HDAC/mTOR Inhibitor Combos Exhibit Activity in Relapsed/Refractory Hodgkin Lymphoma

Filip Janku, MD, PhD

The addition of the histone deacetylase (HDAC) inhibitor vorinostat (Zolinza) to the mTOR inhibitors sirolimus (Rapamune) or everolimus (Afinitor) demonstrated encouraging clinical activity and manageable safety in heavily pretreated patients with relapsed/refractory Hodgkin lymphoma, according to findings from a phase 1 trial (NCT01087554) published in Clinical Cancer Research.¹

Among 40 patients with relapsed/refractory Hodgkin lymphoma, the combination of vorinostat/sirolimus (n = 22) induced a complete response (CR) rate of 27%, with a partial response (PR) rate of 27%. Patients treated with vorinostat/everolimus (n = 18) had a CR rate of 11% and a PR rate of 22%. In this arm, responses were observed across 3 dosing levels.

The objective response rates (ORR) were 55% with vorinostat/sirolimus and 33% with vorinostat/everolimus. In the combined patient population, the ORR was 45%.

“Although the majority of patients with Hodgkin lymphoma have favorable outcomes with standard treatment, approximately 20% to 30% of patients with advanced disease develop refractory disease after primary treatment,” said lead study author Filip Janku, MD, PhD.² “These patients typically have poor outcomes with 5-year survival rates as low as 30%.”

“In our study, we observed a relatively high objective response rate in a patient population that would otherwise have poor outcomes,” added Janku.

Patients in the nonrandomized, open-label, dose-escalation study received 300 mg of daily, oral vorinostat—the recommended phase 2 dose—and 4 mg of daily, oral sirolimus. Everolimus was given as part of a 3+3 design. Patients with advanced cancers, including Hodgkin lymphoma, were given 300 mg of daily, oral vorinostat plus an escalated dose of 5 mg to 10 mg of daily, oral everolimus.

Eligible patients did not have access to standard therapy associated with survival benefit. Additional inclusion criteria included an ECOG performance score of 0 to 3 and adequate organ and bone marrow function.

Patients with prior exposure to cytotoxic chemotherapy were eligible for enrollment; however, patients must have stopped treatment at least 3 weeks prior to receiving study therapy.

Patients continued on therapy until disease progression, unacceptable toxicity, consent withdrawal, or withdrawal due to physician decision or noncompliance.

Of the 40 patients treated, 4 had clinical disease progression (vorinostat/sirolimus, n = 1; vorinostat/everolimus, n = 3) and 1 withdrew consent before the first restaging scan (vorinostat/everolimus).

Among all patients who were enrolled and dosed, the median age was 33 years, and 50% of patients were female.

Exactly half of the patients had an ECOG performance status of 1, while 30% had a status of 0 and the remainder had a status of 2. Patients had stage II (20%), stage III (15%), or stage IV (65%) disease.

Hodgkin lymphoma subtypes varied from classical Hodgkin lymphoma with nodule sclerosis (80%) to classical Hodgkin lymphoma not specified (17.5%) to classical Hodgkin lymphoma with lymphocyte depletion (2.5%).

The majority of patients were heavily pretreated; the median number of prior lines of treatment was 5. Prior therapies included autologous stem cell transplant (65%), allogeneic stem cell transplant (allo-SCT; 30%), brentuximab vedotin (Adcetris; 97.5%), an AKT or mTOR inhibitor (20%), and an HDAC inhibitor (17.5%). No patients had prior treatment with a PD-1 inhibitor since none were approved at the time of enrollment.

In the vorinostat/sirolimus arm, 36% of patients experienced stable disease. Of these patients, 32% had tumor shrinkage of more than 20%.

Further analysis revealed a trend toward higher ORR in patients with an ECOG performance status of 0 versus 1 or greater (P = .07).

In the vorinostat/everolimus arm, 44% of patients experienced stable disease. Additionally, 33% of these patients experienced tumor shrinkage of more than 20%.

A higher ORR was identified in patients with 2 or less metastatic sites compared with more than 2 sites (P = .022) and in patients with stage I, II, or III disease versus stage IV disease (P = .013). No differences were observed with regard to ORR between arms (P = .022).

