production of abnormal BTK protein, or cancer cell growth.^5,6

Mutated immunoglobulins essentially malfunction in their roles as antigen receptors on the surfaces of B cells, especially in the cancer space, by not recognizing antigens as damaging or by not sending the correct signals to destroy the malignant cells.

This is where BTK inhibitors come in: They help to trigger cell death by blocking the B-cell receptor signaling that leukemias and lymphomas use to grow and survive.⁷ The first-generation BTK inhibitor ibrutinib (Imbruvica) came to market in 2013, when it was approved by the FDA to treat adult patients with mantle cell lymphoma. A targeted treatment, it stops cancer cells from surviving and multiplying by blocking abnormal protein signaling.⁸ Other indications, as monotherapy or in combination, have been approved for chronic lymphocytic leukemia, Waldenström macroglobulinemia, small lymphocytic lymphoma, relapsed/refractory marginal zone lymphoma, and chronic graft-versus-host disease.⁹ Ibrutinib is a once-daily oral agent and can be used in the frontline and relapsed settings.¹⁰

Despite its many benefits and indications, however, ibrutinib as BTK inhibition is also associated with numerous adverse effects (AEs) on nonmalignant cells, which range from common to uncommon and from mild to severe, making ibrutinib’s toxicity profile notorious.⁷

Among the most severe AEs are hemorrhage; high blood pressure; heart rhythm irregularities, including ventricular arrhythmias, atrial fibrillation, and atrial flutter; second primary cancers (eg, skin, other organs); and tumor lysis syndrome.¹¹ Some of the most common AEs, occurring in more than 30% of patients, are hematological (eg, decreased platelets, neutrophils, and hemoglobin), musculoskeletal, and respiratory in nature.

Additional possible AEs include diarrhea, constipation, vomiting, skin infections, dizziness, dehydration, petechiae, arthralgia, stomatitis, rash, and fatigue.¹² Ibrutinib carries warnings for use among those with bleeding problems, liver problems, and for those who are planning surgery or recently had surgery; women who are pregnant or thinking of becoming pregnant; women who breastfeed or plan to do so; and men with female partners capable of pregnancy.

Second-generation BTK inhibitors seek to improve upon first-generation agents like ibrutinib by having less cardiotoxicity, fewer AEs that result in stopping treatment, and fewer off-target effects. For example, ibrutinib inhibits the activity of 3 major off-targets: epidermal growth factor, which can result in severe skin toxicities¹³; interleukin-2 inducible kinase, which impairs natural killer cells’ cytotoxic abilities¹⁴; and the Tec family of kinases, decreasing their ability to aid in phosphorylation.¹⁵

In updated results of the ASPEN trial presented at this year’s virtual American Society of Clinical Oncology (ASCO) 2020 Annual Meeting, zanubrutinib (Brukinsa), the most recent second-generation BTK inhibitor to hit the US market, was shown to have a survival advantage over ibrutinib in patients with Waldenström macroglobulinemia who lacked the MYD88 mutation typically associated with successful treatment.¹⁶

ASPEN first compared zanubrutinib with ibrutinib in patients with Waldenström macroglobulinemia who have the MYD88 mutation, and zanubrutinib was shown in December 2019 to increase the incidence of complete response (CR) or very good partial response (VGPR) by close to 46% compared with ibrutinib—28.9% vs 19.8%, respectively—in patients with relapsed or refractory disease.¹⁷

The updated results, from 5 additional months of data, widened this gap, showing a 30.4% CR plus VGPR rate for zanubrutinib compared with 18.2% for ibrutinib, as well as less occurrence of atrial fibrillation/flutter of any grade, bleeding of any grade, major hemorrhage, diarrhea, and hypertension. In addition, patients without the MYD88 mutation had an overall response rate of 80.8%, which included a 50.0% major response rate—which itself included a VGPR rate of 26.9%—and 12-month progression-free survival of 72.4%.¹⁸

