Flinn Highlights Emerging Combos in Non-Hodgkin Lymphoma

Ian W. Flinn, MD, PhD

At the 2018 ASCO Annual Meeting, data for the combinations of the anti-CD47 antibody Hu5F9-G4 (5F9) with rituximab (Rituxan), and ibrutinib (Imbruvica) plus venetoclax (Venclexta), both showed practice-changing potential to transform the complex field of non-Hodgkin lymphoma (NHL).

The combination of 5F9 with rituximab demonstrated strong signals of activity and tolerability in patients with relapsed/refractory NHL. The initial phase Ib/II results revealed the efficacy of 5F9 in patients with rituximab-refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma.¹ Across all doses, the overall response rate (ORR) was 50%, with a complete remission (CR) rate of 36%.

The 22-patient cohort comprised 15 patients with DLBCL and 7 with follicular lymphoma. Objective responses were observed in 6 of the 15 patients with DLBCL and 5 of the 7 with follicular lymphoma. Five patients in the DLBCL subgroup had CRs, as did 3 in the follicular lymphoma subgroup. 5F9 demonstrated efficacy in patients with rituximab-refractory disease.

In a separate abstract, results of the phase II CAPTIVATE study showed the frontline combination of ibrutinib and venetoclax demonstrated a 100% ORR for patients with chronic lymphocytic leukemia (CLL), with 77% of patients testing negative for minimal residual disease (MRD) in the peripheral blood after 6 cycles.²

In 11 patients treated with 12 cycles of ibrutinib and venetoclax with available bone marrow data, the CR rate was 36% and the rate of CR with incomplete hematologic recovery (CRi) was 18%. Remaining responses consisted of nodular partial remissions (nPR; 9%) and PR (36%). All patients with a CR/CRi had confirmed undetectable MRD in the bone marrow. Sixty percent of those with a PR or near PR were MRD negative.

OncLive: Can you discuss the findings of 5F9 in combination with rituximab in patients with relapsed/refractory NHL?

In an interview with OncLive during the 2018 ASCO Annual Meeting, Ian Flinn, MD, PhD, lead investigator on the CAPTIVATE study and director of the Blood Cancer Research Program, Sarah Cannon Research Institute, discussed the activity and tolerability of 5F9 with rituximab in relapsed/refractory NHL, as well as intriguing findings with ibrutinib/venetoclax in frontline CLL.Flinn: 5F9 is an antibody directed against CD47. We can think of it like a checkpoint inhibitor for the innate immune system. CD47 is expressed on a variety of tumor cells, and we can allow the innate immune system to engulf and phagocytize the lymphoma cells by having an antibody that blocks it. The study combined 5F9 with rituximab. There was in vitro data to suggest that these 2 drugs synergize together.

It was a dose-finding study, so we looked at several different doses and found that it was a very well-tolerated regimen. It had a lot of activity in patients with relapsed/refractory DLBCL; 40% of patients responded. Most of the responses in the 15 patients with DLBCL were complete remissions. These are really exciting results in this very hard-to-treat patient population.

What are the next steps following these results?

If the combination were to be approved, how do you see it fitting into the landscape?

You were the lead author on the CAPTIVATE study. What were those results?

The side effects were what we would expect. We know that anemia is an expected side effect because CD47 is on red cells. After a priming dose, patients had a little bit of anemia. They recovered nicely after that…Other than that, and some infusion-related side effects, it was really well tolerated. We are now going on to dedicated phase II trials to expand our experience in both large cell lymphoma and follicular lymphoma. It is a first-in-class agent, so we are [still] learning about it. If the results held up and some of these remissions were durable, then you can imagine this combination being used in patients with relapsed/refractory DLBCL. The next step is to figure out ways of combining it with our standard therapies. We might want to consider combining it with R-CHOP or other chemotherapies as a way to synergize with that. CAPTIVATE is a study combining ibrutinib with venetoclax in previously untreated patients with CLL. Ibrutinib and venetoclax are very active agents in CLL, so we wondered whether the combination would be even better.

With that notion, the study used 3 months of lead-in with ibrutinib to try to debulk patients with CLL. Then, we came in with venetoclax in a typical ramped-up fashion to try to ameliorate tumor lysis adverse events.

The ORR is tremendous, as was the complete remission rate in this patient population. We will have to see how this faces up with other duos like the obinutuzumab (Gazyva) and venetoclax combination, or maybe a 3-drug regimen like obinutuzumab, venetoclax, and ibrutinib. These are really exciting data, but we have a lot of work to do to figure out which of these doublets or triplets is the most important.

References

1. Advani RH, Flinn I, Popplewell L, et al. Activity and tolerability of the first-in-class anti-CD47 antibody Hu5F9-G4 with rituximab tolerated in relapsed/refractory non-Hodgkin lymphoma: initial phase 1b/2 results. J Clin Oncol. 2018;36 (suppl; abstr 7504).
2. Wierda WG, Siddiqi T, Flinn I, et al. Phase 2 CAPTIVATE results of ibrutinib (IBR) plus venetoclax (VEN) in first-line chronic lymphocytic leukemia (CLL). J Clin Oncol. 2018;36 (suppl; abstr 7502).