Extended analysis of data from a trial of the PD-1 checkpoint inhibitor nivolumab has found that more than two-thirds of patients with relapsed or refractory classical Hodgkin lymphoma after autologous stem cell transplant (ASCT) continued to respond to treatment well into their second year, regardless of any history of brentuximab vedotin (BV) therapy.
The new findings from the CheckMate-205 trial were presented at the International Conference on Malignant Lymphoma in Lugano, Switzerland (Hematol Oncol 2017;35:135-136, Suppl S2).
In classical Hodgkin lymphoma (cHL) patients who had received BV treatment before, after, or both before and after ASCT, the objective response rate (ORR) was 73 percent at a median follow-up of 16 months, with complete response (CR) in 12 percent of patients. The median duration of response (DOR) was 15 months, and the median progression-free survival (PFS) was 11.9 months (95% CI: 11.1 to 18.4).
The new data represents the longest follow-up to date of response rates in patients with classical Hodgkin lymphoma treated with a PD-1 inhibitor, said CheckMate-205 investigator Michelle Fanale, MD, Associate Professor in the Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston.
“Treatment options are limited for patients with classical Hodgkin Lymphoma after ASCT has failed, which is why the high objective response rates shown across cohorts of the CheckMate-205 study are encouraging,” Finale noted. “The results are particularly welcome news, as patients experienced responses regardless of brentuximab vedotin treatment history or the depth of their Hodgkin lymphoma's response to brentuximab vedotin.”
The FDA granted accelerated approval in 2016 to nivolumab for cHL patients who have relapsed or progressed after autologous hematopoietic stem cell transplantation and post-transplantation BV therapy.
Approval was based on an ORR of 65 percent in combined analysis of data from the phase II CheckMate-205 and the phase 1 CheckMate-039 trials (CI 95%: 55-75; 62/95 patients). Six-month data showed an ORR of 66.3 percent, with a DOR of 7.8 months, 4.6 months duration of partial response (DPR), and a median PFS rate of 10 months (Lancet Oncol 2016;17:1283-1294).
One-year data, released late in 2016, showed an ORR of 67.5 percent, with a DOR and DPR of 13.1 months, and a median PFS of 14.4 months (2016 American Society of Hematology, Abstract 1110).
In the new report, ORR and DOR were evaluated in three separate groups of patients: BV-naïve (Cohort A); BV therapy after ASCT (Cohort B); and BV-before, after, or before-and-after ASCT (Cohort C). All response rates were independently assessed by a radiology review committee.
In Cohort A, which included 63 treated patients who had never received BV, the ORR was 65 percent at a median follow-up of 19 months, with CR in 29 percent of patients. The median DOR was 20 months and the median PFS was 18.3 months.
In Cohort B, with a median follow-up of 23 months, the ORR was 68 percent, with CR in 13 percent of patients. The median DOR was 16 months and the median PFS was 14.7 months (95% CI: 10.5 to 19.6).
Cohort C included 33 patients who had received BV before ASCT, 58 subjects who had received treatment after transplantation, and nine patients treated both before and after.
The safety profile in all three groups of patients was consistent with previously reported data. The most common treatment-related adverse events (AEs) were fatigue (23%), diarrhea (15%), and infusion reactions (14%). Grade 3 or 4 AEs included fatigue, diarrhea, and rash, each of which occurred in 1 percent of subjects.
Across cohorts, the median OR was not reached, and 40 percent of patients remained on treatment.
Commenting on the updated response data, Manali Kamdar, MD, Assistant Professor of Medicine and Clinical Director of Lymphoma Services at the University of Colorado School of Medicine, Aurora, said it is important to note that not all patients responded to treatment with nivolumab.
“This is very promising, especially for heavily pretreated patients. Before PD-1 drugs were developed, we only had rituximab,” she said. “Most of the patients were at a pretty advanced stage of disease, however, even a 70 percent response rate leaves a sizeable portion of the patient population that did not.”
Interim analysis from another trial evaluating combined therapy with BV and nivolumab in 59 patients was also presented. The ongoing phase I/II clinical trial showed an 85 percent ORR, including 63 percent with CR and 22 percent with PR. A phase III trial is being planned (Hematol Oncol 2017;35:85-86. Suppl S2).
“The phase I/II study combining the antibody-drug conjugate brentuximab vedotin with the PD-1 immune checkpoint inhibitor nivolumab is a promising investigational approach as it combines a targeted therapy with a therapy designed to activate the immune system and the combination may have additive activity,” said Alex Herrera, MD, lead trial investigator and Assistant Professor at the City of Hope, Duarte, Calif. “The interim results support further exploration of this novel regimen, free of traditional chemotherapy.”
The median age of patients was 36 years. Forty-five percent of patients had primary refractory disease and 55 percent progressed after responding to frontline therapy. They were treated once every 4 weeks with up to four cycles of the combination, and patients were eligible to undergo ASCT after the fourth cycle.
At the time of the analysis, 37 patients had initiated an ASCT while 12 had undergone alternative salvage therapy. There were no post-ASCT adverse events and preliminary analysis showed treatment had no impact on stem cell mobilization or graft success.
In another presentation at the conference, researchers reported encouraging response data from a subgroup analysis of another PD-1 inhibitor, pembrolizumab. Findings from the KEYNOTE-087 trial showed treatment resulted in an ORR of 79.5 percent, with a CR rate of 23.3 percent, a PR rate of 56.2 percent, and a PD rate of 11.0 percent. The median time to response was 2.8 months, but median response duration was not reached (Hematol Oncol 2017;35:136-137, Suppl S2).
Last March, pembrolizumab became the second PD-1 inhibitor to be approved for patients with refractory cHL after ASCT and BV therapy. Approval was based on data from the phase II KEYNOTE-087 study, a multicenter, non-randomized, open-label clinical phase II trial, with a median follow-up of 9.4 months. The ORR at that time was 69 percent, with CR in 22.4 percent and 47 percent PR. The estimated median response duration was 11.1 months.
According to Kamdar, many questions about treatment remain unanswered.
“What do we do after patients have been on the drug for 1 or 2 years. Is it safe to remove the drug? Would combinations work better? What is the biology of the effects and what are the risks.”
She told Oncology Times her research group has found that patients receiving nivolumab before ASCT may have higher rejection rates.
“Another concern is the risk of immune-mediated pneumonitis, especially in patients who have received radiation.”
The FDA has issued warnings advising physicians to closely monitor patients for immune-mediated AEs, including pneumonitis, and possible post-transplant complications.
“The landscape for treating patients has improved immensely, but there is more work to be done,” Kamdar concluded.
Kurt Samson is a contributing writer.