Lead investigator, Constantine Tam, MBBS, MD, a clinical hematologist and professor at the Peter MacCallum Cancer Centre in Victoria, Australia, noted of zanubrutinib, “Those patients who potentially have a history of hypertension or have a history of atrial fibrillation—or have an abnormal ECG or abnormal echocardiogram—maybe they’re the ones who would be better off on [zanubrutinib] compared with ibrutinib. We think it’s how clean the targeting is.”¹⁹

Zanubrutinib is associated with less incidence of muscle spasm, peripheral edema, pneumonitis, and pneumonia. In essence, fewer overall AEs with second-generation BTK inhibitors means less of a need to reduce dosing and a greater likelihood of being able to stay on treatment longer. Tam noted that most AEs happen with zanubrutinib during the first year on treatment, before their incidence plateaus, whereas prolonged treatment with ibrutinib has a greater chance of inflicting cumulative damage to the vascular system.20 Compared with first-generation BTK inhibitors, the second-generation drugs are associated with fewer concerns about primary and acquired drug resistance. For example, ibrutinib use among patients with relapsed/refractory mantle cell lymphoma has been shown to both have no effect on the disease and have a negative impact on additional therapies.²¹

These resistance mechanisms of action are 2-fold. They are molecular, in that they involve sustained distal B-cell receptor signaling through PIK3-AKT (protein kinase B) pathway activation, NFkB pathway activation, and cell cycle progression. They also are therapeutic, in that lines of therapy administered after BTK inhibitors do not produce prolonged responses or exceptional overall survival.²¹

Less Cardiotoxicity in Second Generation

Some of the strongest gains in this newer generation of BTK inhibitors, however, can be seen in the cardiovascular space, when compared with the toxicities of the first-generation inhibitors

that often lead to treatment discontinuation, especially among older, sicker patients who have a history of cardiac disease. In fact, most BTK inhibitors are prescribed for older patients, because the class of drugs is used primarily to treat chronic lymphocytic leukemia, for which the average age of onset is older than 60 years.²²

“I think it’s that a lot of the toxicities are related to off-target effects, meaning the binding of the BTK inhibitor drug to receptors or molecules that are not the ones that that they’re supposed to be treating the cancer for,” said Michael Kolodziej, MD, FACP, vice president and chief innovation officer, ADVI Health, in an interview with Evidence-Based Oncology™.

“The big ones that were identified with the first-generation inhibitors were cardiovascular, or hypertension and atrial arrhythmias, atrial fibrillation. And they were not rare side effects.”

Kolodziej explained that the second-generation drugs have fewer off-target effects—less cardiovascular toxicity, atrial arrhythmias, and hypertension—because of their improved toxicity profile, “largely because the drugs are just better at being BTK inhibitors. It’s not any more complicated than that.”

The chief challenge of the first-generation BTK inhibitors is that the AEs cause clinicians and patients to stop treatment with them, Kolodziej noted. The cancer does not become resistant, but the toxicities become unbearable and the patients become intolerant, he emphasized.

“The thinking is that the reduced cardiovascular side effects, the reduced bleeding, are going to allow a better persistence on the second-generation drugs,” he explained.

Tolerability and Payers

Indeed, in a pooled analysis of clinical trials of the second-generation BTK inhibitor acalabrutinib (Calquence), also presented in May at ASCO, lead author Richard R. Furman, MD, of Weill Cornell Medicine in New York, found that at a median follow-up of 26.4 months, 65% of patients were still on treatment. Of the 34% of patients who stopped acalabrutinib, half (17%) did so because their disease progressed; only 9% stopped due to treatment-related AEs.²³

Tolerability, especially as patients define it, is increasingly important to payers, starting with Medicare. The Center for Medicare and Medicaid Innovation has announced that it will incorporate patient-reported outcomes (PROs) into the Oncology Care First model, the proposed successor to the Oncology Care Model.²⁴ Advocates for including PROs in payment models are encouraging drug developers to broaden definitions of tolerability, to include quality-of-life data in trial designs.²⁵

It’s a straightforward idea: When patients can tolerate treatment, it improves their chances of survival. “This is important,” Tam said during ASCO. “The longer you take the drug, the better your responses become.”¹⁹

Author Information

Maggie L. Shaw is associate editor, The American Journal of Managed Care®.

References

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