Response-adapted anti-PD-1-based salvage therapy for Hodgkin lymphoma with nivolumab alone or in combination with ICE

Abstract

This phase 2 trial evaluated PET-adapted nivolumab alone or in combination with ifosfamide, carboplatin, and etoposide (NICE) as first salvage therapy and bridge to autologous hematopoietic cell transplantation (AHCT) in relapsed/refractory (RR) classical Hodgkin lymphoma (cHL). Patients with RR cHL received 240 mg nivolumab every 2 weeks for up to 6 cycles (C). Patients in complete response (CR) after C6 proceeded to AHCT, whereas patients with progressive disease at any point or not in CR after C6 received NICE for 2 cycles. The primary endpoint was CR rate per the 2014 Lugano classification at completion of protocol therapy. Forty-three patients were evaluable for toxicity; 42 were evaluable for response. Thirty-four patients received nivolumab alone, and 9 patients received nivolumab+NICE. No unexpected toxicities were observed after nivolumab or NICE. After nivolumab, the overall response rate (ORR) was 81%, and the CR rate was 71%. Among 9 patients who received NICE, all responded, with 8 (89%) achieving CR. At the end of protocol therapy, the ORR and CR rates were 93% and 91%. Thirty-three patients were bridged directly to AHCT, including 26 after Nivo alone. The 2-year progression-free survival (PFS) and overall survival in all treated patients (n = 43) were 72% and 95%, respectively. Among 33 patients who bridged directly to AHCT, the 2-year PFS was 94% (95% CI: 78-98). PET-adapted sequential salvage therapy with nivolumab/nivolumab+NICE was well tolerated and effective, resulting in a high CR rate and bridging most patients to AHCT without chemotherapy. This trial was registered at www.clinicaltrials.gov #NCT03016871.

Graphical abstract

Figure 1.

CONSORT diagram, treatment schema, and patient response data.

Figure 2.

Survival outcomes. (A) PFS in all treated patients, (B) PFS in patients who proceeded directly to AHCT after protocol therapy, and (C) OS in all treated patients.

Figure 3.

Baseline total MTV and TLG (plotted on a log scale) are associated with response status at end of Nivo. (A) Baseline MTV and CR at end of Nivo. (B) Baseline TLG and CR at end of Nivo. (C) Baseline MTV and response at end of Nivo. (D) Baseline TLG and response at end of Nivo.

Figure 4.

Spatial features of the TME associated with CR to second-line Nivo. (A) Density of CD8⁺PD-1⁺ T cells in CR vs non-CR patients. (B) Density of CD163⁺PD-L1⁺ macrophages in CR vs non-CR patients. (C) CD8⁺PD-1⁺ T cells within 40 μm of HRS cells in CR vs non-CR patients. (D) CD163⁺PD-L1⁺ macrophages within 40 μm of HRS cells in CR vs non-CR patients. (E) CD56⁺ NK cells within 40 μm of HRS cells in CR vs non-CR patients.