PI3K Inhibitors Main Focus of Drug Pipeline for Lymphoma

February 2014 Vol 7, No 1, Special Issue ASH 2013 Payers' Perspectives in Oncology
Caroline Helwick

New Orleans, LA—Treatments for non-Hodgkin lymphoma (NHL) may take a new turn with several inhibitors of the PI3 kinase (PI3K) nearing approval. PI3K-delta signaling is critical for B-cell activation, proliferation, and survival, and it is hyperactive in many B-cell malignancies. PI3K-delta inhibition reduces B-cell survival, and as a result of this strong mechanism of action, a number of PI3K inhibitors are being investigated for the treatment of patients with lymphomas.

PI3K Dysregulation
The selective oral PI3K-delta inhib­itor idelalisib produced a high response rate in patients with indolent NHL (iNHL) refractory to rituximab and to an alkylating agent, with responses persisting for 1 year in the average patient, according to mature response data from a phase 2 clinical trial presented at ASH 2013.

“Idelalisib may provide meaningful disease control in double-refractory iNHL patients,” said Ajay Gopal, MD, Medical Oncology, University of Washington School of Medicine, Seattle.

Bruce D. Cheson, MD, Director of Hematology Research, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, commented, “These are very exciting data, and are potentially practice-changing.”

Study 101-09 included 125 previously treated patients who had follicular lymphoma (FL), small lymphocytic lymphoma, marginal zone lymphoma, or lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia. Patients received oral idelalisib 150 mg twice daily until disease progression. As of June 2013, approximately 33% of patients remained on treatment and 66% had discontinued treatment. The mean duration of idelalisib treatment was 8.1 months.

The overall response rate (ORR) with idelalisib monotherapy was 57%, including complete responses (CRs) in 6% of patients, partial responses (PRs) in 50% of patients, and minor responses in 1%. In addition, 34% of patients had stable disease. Responses were consistent across patient subsets, with the highest responses seen in patients with lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (80%).

“Virtually all patients had some degree of tumor reduction,” Dr Gopal pointed out. “A number had prolonged stable disease, and this is also what I’ve seen in my clinic.”

Idelalisib was well tolerated, with the primary adverse event being diarrhea (13% grade ≥3). Neutropenia of grade ≥3 was observed in 27% of patients, but only 5% had neutropenia at baseline. Transaminase elevations were common, with grades 1-2 observed in 35% of patients, grade 3 in 10%, and grade 4 in 2% of patients; these elevations were managed with drug interruption.

BAY 80-6946, now known as copanlisib, is administered as a weekly infusion. At the meeting, Martin Dreyling, MD, Department of Medicine, University Hospital Grosshadern, Munich, Germany, reported single-agent activity for weekly infusions of copanlisib in 67 patients with relapsed or refractory lymphoma, some with indolent lymphoma and some with aggressive lymphomas.

The preliminary results are encouraging. After a median of 3 cycles, significant activity, including many CRs, was observed. The ORRs were high in patients with FL (40%), chronic lymphocytic leukemia (43%), mantle-cell lymphoma (MCL; 71%), peripheral T-cell lymphoma (50%), and diffuse large B-cell lymphoma (13%).

Dr Dreyling called the high response rates in the aggressive lymphomas, such as MCL, “striking.” For example, 1 patient with MCL reported the elimination of symptoms after only 1 week of treatment, and radiologic imaging revealed an almost complete disappearance of a large pleural effusion.

“Compared to other compounds...this is a much quicker response than we are used to seeing,” Dr Dreyling noted.

Gastrointestinal toxicity was minor and self-limiting, and hematologic toxicity was not a problem, he stated. Metabolic side effects did occur, “but they were manageable with conventional therapy,” he added.

SAR245409 is a potent oral pan-­inhibitor of PI3K that also inhibits mTORC1 and mTORC2, another component of the PI3K dysregulated pathway. The multicenter phase 2 ARD12130 study evaluated the efficacy of SAR245409, given continuously as a single agent, in 28 patients with FL who had received a median of 3 previous regimens.

“Single-agent SAR245409 exhibited clinical activity in patients with relapsed or refractory follicular lymphoma,” reported Jennifer R. Brown, MD, PhD, Director, Chronic Lymphocytic Leukemia Center, Dana-Farber Cancer Institute, Boston.

In 27 efficacy-evaluable patients, the ORR was 44%, including CRs in 15%. All but 4 patients had a reduction in target lesions, which exceeded 50% in more than 50% of patients. More than 50% of the patients had not progressed at 6 months.

The most common adverse event was diarrhea, with grade ≥3 in 2 patients. In addition, 14 patients had rash, with grade ≥3 in 2 patients; 5 patients had hyperglycemia and elevated blood glucose, with grade ≥3 in 2 patients; 4 patients had liver toxic­ities, including 2 patients with grade ≥3. Dr Brown noted that transaminitis is relatively common with targeted kinase inhibitors.

Targeting the Bcl2 Gene
In a departure from PI3K, other investigators are targeting the Bcl2 gene, which plays a role in lymphomagenesis, is involved in chemotherapy resistance, and leads to cell death when disrupted.

PNT2258, which is very early in development, is a DNA “interference” molecule (DNAi) that targets the Bcl2 gene.

A total of 12 patients with different NHL subtypes and relapsed or refractory disease received PNT2258 intravenously for 5 days every 3 weeks, for 6 cycles. PNT2258 exhibited antitumor effects, and 9 of 11 evaluable patients demonstrated clinical benefit, including CRs in 2 patients and a PR in 1 patient, reported Ayad Al-Katib, MD, FACP, Medical Director, Van Elslander Cancer Center, Grosse Pointe Woods, MI.

The patients with FL had 200 to 250 days of progression-free survival, which is ongoing in some patients. The patients tolerated the administration of the drug well and maintained their baseline performance status, Dr Al-Katib said. “We feel that the DNAi strategy warrants further exploration as a cancer therapy,” he noted.

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