Numerous Drug Classes Studied for Use in Follicular Lymphoma

Bruce D. Cheson, MD

Follicular lymphoma (FL) is characterized by repeated treatment responses and then relapses, and until more effective frontline therapies become available, researchers will need to generate a growing list of drug choices to keep pace with patients’ needs, according to Bruce D. Cheson, MD, of the Lombardi Comprehensive Cancer Center at Georgetown University, Washington, DC, and chair of the Lymphoma Committee of the Alliance for Clinical Trials in Oncology/ Cancer and Leukemia Group B (CALGB).

Cheson, who spoke at the 17th Annual International Congress on Hematologic Malignancies, noted that although there are no new chemotherapy drugs in development for FL, work is being done to bring other classes of agents into the treatment armamentarium— particularly monoclonal antibodies, signaling pathwaytargeting agents, apoptosis-inducing compounds, and immunomodulatory drugs. FL, a typically indolent form of non-Hodgkin lymphoma (iNHL), makes up about 20% of the lymphomas diagnosed in the United States, according to the American Cancer Society.

Rituximab, a monoclonal antibody approved to treat FL, will soon go off patent, but other anti-CD20 antibodies are in development, Cheson said. However, to have value, he noted, such drugs will need to be more effective than rituximab or work in rituximab-resistant disease.

Ofatumumab, a humanized monoclonal anti-CD20 antibody approved under the trade name Arzerra for use in chronic lymphocytic leukemia (CLL), has shown some promise as a single agent in patients with rituximab-resistant FL. In a study of patients with rituximab-refractory FL (N = 116), ofatumumab was well tolerated and modestly active.¹ In the study, 27 patients had an overall response rate (ORR) of 22% to the antibody. For all participants, median progression-free survival (PFS) was 5.8 months. PFS jumped to 9.1 months in the 46% of patients who demonstrated tumor reduction three months after the start of therapy.

Cheson said the jury is still out on the antibody obinutuzumab (GA101), which was tested in patients with relapsed FL, and generated response rates and PFS results similar to those associated with rituximab.^2,3 “Whether that will go anywhere remains to be demonstrated by the ongoing trial of [alkylating agent] bendamustine with or without GA101 in rituximab-refractory patients,⁴” he said.

Meanwhile, two antibody drug conjugates that showed promise in phase I trials—DCDT2980S, an anti-CD22 agent, and DCDS4501A, an anti-CD79b agent—are being tested in a randomized phase II study⁵ Investigators are combining either of the drugs with rituximab in patients with FL and diffuse large B-cell lymphoma, and are allowing crossover at progression to check for non—cross-resistance between the two molecules, Cheson said.

Also on tap is a phase II study of ibrutinib, a specific and irreversible inhibitor of Bruton’s tyrosine kinase that demonstrated an ORR of about 40% in patients with FL in an earlier study, Cheson said. The pill-a-day regimen has been successful for as long as two years in patients with relapsed, refractory FL, he said, and the trial will shed more light on the drug’s toxicity and response rate and duration.⁶

Selected Novel Agents in Follicular Lymphoma

Drug

Description

Target

Ofatumumab

Monoclonal antibody

CD20

Obinutuzumab (GA101)

Monoclonal antibody

CD20

DCDT2980S

Antibody—drug conjugate

CD22

DCDS4501A

Antibody—drug conjugate

CD79b

Ibrutinib

Kinase inhibitor

Bruton's tyrosine kinase

Idelalisib (GS-1101)

Kinase inhibitor

Delta isoform-specific targeter of PI3 kinase

IPI-145

Kinase inhibitor

Inhibits PI3K delta and PI3K gamma

ABT-199

BH3-mimetic

BCL-2 to induce apoptosis

Lenalidomide

Immunomodulatory

Angiogenesis

Another promising development is idelalisib (GS- 1101), a delta isoform-specific PI3 kinase inhibitor, Cheson said. In a single-agent, phase I trial, 59% of heavily pretreated patients with iNHL subtypes responded to a dosage of 100 mg or more of the drug twice a day.⁷ The drug’s tolerability was “exceptional,” Cheson said. Grade 3-4 adverse events occurring in 5% or more of patients and due to any cause were fatigue (6%), neutropenia (8%), diarrhea (8%), pneumonia (10%), anorexia (10%), and ALT/AST elevations (27%). No pattern of drug-related symptomatic adverse events was seen.

A separate phase I trial combined idelalisib with rituximab, bendamustine, or a combination of the two in previously treated patients with iNHL.⁸ All combinations resulted in “profound reductions” in lymphadenopathy. The ORR in the intent-to-treat group was 77% to 85% with any regimen, and the PFS at one year was 78% to 90% with any regimen. There were no overlapping toxicities with the drugs. The results indicate that “maybe you don’t need the chemotherapy after all,” Cheson said.

