CHMP Issues Positive Opinion for Nivolumab in Hodgkin Lymphoma

Emmanuel Blin

The Committee for Medicinal Products for Human Use (CHMP) has recommended approval of nivolumab (Opdivo) for the treatment of patients with relapsed/refractory classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and treatment with brentuximab vedotin (Adcetris), according to Bristol-Myers Squibb (BMS), the manufacturer of the PD-1 inhibitor.

The application for nivolumab was based in part on data from the phase II CheckMate-205 trial, in which the treatment induced responses in 66% of patients with cHL who had progressed following ASCT and brentuximab vedotin. The responses with nivolumab were durable and included 7 complete remissions (CR) and 46 partial remissions (PR). Among the 43 patients who did not respond to brentuximab vedotin, 72% (n = 31) responded to nivolumab.

The positive opinion has been sent to the European Commission, which usually issues its final approval decision within 2 to 3 months of the CHMP recommendation.

“We recognize the enormous challenges facing classical Hodgkin lymphoma patients who do not respond to or who progress following currently available treatments, and we are dedicated to helping these patients in their fight against this devastating disease,” Emmanuel Blin, senior vice president and chief strategy officer, BMS, said in a statement. “Today’s CHMP positive opinion marks an important milestone in applying our immuno-oncology science to delivering a treatment option for patients with this hematologic malignancy. If approved by the European Commission, Opdivo will become the first PD-1 inhibitor approved to treat a hematologic malignancy in the European Union, further building on our established heritage in blood cancer care.”

The overall CheckMate-205 trial evaluated nivolumab in both newly diagnosed and previously treated patients with cHL. Individuals enrolled in 1 of the study’s 3 pretreated patient cohorts received 3 mg/kg of nivolumab as an IV injection every 2 weeks. The treatment-naïve patient cohort received 240 mg of nivolumab as an IV injection every 2 weeks plus 25 mg/m² of doxorubicin, 6 mg/m² of vinblastine, and 375 mg/m² of dacarbazine. The primary outcome measure was overall response rate (ORR).

Data were presented at the 2016 ASCO Annual Meeting for a cohort of 80 patients from CheckMate-205 who had previously received ASCT and brentuximab vedotin.¹ The median age of these patients was 37 years (range 18-72) and 96% of patients (n = 77) were aged <65 years. Sixty-four percent of patients (n = 51) were male, with 52.5% (n = 42) and 47.5% (n = 38) of patients having an ECOG performance status of 0 and 1, respectively.

Patients had received a median of 4 prior lines of therapy (range, 3-15) and 39 patients (49%) had ≥5 prior lines. Of the 80 patients, 74 (92.5%) had underwent 1 prior ASCT, and 6 (7.5%) had underwent ≥2 prior ASCT. All patients had received brentuximab vedotin, and 54% of patients (n = 43) did not have a response to the antibody-drug conjugate.

At a data cutoff in October 2015, the median follow-up was 8.9 months (95% CI, 1.9-11.7) and 64% of patients (n = 51) remained on treatment. Of the 36% of patients (n = 29) who stopped treatment, the reasons for discontinuation included progression (16%), toxicity (5%), proceeding to allogeneic stem cell transplant (6%), proceeding to ASCT (1%), and other (8%). All of the 6 patients who opted to end nivolumab treatment and undergo stem cell transplant were alive at the data cutoff.

ORR by independent radiologic review was 66% (n = 53; 95% CI, 54.8-76.4), which included a CR rate of 8.8% (95% CI, 3.6-17.2) and a PR rate of 57.5% (95% CI, 45.9-68.5). Of these responders, 62% (n = 33) remained in response at the data cutoff. Eighteen patients (23%) had stable disease (SD), 6 patients (8%) had progressive disease, and the status was unable to be determined for 3 patients (4%). The median time to response was 2.1 months (range, 1.6-5.7) and the median duration of response was 7.8 months (95% CI, 6.6 to not estimable).

The 6-month progression-free and overall survival rates per independent review were 76.9% (95% CI, 64.9-85.3) and 99%, (95% CI, 91-100) respectively. The median progression-free survival was 10 months (95% CI, 8.4 to N/A).

The investigator assessed ORR was 73% (n = 58; 95% CI, 61.4-81.9), which included CR and PR rates of 27.5% (n = 22; 95% CI, 18.1-38.6) and 45% (n = 36; 95% CI, 33.8-56.5), respectively. Eighteen patients (23%) had SD, 3 patients (4%) had progressive disease, and the status was unable to be determined for 1 patient.

In its evaluation, the CHMP also considered data from the phase I CheckMate-039 trial. Results from the study presented at the 2015 ASH Annual Meeting included 23 patients with relapsed/refractory cHL who received nivolumab at weeks 1 and 4, and then every 2 weeks for up to 2 years or until disease disease progression or unacceptable toxicity.²

At a median follow-up of 86 weeks (range, 32-107 weeks) the ORR was 87% (n = 20), including 6 CRs and 14 PRs. Fifty percent of the responders had durable responses as defined by the study protocol.

The time to CR ranged from 3 to 88 weeks following initiation of nivolumab therapy, including 2 patients whose PRs converted to a CR. Of the 20 responses, 75% (n = 15) occurred within 16 weeks of starting treatment, including 5 patients who proceeded to stem cell transplant (1 CR, 4 PR). Three patients had a best overall response of stable disease.

The safety evaluation by the CHMP included 263 patients from CheckMate-205 and -039. The most frequently reported adverse events were fatigue (32.3%), diarrhea (28.9%), pyrexia (27.1%), and cough (25.9%).

The FDA granted an accelerated approval to nivolumab in May 2016 for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after ASCT and posttransplantation brentuximab vedotin.

References

1. Younes A, Santoro A, Zinzani PL, et al. Checkmate 205: Nivolumab (nivo) in classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and brentuximab vedotin (BV)—A phase 2 study. J Clin Oncol 34, 2016 (suppl; abstr 7535).
2. Ansell S, Armand P, Timmerman JM , et al. Nivolumab in patients (Pts) with relapsed or refractory classical hodgkin lymphoma (R/R cHL): clinical outcomes from extended follow-up of a phase 1 study (CA209-039). Blood. 2015;126(23):583.