Nivolumab Elicits Durable Responses in Lymphoma

John Timmerman, MD

Nivolumab continued to show high activity and a good safety profile after more than a year of follow-up in heavily pretreated patients with relapsed or refractory lymphoid malignancies or those with classical Hodgkin lymphoma (cHL), according to findings presented at the 13th International Conference on Malignant Lymphoma in Lugano, Switzerland.

After a median follow-up of 74 weeks, the median duration of response had not yet been reached, but was maintained for longer than 91 weeks across 4 malignancies. The objective response rate (ORR) in patients with cHL was 87%, with a median response duration ranging from 9 to more than 91 weeks. In those with follicular lymphoma, the ORR was 75% with a duration ranging from 27 to greater than 82 weeks. Most responses remained ongoing at the time of the analysis.

Two patients with cutaneous T-cell lymphoma (CTCL) who received nivolumab responded and 1 of 2 patients with peripheral T-cell lymphoma (PTCL) who received the drug continued to have an ongoing response at 79 weeks. One patient with multiple myeloma showed an ongoing response of 12+ weeks and 1 patient with diffuse large B-cell lymphoma (DLBCL) maintained a response for a median of 22 weeks.

“The response to nivolumab can be very dramatic. Some patients have a rapid response and began to show benefit within one day. But one patient with multiple myeloma that initially had stable disease achieved complete response quite late,” said lead investigator John Timmerman, MD, Jonsson Comprehensive Cancer Center, University of California. “Durable responses such as these raise the question of whether it is better for a patient to go on to transplant or remain on nivolumab.”

The phase I study, enrolled 104 heavily pretreated patients, including 23 patients with cHL, 31 with B-cell NHL, 23 with T-cell NHL, and 27 patients with multiple myeloma, with 88%, 78%, 68%, and 66% having received ≥3 prior regimens, respectively. Autologous stem cell transplantation had previously been performed in 75% of patients with cHL, 56% of those with multiple myeloma, 13% with B-NHL, and in 9% of patients with T-NHL.

Nivolumab was administered by dose-escalation of 1 and 3 mg/kg given every 2 weeks for 2 years. The primary endpoint of the study was safety, with secondary outcome measures focused on efficacy.

In a 40-week analysis of the phase I study, which was also known as CA209-039, the ORR was 87% in patients with cHL, 40% in B-cell FL, 36% in DLBCL and 17% in T-cell non-Hodgkin lymphoma (NHL). Patients with multiple myeloma achieved a stable disease rate of 67%.

At the follow-up analysis, responses for patients with cHL were comprised of complete responses (CR), which were seen in 6 patients (26%), partial responses (PR) in 14 patients (61%), and stable disease (SD) in 3 patients (13%). In the B-NHL cohort, 3 patients achieved a CR (10%), 5 a PR (16%), and 16 had SD (52%). In those with T-NHL there were 4 PRs (17%) and 10 patients achieved SD (43%). One (4%) patient with multiple myeloma achieved a CR and 17 had SD (63%).

The median follow-up in the cHL cohort was 86 weeks. Of the 20 patients who responded to nivolumab, 5 later experienced disease progression, 5 went on to stem cell transplant, and 20 patients maintain an ongoing response.

In all, 72 (69%) patients had a drug-related adverse event (DRAE) and Grades 3 / 4 DRAEs occurred in 22 (21%) patients; 15 (14%) patients discontinued due to a DRAE. Immune-related adverse events were reported in 83% of patients and all cases resolved using protocol-prescribed procedures.

“The safety profile in this study was consistent with that seen in trials of nivolumab in solid tumor studies and with earlier reports from this trial,” Timmerman said.

Nivolumab is a fully human IgG4 monoclonal antibody targeting PD-1 that restores immune activity following co-option of the PD-1 pathway by tumors to avoid immune attack, explained Timmerman. The preclinical rationale for PD-1/PD-L1 blockade was based on PD-L1 expression on tumor cells and /or infiltrating macrophages.

Anas Younes MD, Memorial Sloan Kettering, who was not involved in the study, repeated the observation that Hodgkin and Reed Sternberg (HRS) cells express high levels of PD-L1, which could partially explain the response seen in patients with cHL. “The highest response rate with PD-1 blocking antibodies is observed in relapsed cHL patients,” he commented.

In May 2014, nivolumab received a breakthrough therapy designation from the FDA for the treatment of patients with Hodgkin lymphoma following autologous stem cell transplant (ASCT) and brentuximab vedotin (Adcetris). An international phase II trial of nivolumab in Hodgkin lymphoma is underway along with studies exploring the drug in FL and DLBCL. In addition to single-agent trials, investigations are evaluating nivolumab in combination with the anti-KIR agent lirilumab and the anti-CTLA-4 antibody ipilimumab.

Timmerman J, Armand P, Lesokhin AM, et al. Nivolumab in patients with relapsed or refractory lymphoid malignancies and classical Hodgkin lymphoma: updated results of a phase 1 study (CA209-039). Presented at: 13th International Conference on Malignant Lymphoma; June 16-20, 2015; Lugano, Switzerland. Abstract 010.