During protocol amendment, 9 additional patients were treated. All had received prior brentuximab vedotin, 3 had received prior AKT or mTOR inhibition, and 1 had received a prior HDAC inhibitor. All patients had heavily pretreated Hodgkin lymphoma, were in urgent need of therapy, had no alternative treatment options, and received vorinostat/sirolimus. Among the patients in the expansion cohort, 44% achieved a CR and 33% achieved a PR, reflecting an ORR of 78%. These patients were not included in the final analysis.

The median follow-up was 43.3 months for patients treated with vorinostat and sirolimus. At the time of analysis, 13 patients discontinued treatment due to disease progression, 1 withdrew due to grade 3 neuropathy, 3 withdrew consent due to logistical reasons, such as the inability to travel, 1 was excluded due to noncompliance, and 2 were excluded due to subsequent alloSCT. The remaining 2 patients achieved a CR and continued on therapy for 43.3 and 46.3 months, respectively.

The median progression-free survival (PFS) was 5.8 months (95% CI, 3.7-7.9) overall and 18 months (95% CI, 3.1-32.9) in patients who obtained a CR or PR (versus 3.2 months in patients who did not; 95% CI, 1.0-5.4; P = .019). A trend toward longer PFS was observed in patients with an ECOG performance status of 0 versus 1 or greater.

The median overall survival (OS) had not been reached at the time of analysis.

In the vorinostat/everolimus arm, at a median follow-up of 21 months, 14 patients discontinued therapy due to progression, 1 withdrew consent due to grade 3 thrombocytopenia, 1 was excluded due to noncompliance, 1 was excluded as a result of donor lymphocyte infusion, and 1 was excluded due to physician decision.

The median PFS was 4.8 months (95% CI, 3.0-6.6), and no difference in PFS was observed between patients who achieved a CR or PR and those who did not.

A longer median PFS was observed in patients with normal lactate dehydrogenase (LHD) versus high LDH and in patients with normal albumin versus low albumin (P < .001).

At the time of analysis, 5 patients had died, and the median OS had not been reached.

All 40 patients who were treated were evaluable for safety. Overall, 98% of patients experienced any-grade toxicity. Moreover, 68% of patients reported a grade 3 adverse effect (AE), and 30% of patients reported a grade 4 AE.

All-grade AEs included thrombocytopenia (n = 35), neutropenia (n = 17), febrile neutropenia (n = 1), anemia (n = 19), mucositis (n = 15), rash (n = 12), transaminitis (n = 14), elevated bilirubin (n = 1), elevated creatinine (n = 8), elevated cholesterol (n = 4), elevated triglycerides (n = 12), dry skin (n = 1), neuropathy (n = 4), anorexia (n = 5), fatigue (n = 5), nausea (n = 2), and diarrhea (n = 1).

In patients treated with vorinostat and sirolimus, grade 3 AEs included thrombocytopenia (n = 4), neutropenia (n = 4), febrile neutropenia (n = 1), anemia (n = 5), transaminitis (n = 1), elevated triglycerides (n = 1), and neuropathy (n = 1). Grade 4 AEs included thrombocytopenia (n = 8) and neutropenia (n = 2).

In patients treated with vorinostat and everolimus, grade 3 AEs included thrombocytopenia (n = 10), neutropenia (n = 4), anemia (n = 3), mucositis (n = 1), transaminitis (n = 1), and elevated triglycerides (n = 2). Grade 4 AEs included thrombocytopenia (n = 2).

The majority of dose interruptions and/or dose reductions were due to thrombocytopenia.

“In our early-phase study, we demonstrated that oral combinations of the HDAC inhibitor vorinostat with the mTOR inhibitors sirolimus or everolimus have encouraging activity in patients with heavily pretreated Hodgkin lymphoma,” said Janku in a statement to OncLive^®. “We believe that durable responses observed in some patients warrant further investigation of these oral and easy-to-administer combinations.”

References:

1. Janku F, Park H, Call SG, et al. Safety and efficacy of vorinostat plus sirolimus or everolimus in patients with relapsed refractory Hodgkin lymphoma. Clin Cancer Res. 2020;26:1-9. Published online ahead of print October 14, 2020. doi:10.1158/1078-0432.CCR-20-1215
2. Combined inhibition of HDAC and mTOR may improve outcomes in patients with relapsed/refractory Hodgkin lymphoma. News release. AACR. October 14, 2020. Accessed October 14, 2020. https://bit.ly/3dyyncU