PI3Kδ and JAK1 Inhibitors Show Promise in Advanced Hodgkin Lymphoma

Andres Forero-Torres, MD

Outcomes with the novel PI3Kδ inhibitor INCB040093 alone or in combination with the investigational JAK1 inhibitor INCB039110 compared favorably with approved treatments in patients with relapsed/refractory classical Hodgkin lymphoma (cHL), according to results from a small study presented at the 13th International Conference on Malignant Lymphoma in Lugano, Switzerland.

Lead author Andres Forero-Torres, MD, University of Alabama at Birmingham, noted that the JAK-STAT and PI3K pathways are constitutively activated in Hodgkin and Reed-Sternberg cells, making them potential therapeutic targets in cHL, both directly and through modulation of the tumor microenvironment. Furthermore, preclinical and early clinical evidence suggests that inhibition of both pathways may be synergistic.

Forero-Torres presented findings from a cohort of 22 patients with relapsed or refractory cHL participating in an ongoing, open-label, dose escalation study that enrolled adult patients with relapsed/refractory lymphoid malignancies, including cHL or any non-Hodgkin B-cell malignancy, excluding Burkitt’s and precursor B-cell lymphoblastic lymphomas. Patients eligible for stem cell transplant or other potentially curative therapy were also excluded.

The median patient age was 36.5 years (range, 20-70 years) and 75% were male. Patients had received a median of five prior treatment regimens, 79% had undergone hematopoietic stem cell transplantation, 93% of had received brentuximab vedotin (Adcetris), and 73.3% had received radiotherapy.

Patients received INCB040093 monotherapy at 100 mg once daily, 100 mg twice daily, 150 mg twice daily, or 300 mg once daily. Combination therapy of INCB040093 plus JAK INCB039110 was administered for INCB040093 at 150 mg daily, 100 mg twice daily, or 150 mg twice daily plus INCB039110 at either 400 mg or 600 mg once daily. Patients received INCB039110 monotherapy (n = 12) or combination treatment (n = 10) for a median of 209 days (range, 22+ to 388).

Eleven evaluable patients receiving INCB040093 monotherapy demonstrated an objective response rate (ORR) of 36.4%, including one complete response (CR), and three partial responses (PR).

Eight evaluable patients receiving combination INCB040093/INCB039110 demonstrated an ORR of 62.5%, including two CRs and three PRs.

Stable disease was achieved by two monotherapy patients (28.2 %) and two patients receiving the combination (25%), yielding a disease control rate in the respective cohorts of 54.5% and 87.5%. Nearly half of monotherapy patients (45.54%) compared to just 12.5% of patients receiving combination therapy experienced progressive disease (PD).

In a third cohort of two patients who initially received monotherapy followed by the combination, one CR and one PD were observed.

The most commonly reported nonhematologic adverse events of any grade in the monotherapy cohort were cough and headache, each occurring in 41.7% of patients. AEs of grade ≥3 included increased alkaline phosphatase (16.7%), and abdominal pain and pyrexia were each reported in one patient. Laboratory abnormalities in this group included increased ALT and AST, thrombocytopenia, neutropenia, and anemia. Grade ≥3 anemia occurred in one patient, increased AST was reported in one patient, and increased ALT was seen in three patients.

AEs of any grade in the combination cohort were neutropenia, thrombocytopenia, and anemia that occurred in 70%, 60%, and 40% of patients, respectively. Grade ≥3 thrombocytopenia and neutropenia occurred in 30% and 10% of patients, respectively. Increased ALT and AST of any grades occurred in 30% and 50% patients, respectively, and no cases of grade ≥3 increased ALT or AST were reported.

“These treatments were really well tolerated, with elevated liver enzymes being the main problem in the monotherapy group,” Forero-Torres commented. “What was surprising was that the combination cohort showed the opposite effect, with no grade 3 or higher elevation of liver enzymes. The combination treatment was really well tolerated.”

Commenting on the next steps with the research, Forero-Torres said, “Clinical activity observed in this heavily pretreated cHL population prompted further investigation of INCB040093 100 with and without INCB039110 in a phase II study.” He added that the results support taking forward doses of 100 mg twice daily of INCB040093 as monotherapy, and 100 mg twice daily of INCB040093 plus 400 mg of INCB039110 once daily for the combination.

Forero-Torres A, Barr PM, Diefenbach CSM, et al. A phase 1 study of pi3kδ inhibitor INCB040093 alone or in combination with selective jak1 inhibitor INCB039110 in patients with relapsed/refractory hodgkin lymphoma. Presented at: 13th International Conference on Malignant Lymphoma; June 16-20, 2015; Lugano, Switzerland. Abstract 107.

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