HL

ASCO 2016 Poster Discussion - PD-1 Inhibitors in Hodgkin Lymphoma, Abstracts 7535 and 7555

The ‘Hematologic Malignancies-Lymphoma and Chronic Lymphocytic Leukemia’ poster discussion session took place on Monday June 6, 2016, between 13:15–14:45. The session was jointly chaired by Susan Mary O’Brien, MD, Associate Director for Clinical Science, at Chao Comprehensive Cancer Center in the University of Irvine, California, and John Leonard, MD, of Weill Cornell Medicine, New-York.

Nancy L Bartlett, MD, Professor of Medicine at the Siteman Cancer Center, Washington University in Saint-Louis, MO, presented ‘Discussion – PD-1 Inhibitors in Hodgkin Lymphoma, Abstracts 7535, 7555’.

Bartlett began by outlining phase II treatment regimens:

  • Nivolumab 3mg/kg IV Q 2 weeks
    • Same dose/schedule as dose expansion study
  • Pembrolizumab 200mg flat dose IV Q 3 weeks
    • Dose expansion/schedule 10mg/kg Q 2 weeks
    • Flat exposure-response relationship for efficacy and safety in the 2mg/kg – 10mg/kg range across clinical studies (200mg “in range” if you weigh <100kg)
  • Continue until PD or unacceptable toxicity
    • Patients allowed to continue treatment past PD if clinical benefit

The talk then discussed whether standard PET criteria are adequate for response assessment. Possible false positive PETs occur due to PD-1 blockade activating T-cells at tumor site, this may explain lower CR rates and differences in investigator determined CR vs IRRC (28% vs 9%).

It was then discussed if nivolumab could act as a bridge to allo-SCT. However, a “warning and precaution” has been issued by the FDA for complications of allo-SCT post-nivolumab. In a phase I/dose expansion study using Nivolumab as a bridge to allo-SCT, 4/5 patients died of transplant complications (Ansell ASH, 2015, Blood, 126:583). It is of utmost important to follow patients closely for hyperacute and severe acute GVHD, VOD, and other immune-mediated reactions. In a phase II Nivolumab study, 6 patients went on to allo-SCT (all alive at data cut-off).

Abstract 7535: Checkmate 205: Nivolumab (nivo) in classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and brentuximab vedotin (BV)—A phase 2 study

Background: cHL is characterized by amplification at 9p24.1, causing overexpression of PD-1 ligands. Thus, cHL may be uniquely sensitive to PD-1 blockade. Nivo is a fully human IgG4 immune checkpoint inhibitor targeting PD-1 that showed promising results in a phase 1b study (NCT02181738) in pts with relapsed/refractory cHL (Ansell SM et al NEJM 2015;372:311–9), who currently have limited treatment options. 

Methods: This study evaluated the efficacy and safety of nivo in pts with cHL who had received BV after failed ASCT, as Cohort B of the larger Phase 2 Checkmate 205 study (NCT02181738). Nivo was given at 3 mg/kg IV q2w. Response was assessed by independent radiologic review committee (IRRC) and investigators (Inv), using 2007 IWG criteria. Primary endpoint was IRRC ORR. 

Results: The main characteristics of 80 treated cHL pts were: median age 37 y, median (range) 4 prior regimens (3–15). 90% of pts had drug-related AEs: 25% G3–4, 1% G5 (multi-organ failure). Most common drug-related AEs were fatigue (25%), infusion reaction (IR; 20%) and rash (16%). Most common SAEs were pyrexia, tumor progression, arrhythmia, IR, septic meningitis, and pneumonia ( ≤ 4% each). Select immune-related AEs, all G1–2, occurred in 26%. At database lock (DBL; October 2015), median (range) follow-up was 8.9 mo (1.9–11.7). 64% of pts remained on therapy; main reason for discontinuation was disease progression (16%). IRRC ORR (95% CI) was 66% (54.8–76.4); CR and PR rates were 8.8% (3.6–17.2) and 57.5% (45.9–68.5), respectively. Inv ORR, a pre-specified secondary endpoint, was 73% (61.4–81.9); CR and PR rates were 27.5% (18.1–38.6) and 45.0% (33.8–56.5). 62% (33/53) of IRRC responders remained in response at DBL. 6 pts elected to stop nivo and undergo stem cell transplant, all of these pts were alive at data cut-off. IRRC 6-mo PFS was 77%; OS was 99%. In 43 pts who had no prior BV response, nivo treatment resulted in an IRRC ORR of 72% (31/43). 

