Ibrutinib/Nivolumab Combo Shows Promise in Richter’s Transformation

Sixty-five percent of patients with Richter’s transformation had a response to treatment with the combination of PD-1 inhibitor nivolumab and BTK inhibitor ibrutinib, according to the results of a phase 1/2a study. However, the preliminary activity of the drug combination reported in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), follicular lymphoma (FL), and diffuse-large B-cell lymphoma (DLBCL) was similar to that seen with ibrutinib monotherapy.

Researchers led by Anas Younes, MD, of Memorial Sloan Kettering Cancer Center, noted that the study only included 20 patients with Richter’s transformation and can therefore only describe preliminary activity.

“The overall response with the ibrutinib and nivolumab combination regimen in patients with Richter’s transformation was promising and warrants confirmation in patients with Richter’s transformation who did not respond to previous ibrutinib single-agent therapy,” the researchers wrote.

In the two-part, phase I/IIa study, Younes and colleagues enrolled 141 patients from 21 hospitals to evaluate dose escalation and safety of combination treatment with nivolumab and ibrutinib for released non-Hodgkin lymphoma or CLL.

Patients were assigned to oral daily doses of 420 mg or 560 mg ibrutinib (based on disease type) combined with nivolumab at a dose of 3 mg/kg given every 2 weeks. The ibrutinib dose could be reduced to 280 mg if needed; no reductions in nivolumab were permitted. The phase II portion treated patients with the recommended dose plus nivolumab 3 mg/kg.

Included patients had relapsed or refractory CLL (n = 30), SLL (n = 6), FL (n = 40), DLBCL (n = 45), and Richter’s transformation (n = 20). The results were published in Lancet Haemtaology.

One dose-limiting toxicity was reported at the 420 mg ibrutinib dose in the DLBCL cohort, none were reported at the 560 mg dose cohort. The recommended phase II dose was 420 mg for patients with CLL/SLL and 560 mg for patients with FL, DLBCL, and Richter’s transformation.

For both parts of the study, the most common adverse events were diarrhea (33%), neutropenia (31%), and fatigue (26%). The most common grade 3/4 events were neutropenia (28%) and anemia (23%). Serious adverse events included anemia (4%) and pneumonia (4%).

Reported overall response rates were 61% for patients with CLL/SLL, 33% for patients with FL, 36% for patients with DLBCL, and 65% for patients with Richter’s transformation.

Among patients with Richter’s transformation, 10% achieved complete response and 55% achieved partial response. All patients with Richter’s transformation were ibrutinib naïve.

The researchers noted that the clinical cutoff was 6 months after the last patient received the first dose, meaning that many patients had relatively short follow-up.

“This factor is important for the chronic lymphocytic leukemia or small lymphocytic lymphoma cohort, in which responses have been shown to improve with time,” they wrote.

In an editorial that accompanied the study, Pek Sang Tang, of St. Vincent’s Hospital, Melbourne Australia, and Constantine S. Tam, MD, of Peter MacCallum Cancer Centre and University of Melbourne, Australia, wrote “Taken together, the combination of BTK and PD-1 inhibition shows promising activity in patients with Richter’s transformation, which deserves continued investigation in clinical trials. It remains unclear whether or not the current response in patients with Richter’s transformation is translatable to the growing number of patients exposed to novel agents at earlier disease stages.”

Commenting on these results, Tanya Siddiqi, MD, of City of Hope Medical Center, told Cancer Network, “Younes et al have treated 141 patients internationally on this Phase I/IIa study of ibrutinib plus nivolumab. This combination appears to be safe and responses seem to be most promising in Richter’s transformation, where there is a huge unmet need for effective treatments. It is uncertain whether nivolumab will add more to the outcomes in CLL/SLL or FL patients over what ibrutinib can do as a single agent.”