Addressing Challenges in Indolent Non-Hodgkin Lymphoma and Mantle Cell Lymphoma

Following are some of the drugs in development for lymphoma:

Ibrutinib (Imbruvica):Ibrutinib has received accelerated approval from the FDA for treatment of patients with MCL who have received at least one prior therapy. MCL is an aggressive subtype of NHL that has a poor prognosis. In a large, international, open-label, single-arm phase II trial in 115 patients, the estimated median progression-free survival (PFS) was 13.9 months.¹The overall response rate (ORR) was 68% (75 patients); of these, 21% had a complete response. Ibrutinib is currently being reviewed by the FDA for a potential indication in relapsed and/or refractory MCL based on these phase II results. Ibrutinib is a first-in-class BTK inhibitor and has a Breakthrough Therapy designation from the FDA for MCL and two other hematologic malignancies.

Idelalisib: An oral PI3K delta isoform inhibitor, idelalisib is in development for indolent NHL that is refractory to rituximab and alkylating-agent chemotherapy. The drug is also under review by the FDA for indolent NHL, as of September 11, 2013, based on an open-label, single-arm phase II trial in 125 patients. Interim results of the trial, presented at the International Conference on Malignant Lymphoma in Lugano, Switzerland in June 2013, showed that patients treated with idelalisib had an ORR of 53.6% and a median PFS of 11.4 months.²Trials of idelalisib in combination with other therapies are ongoing.

IPI-145: IPI-145 is an oral inhibitor of both the delta and gamma isoforms of PI3K. A phase II trial in refractory indolent NHL is currently recruiting patients. Preliminary phase I data presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in June 2013 showed a 68% ORR in 19 treated patients.³Four out of 6 patients with MCL also responded to the treatment.

Andrew D. Zelenetz, MD, PhD

ABT-199: A B-cell lymphoma (Bcl)-2 inhibitor, ABT-199 targets the apoptosis pathway, inhibiting the ability of cancer cells to survive. The drug is still in phase I, but so far appears active in MCL. Eight of 8 patients with MCL treated in the phase I trial achieved a partial response, with both complete and partial responses seen for other types of refractory NHL.⁴Of 29 patients treated, the ORR was 53%, with 1 complete response in a patient with diffuse large B-cell lymphoma. The results were presented at the ASCO 2013 annual meeting.

Obinutuzumab (GA101): A novel engineered antibody that targets the CD20 surface cell marker, obinutuzumab is being compared to rituximab, a currently approved anti-CD20 antibody. Positive phase III results in chronic lymphocytic leukemia were recently reported. The antibody is also being tested in two phase III trials for indolent NHL: in combination with chemotherapy in treatment-naïve indolent NHL and in combination with bendamustine in relapsed or refractory patients.^{5, 6}

References

1. Wang ML, Rule S, Martin P. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma.N Engl J Med. 2013,369:507-516.
2. Salles, G. “Interim results from a phase 2 study of PI3K inhibitor idelalisib in patients with relapsed indolent Non-Hodgkin Lymphoma (iNHL) refractory to both rituximab and an alkylating agent” 12th International Conference on Malignant Lymphoma, June 19-22, 2013. Abstract 064bis.
3. Horwitz SM, Flinn I, Patel MR. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory lymphoma.J Clin Oncol.2013;31(suppl; abstr 8518).
4. Davids MS, Seymour JF, Gerecitano JF. Updated results of a phase I first-in-human study of the BCL-2 inhibitor ABT-199 (GDC-0199) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL).J Clin Oncol. 2013;31(suppl; abstr 8520).
5. Clinical trial: A Study of Obinutuzumab (RO5072759) Plus Chemotherapy in Comparison With MabThera/Rituxan (Rituximab) Plus Chemotherapy Followed by GA101 or MabThera/Rituxan Maintenance in Patients With Untreated Advanced Indolent Non-Hodgkin's Lymphoma (GALLIUM). Trial ID: NCT01332968.
6. Clinical trial: A Study to Investigate the Efficacy and Safety of Bendamustine Compared With Bendamustine+RO5072759 (GA101) in Patients With Rituximab-Refractory, Indolent Non-Hodgkin's Lymphoma (GADOLIN). Trial ID: NCT01059630.