Conclusions: Nivo demonstrated a high response rate, long-lasting responses, and an acceptable safety profile in pts with cHL after ASCT and BV, including pts with no prior BV response. PFS and OS are encouraging in this heavily pretreated population. Clinical trial information: NCT02181738.

Abstract 7555: Pembrolizumab for relapsed/refractory classical Hodgkin lymphoma (R/R cHL): phase 2 KEYNOTE-087 study

Background: Patients (pts) with cHL who relapse after Autologous Stem-Cell Transplant (ASCT) or progress after brentuximab vedotin (BV) have a poor prognosis. The PD-1 ligands PD-L1 and PD-L2 are frequently overexpressed in R/R cHL. Pembrolizumab is a humanized monoclonal antibody against PD-1 preventing binding to PD-L1 and PD-L2. In the phase 1b KEYNOTE-013 study, pembrolizumab demonstrated high antitumor activity (ORR = 65%) in heavily pretreated cHL pts. KEYNOTE-087 (NCT02453594) is a multicohort phase 2 study designed to confirm clinical activity of pembrolizumab in cHL pts.

Methods: The study has 3 cohorts: R/R cHL after ASCT and subsequent BV therapy (cohort 1); ineligible for ASCT due to chemo-resistance (no response to salvage chemotherapy) and BV therapy failure (cohort 2); R/R cHL after ASCT but not treated with BV after ASCT (cohort 3). Pts receive pembrolizumab at a fixed dose of 200 mg IV Q3W. Primary end point is ORR, with response assessed every 12 wk according to Revised Response Criteria for Malignant Lymphomas. Prespecified interim analysis, based on investigator-assessed response, was performed after 30 pts reached first response assessment in cohorts 1 and 2.

Results: At time of data cutoff (Feb 1, 2016), 60 pts were evaluable for cohorts 1 and 2. Median (range) age was 36 (19-64) years in cohort 1 and 33 (20-71) in cohort 2. 67% received ≥ 4 prior lines of therapy, and by design 100% failed prior BV. ORR among 30 pts in cohort 1 is 70% (95% CI, 51-85). 6 pts (20%) achieved CR (residual mass permitted if PET negative), 15 (50%) PR, and 6 (20%) stable disease as best response. ORR among 30 pts in cohort 2 is 80% (95% CI, 61-92). 8 pts (27%) achieved CR, 16 (53%) PR, and 4 (13%) stable disease as best response. With a median of 6 treatment cycles, most common treatment-related AEs in the combined cohorts are pyrexia (13%), diarrhea (8%), fatigue, back pain, platelet count decrease, dry skin, and cough (7% each).

Conclusions: PD-1 blockade with pembrolizumab shows early responses in heavily pretreated cHL pts. Of note, pembrolizumab shows an unprecedented high ORR (80%) in pts who were not candidates for ASCT and failed previous BV therapy. Cohort 3 continues accrual and interim analysis results will be presented. Clinical trial information: NCT02453594.

References
  1. Ansell S, 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; 126:583.
  2. Younes A, 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).
  3. Chen RW, et al. Pembrolizumab for relapsed/refractory classical Hodgkin lymphoma (R/R cHL): phase 2 KEYNOTE-087 study. J Clin Oncol 34, 2016 (suppl; abstr 7555).