Safety and Efficacy of BTK Inhibitors in R/R MCL

Kami Maddocks, MD: We have great data on the long-term safety and efficacy of ibrutinib used as a single agent. There was a poor analysis of 3 different single-agent ibrutinib studies that showed long-term outcomes at 7½ years of therapy. And this showed that the 5-year progression-free survival was close to 20% but was very favorable in patients who had treatment with ibrutinib as a second-line therapy.

The median progression-free survival and duration of response were over double when ibrutinib was used as second-line therapy as opposed to a later line of therapy. Somewhere close to twice as many patients achieve a complete remission when this therapy is used as second line as opposed to further lines of therapy. The patients who were able to achieve a complete remission do very well in the long term with a median duration of response of over 5 years.

As far as overall survival, it was also better for patients who had received ibrutinib earlier in therapy. For those who achieved a complete remission, a median overall survival in this long-term follow-up was not reached.

Patients treated with ibrutinib who have better prognostic markers do even better, so they have higher overall response rates in a prolonged progression-free survival. Patients who have good performance status, a low-risk MIPI [Mantle Cell Lymphoma Prognostic Index score], nonbulky disease—defined by less than 5 cm—and nonblastoid histology.

Interestingly, the overall response rate is similar in blastoid versus nonblastoid histology. However, the progression-free-survival is shorter with blastoid histology.

The late plateau curve from the 7½-year follow-up shows that there are a proportion of patients, overall about 20%, who will still be in remission at 5 years while they continue their ibrutinib therapy. There are those patients who get a complete remission, even a duration of response greater than 5½ years. So there are patients who can be on ibrutinib 5, 6 years plus, being well tolerated and their disease under control.

Prior lines of therapy and what was used in those lines of therapy are important in determining what to use with patients. For patients who have had chemoimmunotherapy, you’re going to want to look out at that targeted agent if that wasn’t included in frontline therapy or in a clinical trial therapy. For chemoimmunotherapy in a patient who gets a limited response, you’re not going to want to reuse chemoimmunotherapy, because the chance that they’re going to get any sort of prolonged remission duration is pretty low. And they’re going to have higher toxicity associated with most chemotherapy regimens.

Differentiating the 3 BTK inhibitors can become a little tricky because they were all approved on phase 2 single-arm studies. There are ongoing phase 3 studies in different diseases, like CLL [chronic lymphocytic leukemia], that will probably help us find the differences in toxicity among the different BTK inhibitors.

When you look across the 3 approved BTK inhibitors—ibrutinib, acalabrutinib, and zanubrutinib—the responses overall are probably pretty similar. Some of the response assessments were done by CT [computed tomography] and some were done by PET [positron emission tomography]. There was probably somewhere between a 70% and 80% overall response rate with single-agent therapy with any of these agents. There was a complete remission rate of about 40%—a little higher in the zanubrutinib using PET/CT, but they were probably similar in general.

You may see more variability in the toxicity. Ibrutinib was the first developed BTK inhibitor. Acalabrutinib and zanubrutinib are felt to be more specific for BTK selectivity and have less off-target adverse effects.

If you have the adverse effects that are presumed by the study to be seen a little less with zanubrutinib and acalabrutinib—including atrial fibrillation and bleeding—although these are not in 0 with these agents, it is reported in a smaller number of patients.

In general, a lot of these responses and the toxicities are going to be similar. In a patient who has issues, maybe required anticoagulation or dual antiplatelet therapy, or in a patient who has a history of hard-to-control atrial fibrillation, where you’re really concerned about atrial fibrillation and bleeding, that is reasonable to think of acalabrutinib or zanubrutinib before ibrutinib. But again, hopefully, phase 3 data will tell us really the differences in those toxicities.

Transcript edited for clarity.

Case: A 76-Year-Old Woman with High Risk Mantle Cell Lymphoma

Initial presentation

• A 76-year-old woman presented with a 2-month history of occasional night sweats, intermittent fatigue and decreased appetite
• PMH: DM, medically controlled; GERD controlled on OTC medication
• PE: bilateral cervical lymphadenopathy, splenomegaly
  
  

Clinical workup

• LDH 405 U/I, ANC 3200/mm3, beta-2-microglobulin 4.1 µg/L, leukocytes, 5.42 X 109/L, hemoglobin 9.1 gm/dL
• FISH: t(11;14)
• Immunocytochemistry: cyclin D1+, CD5+, CD20+, CD43+, CD10-, CD23-
• Bone marrow biopsy positive for lymphoid cells with cyclin D1
• PET/CT scan showed widespread lymphadenopathy including inguinal node (5.1 cm) and splenomegaly
• Ann Arbor stage IV; MIPI score 6.4; ECOG PS 0
  
  

Treatment

• She was started on bendamustine + rituximab
  • Achieved PR
  • Continued on maintenance rituximab q8W
• At 18 months the patient had clinical disease relapse, including an unintentional 7-lb weight loss
  • She was started on ibrutinib 560 mg PO qDay
  • Imaging at 10-week follow-up showed substantial decrease in disease burden