Due to some data indicating that simultaneously inhibiting two pathways may lead to better results, agents including PI3K/mTOR inhibitors and delta/ gamma inhibitors are being investigated, Cheson said.

In the arena of apoptosis-inducing drugs, Cheson mentioned six agents in development, including ABT-199, which induces cancer cell death by targeting BCL-2. In an early study, 1 of 8 patients with FL had a partial response to the drug, but the agent may work better if combined with another treatment, Cheson pointed out.⁹

Cheson was part of the CALGB team that conducted study 50401 of the immunomodulatory drug lenalidomide, with or without rituximab, in patients whose FL had relapsed after one or more rituximab-based regimens.¹⁰ The ORR was 72.7% in the experimental arm versus 51.1% in the control arm. The complete response rate was 36.4% for the experimental arm versus 13.3% for the control arm; the partial response rate was 36.4% versus 37.8%, respectively; and the two-year event-free survival was 44% versus 27%, respectively.

While there was “no real difference in overall survival,” Cheson noted that some “astounding” results came out of a phase II study of lenalidomide and rituximab in untreated indolent lymphoma, conducted by Fowler et al.¹¹ In 46 patients with FL, the ORR was 98%, with 87% of those responses complete. PFS was 89% at 36 months, and the toxicity profile was mild, with manageable hematologic side effects.

“This has the potential to totally change the way we approach follicular lymphoma,” Cheson said.

Those results led to the randomized, phase III RELEVANCE trial,¹² which is testing rituximab and lenalidomide against rituximab and any of several chemotherapy regimens, Cheson said. The study is scheduled to continue through 2024.

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Dr. Cheson on Novel ADCs in Non-Hodgkin Lymphoma

Pending CALGB trials include a study testing rituximab and lenalidomide plus ibrutinib in untreated follicular NHL, and another testing rituximab and lenalidomide plus idelalisib in relapsed or refractory follicular NHL after at least one anti-CD20-based regimen.

Looking ahead, challenges will involve determining how to develop rational combinations of new drugs, choosing appropriate endpoints for clinical trials, and figuring out who will pay for studies, Cheson said.

“We need to recognize the heterogeneity of lymphomas and do correlative studies to figure out which drugs and combinations will most likely benefit each individual patient,” he said, adding that it is important to enroll eligible patients in trials to support research efforts.

References

1. Czuczman MS. Fayad L, Delwail V, et al. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood. 2012;119(16):3698-3704).
2. Salles GA, Morschhauser F, Thieblemont C, et al. Efficacy and safety of obinutuzumab (GA101) monotherapy in relapsed/refractory indolent non-Hodgkin’s lymphoma: results from a phase I/II study (BO20999). Blood. 2011;118(suppl; abstr 268).
3. Sehn LH, Goy A, Offner FC, et al. Randomized phase II trial comparing GA101 (obinutuzumab) with rituximab in patients with relapsed CD20 indolent B-cell non-Hodgkin lymphoma: preliminary analysis of the GAUSS study. Blood. 2011;118(suppl; abstr 269).
4. Clinical Trials Identifier NCT01059630. www.clinicaltrials.gov.
5. Clinical Trials Identifier NCT01691898. www.clinicaltrials.gov.
6. Advani RH, Buggy JJ, Sharman JP, et al. Bruton’s tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/ refractory B-cell malignancies [published online ahead of print October 8, 2012]. J Clin Oncol. 2013;31(1):88-94.
7. Kahl B, Byrd JC, Flinn IW, et al. Clinical safety and activity in a phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110, in patients with relapsed or refractory non-Hodgkin lymphoma. Blood. 2012;166(suppl; abstr 1777).
8. Fowler NH, de Vos S, Schreeder MT, et al. Combinations of the phosphatidylinositol 3-kinase-delta (PI3K) Inhibitor Gs-1101 (CAL-101) with rituximab and/or bendamustine are tolerable and highly active in previously treated, indolent non-Hodgkin lymphoma: results from a phase I study. Blood. 2012;120(suppl; abstr 3645).
9. Davids MS, Roberts AW, Anderson MA, et al. The BCL-2-specific BH3- mimetic ABT-199 (GDC-0199) is active and well-tolerated in patients with relapsed non-Hodgkin lymphoma: interim results of a phase I study. Blood. 2012;120(suppl; abstr 304).
10. Leonard J, Jung S-H, Johnson JL. CALGB 50401: a randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: final results of a phase II study. J Clin Oncol. 2012;30(suppl; abstr 8000).
11. Fowler N, Neelapu SS, Hagemeister FB, et al. Lenalidomide and rituximab for untreated indolent lymphoma: final results of a phase II study. Blood. 2012;120(suppl; abstr 901).
12. Clinical Trials Identifier NCT01476787. www.clinicaltrials.gov.