Chemotherapy-Free Triplet Achieves 100% Response Rates in 3 Lymphoma Subtypes

Loretta J. Nastoupil, MD

The first known trial of combined ublituximab (TG-1101), ibrutinib (Imbruvica), and umbralisib (TGR-1202) showed that the combination was well tolerated and had activity across heavily pretreated patients with high-risk B-cell malignancies, investigators reported during the 2017 European Hematology Association (EHA) Congress in Madrid, Spain.

Objective response rates (ORR) of 100% were demonstrated across 3 disease subtypes: chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL).¹ Nineteen patients with CLL/SLL showed 100% ORR, which included 6 patients showing complete response (CR) and 13 with partial responses (PR). Four patients with MCL demonstrated ORR of 100%, with 2 patients each having CR and PR, and an ORR of 100% was also demonstrated in 2 patients with MZL with 1 patient achieving CR and 1 achieving PR.

The ORR was 80% in 5 patients with follicular lymphoma, which included 1 CR and 4 PR. In diffuse large B-cell lymphoma (DLBCL), only 1 out of the 6 patients in the cohort showed a PR, for an ORR of 17%. The ORR was 83% across 36 patients who were evaluable for efficacy, out of the total 38 patients enrolled in the trial.

The best percent change from baseline demonstrated a 100% reduction in disease burden for 10 patients, and 75% or greater reduction in all but 9 patients. Responses were durable, with 81% of responding patients remaining on study for more than 6 months. The median time of study was 11.1 months (range, 0.4-30+ months).

“Many patients continued on therapy, with approximately half of the patients continuing beyond 1 year,” said Loretta J. Nastoupil, MD, associate professor at the Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.

This phase I trial explored targeting multiple pathways with ublituximab, a novel glycoengineered monoclonal antibody against a unique epitope on the CD20 antigen, the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, and the next-generation PI3K-delta inhibitor umbralisib in patients with advanced CLL or B-cell non-Hodgkin lymphoma (NHL).

“We know from this study that the triplet appears to be safe, but the mechanism and whether synergy is present are still unknown,” Nastoupil said. “Single agent activity has been observed with ublituximab in rituximab [Rituxan]-refractory patients.” The median patient age was 65 years (range, 32-85). The 29 male and 9 female patients had received a median of 3 prior regimens (range, 0-6). All but the 3 treatment-naïve CLL patients were relapsed or refractory to prior treatment, which included 39% of patients who were refractory to rituximab. In all, 55% of patients had received ≥3 prior regimens.

The study had a dose escalation component for umbralisib; both ibrutinib (420 mg in patients with CLL or 560 mg in NHL) and umbralisib (400 mg, 600 mg, and 800 mg) were administered once daily, and ublituximab was given at 900 mg IV. Response was evaluated by scans at week 8 and every 12 weeks thereafter.

In the cohort of patients with CLL, 50% had 17p and/or 11q deletions, and 3 patients were refractory to BTK or PI3K-delta inhibitors, including 1 patient who failed both idelalisib (Zydelig) and ibrutinib. Of patients with follicular lymphoma, 2 had received prior autologous stem cell transplants, 1 was refractory to ibrutinib, and 1 patient had received 5 prior lines of rituximab. Patients with DLBCL, who showed the lowest response, had received a median of 4 prior therapies; the sole responder had germ cell B-cell subtype disease.

“The safety profile of this novel combination was favorable, suggesting that umbralisib may be safely combined with targeted agents to overcome mechanisms of resistance,” noted Nastoupil. “The majority of patients in this study were either high risk, heavily pre-treated or both.”

Just 1 dose limiting toxicity occurred in the 400 mg umbralisib CLL cohort, which was unrelated to treatment.

“Correlative studies are planned to understand the potential synergism of this combination and to identify the optimal subtype to pursue for additional study,” Nastoupil said. Additionally, the combination of ublituximab plus umbralisib is currently being evaluated in registration directed studies for CLL and NHL in the UNITY-CLL and UNITY NHL trials.²

References

1. Nastoupil L, Lunning MA, Vose JM, et al. Chemo-free triplet combination of TGR-1202, ublituximab, and ibrutinib is well tolerated and highly active in patients with advanced CLL and NHL. Abstract presented at: 2017 EHA Congress; June 22-25, 2017; Madrid, Spain. Abstract S772. https://learningcenter.ehaweb.org/eha/2017/22nd/182059/loretta.nastoupil.chemo-free.triplet.combination.of.tgr-1202.ublituximab.and.html.
2. Lunning MA, Vose J, Fowler N, et al. Ublituximab + TGR-1202 demonstrates activity and a favorable safety profile in relapsed/refractory B-cell NHL and high-risk CLL: phase I results. Abstract presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 1538.

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