Imbruvica-Opdivo Combination Shows Promise in Richter’s Transformation

Imbruvica-Opdivo Combination Shows Promise in Richter’s Transformation

A combination of Imbruvica (ibrutinib) and Opdivo (nivolumab) reduced tumor burden in 65% of patients with Richter’s transformation — a kind of diffuse large B-cell lymphoma (DLBCL) with very poor prognosis, derived from B-cell chronic lymphocytic leukemia (CLL) — treated in a Phase 1/2a trial, largely exceeding investigators’ expectations for this group of patients.

The combination, however, induced similar response rates as Imbruvica or Opdivo alone in patients with CLL or small lymphocytic lymphoma (SLL), follicular lymphoma, or DLBCL.

The study, “Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study,” was published in The Lancet Haematology.

While immune checkpoint inhibitors, such as Opdivo, have shown great promise in lymphoma, most patients become resistant to them and see their disease return or worsen. Studies suggest that inhibiting the BTK protein, involved in survival and proliferation of B-cells, may increase the effects of Opdivo and other inhibitors of the PD-1/PD-L1 pathway.

Thus, researchers conducted an open-label, Phase 1/2a study to determine whether a combination of Opdivo and the BTK inhibitor Imbruvica could improve responses among patients with B-cell cancers who had failed prior treatments.

The trial (NCT02329847) enrolled 141 patients — 30 with CLL, six with SLL, 40 with follicular lymphoma, 45 with DLBCL, and 20 with Richter’s transformation — from 21 hospitals in Australia, Israel, Poland, Spain, Turkey, and the United States. Participants had a median age of 65 years, and had received a median of three prior treatments.

In Phase 1 of the study, patients received one of two doses of oral Imbruvica — 420 mg or 560 mg daily — in combination with Opdivo, to determine the safest and most effective dose. During this part, only one dose-limiting toxicity event — severely high levels of a liver enzyme — was reported in a DLBCL patient receiving the 420 mg dose. It resolved after five days.

Overall, researchers defined the 420 mg dose as the optimal dose for patients with CLL/SLL and the 560 mg dose for those with follicular lymphoma, DLBCL, or Richter’s transformation. These doses were given to 127 patients in the Phase 2 part to determine the treatment’s efficacy.

Among patients with high-risk CLL/SLL, 61% achieved a partial response to the combination treatment, and an additional 14% remained stable without signs of disease progression. Responses lasted for a median of 19.2 months.

For follicular lymphoma patients, response rates were 33% — including 10% complete responses —and an additional 33% of patients had their disease stabilized. These patients responded to the treatment for a median of 10.2 months and lived without disease worsening for a median of 9.1 months.

Similarly, 36% of DLBCL patients responded to the combination — including 16% complete responses — and 13% had stable disease. In this group, the median duration of stable disease or better was 18.4 months, but patients remained alive and without signs of disease progression for a median of only 2.6 months.

For the patients with Richter’s transformation, the treatment induced a complete response in 10% and a partial response in 55%. Only 25% of patients experienced disease progression. The median duration of response was 6.9 months, and the progression-free survival was five months.

The responses to the combination treatment were similar to those seen with Imbruvica or Opdivo alone in CLL/SLL, follicular lymphoma, and DLBCL. However, “the proportion achieving an overall response with Richter’s transformation (65%) exceeded expectations,” researchers said.

The safety of the combination was generally similar to previously reported safety profiles of the single agents. The most common adverse events were diarrhea, low number of neutrophils, and fatigue. Eleven patients experienced adverse events that led to death, none of which was related to treatment.

“The clinical activity of the combination regimen was generally similar to the activity reported for single-agent ibrutinib in patients with CLL or SLL, follicular lymphoma, and DLBCL,” researchers wrote, adding that the additional toxic effects of the combination are not worth using the combination in these patients.

However, “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,” they concluded.

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