Emerging Agents, Strategies Propel Progress in Follicular Lymphoma

John P. Leonard, MD

Novel agents and treatment strategies continue to expand the armamentarium in follicular lymphoma, explained John P. Leonard, MD, in a session at the 36th Annual CFS^®.

Maintenance Therapy

Leonard, associate dean for Clinical Research and Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medicine and New York-Presbyterian Hospital, provided expert insight on the latest advances in both the induction and relapsed/refractory setting.Standard induction approaches for advanced-stage follicular lymphoma include the chemoimmunotherapy regimens of rituximab (Rituxan) combined with CHOP (R-CHOP), CVP (R-CVP), or bendamustine (BR). Researchers have attempted to build on the success of these regimens through maintenance therapy.

Long-term follow-up data from the phase III PRIMA study showed a 10-year progression-free survival (PFS) rate of 51% for patients receiving 2 years of rituximab maintenance after R-CHOP/R-CVP induction compared to 35% for those receiving chemoimmunotherapy induction alone (HR, 0.61; P <.0001).¹ However, there was no overall survival benefit (OS) observed, with a 10-year OS rate of 80% for both arms.

“This has led some to use maintenance rituximab, and others to say, ‘Well in the absence of an overall survival benefit, perhaps the value is more limited,’” said Leonard.

Another novel approach has been replacing rituximab with another anti-CD20 monoclonal antibody, obinutuzumab (Gazyva), in the upfront and maintenance settings. The phase III GALLIUM study randomized patients to induction with obinutuzumab plus CHOP, CVP, or bendamustine, followed by 2 years of obinutuzumab maintenance or standard R-CHOP, R-CVP, or BR, followed by 2 years of rituximab maintenance.

The 3-year PFS rates were 80% for the obinutuzumab arm compared with 73.3% for the rituximab arm (HR, 0.66; P = .001); however, there was no OS benefit associated with obinutuzumab.²

Chemotherapy-Free Approach

The phase III RELEVANCE trial explored lenalidomide/rituximab (R²) versus R-chemo in previously untreated patients with advanced follicular lymphoma. Patient in both treatment arms received maintenance rituximab following their primary regimen. The study did not show superiority for R² over R-chemo—best overall response rate (ORR) was 84% for the R² arm versus 89% for the R-chemo arm.³ PFS was also similar between the arms.

Relapsed/Refractory Setting

“These are similar regimens as far as efficacy…The key attributes here come down to safety and toxicity. Neutropenia [in the trial] was a little bit more with R-chemo…Febrile neutropenia was a little more with R-chemo. And there was a little more rash with lenalidomide/rituximab…So at the end of the day, I think it’s really somewhat of a subjective decision as to which toxicity profile your patient would prefer.Patients who progress early—within 2 years of their induction therapy—have a less favorable outcome. Researchers are addressing this high-risk population through studies such as S1608, which Leonard said is asking, “Can novel agents outperform chemoimmunotherapy in these early progressing patients that have a high unmet need.”

S1608 is examining 3 regimens in patients who relapsed or failed to achieve a complete remission within 2 years of starting induction chemoimmunotherapy: lenalidomide/obinutuzumab; obinutuzumab/umbralisib; and obinutuzumab plus either CHOP or bendamustine, whichever was not given as induction.

Leonard next highlighted the phase III GADOLIN study, which showed that obinutuzumab plus bendamustine followed by maintenance obinutuzumab improved PFS versus bendamustine alone in patients with rituximab-refractory follicular lymphoma (median PFS not reached vs 14.9 months; HR, 0.55; P = .0001).⁴

Several new PI3K inhibitors are building on the initial success of idelalisib (Zydelig) in relapsed/refractory follicular lymphoma. The phase II CHRONOS-1 trial showed a 59% response rate with copanlisib (Aliqopa) in patients with relapsed/refractory indolent lymphomas.⁵ Additionally, in the phase II DYNAMO study, duvelisib (Copiktra) demonstrated an ORR of 46% for patients with indolent non-Hodgkin lymphoma, including 41% in patients with follicular lymphoma.⁶

Beyond PI3K inhibitors, the R² regimen has also been explored in the relapsed/refractory setting. The phase II CALGB 50401 ALLIANCE trial showed that R² led to a 76% ORR versus 53% with lenalidomide alone in patients with recurrent follicular lymphoma after ≥1 rituximab-based regimen.⁷ This trial led to the phase III NHL-007 (AUGMENT) trial, which is comparing R² versus rituximab in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma.

Leonard concluded by highlighting the potential of the investigational EZH2 inhibitor tazemetostat. He explained that EZH2 is mutated in about a quarter of follicular lymphoma patients, and that tazemetostat has shown a high ORR in this subpopulation.

References

1. Salles GA, Seymour JF, Feugier P, et al. Long term follow-up of the PRIMA study: half of patients receiving rituximab maintenance remain progression free at 10 years. Presented at: 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, GA. Abstract 486.
2. Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017;377(14):1331-1344. doi: 10.1056/NEJMoa1614598.
3. Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379(10):934-947. doi: 10.1056/NEJMoa1805104.
4. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016;17(8):1081-1093. doi: 10.1016/S1470-2045(16)30097-3.
5. Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol. 2017;35(35):3898-3905. doi: 10.1200/JCO.2017.75.4648.
6. Zinzani P, Wagner-Johnston N, Miller C, et al. DYNAMO: a phase 2 study demonstrating the clinical activity of duvelisib in patients with double-refractory indolent non-Hodgkin lymphoma. Hematol Oncol. 2017;35(52):69-70.
7. Leonard JP, Jung SH, Johnson J, et al. Randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (ALLIANCE). J Clin Oncol. 2015;33(31):3635-3640. doi: 10.1200/JCO.2014.59.9258.

“This has led to, again, to some using obinutuzumab in this setting because of the PFS benefit. Others have said, again, ‘Well without an overall survival benefit and with the commitment based on this study to use maintenance, perhaps sticking with rituximab is just fine. So, there are differences in practice, in this regard.’”Leonard explained that, “to the extent that lenalidomide (Revlimid) is not chemotherapy,” another novel upfront strategy is implementing a “chemotherapy-free approach” by replacing chemotherapy with lenalidomide in standard regimens.