Immune checkpoint blockade: the role of PD-1-PD-L axis in lymphoid malignancies

Figures & data

Figure 1 PD-1- PD-L1 axis blockade in cancer.

Notes: Signaling through PD-1 induces T cell anergy, with the physiological role of protecting from autoimmune damage. This mechanism is exploited by tumor cells expressing PD-1 ligands to escape immunity by suppressing host antitumor T cell responses (left). PD-1 or PD-L1 blocking antibodies have the capability to restore cytotoxic T cell functions including IFN-y and perforin production, which can lead to impressive antitumor responses (right).
Abbreviations: PD, programmed cell death; PD-L1, programmed cell death receptor ligand-1.

Table 1 US Food and Drug Administration-approved PD-1 checkpoint blockers

Drug	Activity	Approved for	Observations
Nivolumab	Anti-PD-1 human IgG4 mAb	Metastatic melanoma	Single or in combination with ipilimumab
		Classical Hodgkin’s lymphoma	After ASCT and brentuximab vedotin failure
		Nonsmall cell lung cancer	Progression after platinum and/or other agents
		Renal cell carcinoma	After prior anti-angiogenic therapy
Pembrolizumab	Anti-PD-1 humanized IgG1 mAb	Melanoma (unresectable/metastatic)
		Nonsmall cell lung cancer	Approval restricted to PD-L1 expressing tumors
		Head and neck squamous cell carcinoma	Progression after or on platinum-containing treatment
Atezolizumab	Anti-PD-L1 humanized IgG1 mAb	Metastatic nonsmall cell lung cancer	Progression after platinum and/or other agents
		Urothelial cancer	Metastatic or locally advanced

Abbreviations: ASCT, autologous stem cell transplantation; PD-1, programmed cell death receptor 1; PD-L1, programmed cell death receptor ligand 1.

Table 2 Selected clinical trial results of PD-1-PD-L checkpoint blockade efficacy in lymphoid malignancy

Interventional clinical trial number	Type of study	Participants	Description: dose and trial duration	Posted/published results	Comments/limits
Hodgkin’s lymphoma
NCT01592370 CheckMate-039	Interventional Phase I dose-escalation and expansion, nivolumab Ansell et al^Citation93	23 patients with R/R HL, 87% had >2 previous regimens, 78% had ASCT, 78% had BV, Median age 35 years	Nivolumab 3 mg/kg at week 1, week 4, and then every 2 weeks until progressive disease, CR, toxicity or for a maximum of 2 years. Median duration of follow-up was 40 weeks	ORR: 20 (87%) CR: 4 (17%) PR: 16 (70%) SD: 3 (13%)	Acceptable safety profile Good overall response Majority of adverse events grade 1 or 2
	Extended follow-up, nivolumab Ansell et al^Citation127	Same as above	Same dose as above; median duration of follow-up was 86 weeks	20 responders, 10 durable responses Responses occurred within 16 weeks of initiation in 15 of 20 patients 5 patients with early responses proceeded to SCT (4 allo-, 1 ASCT) Responses lasted ≥1 year in 7 of 10 patients who did not undergo SCT	Positive study for extended response
NCT02181738 CheckMate-205	Noncomparative, multi-cohort, single arm, open-label, Phase II study of nivolumab in cHL subjects. Report on cohort B. Timmerman et al^Citation95	80 patients in R/R previously treated with BV after ASCT failure Median age 37 years (18–72) Median prior therapies: 4	Nivolumab 3 mg/kg every 2 weeks Median follow-up 15.4 months 43 (54%) still on therapy at cutoff	ORR: 68% CR: 8% PR: 60% Median duration of CR: NR Median duration PR: 13.1 months Median PFS: 14.8 months 12 month PFS: 54.6% 12 month OS: 94.9%	Positive study Preliminary results of this study together with Checkmate-039 results led to FDA approval of nivolumab in May 2016 for R/R cHL after ASCT and brentuximab
NCT01953692 Keynote-013	Phase Ib study of pembrolizumab in cHL patients after BV failure: long-term efficacy report Armand et al^Citation128	31 patients relapsed after or ineligible for ASCT and R/R after BV, median prior therapy lines 5	Pembrolizumab 10 mg/kg every 2 weeks until progressive disease, toxicity or up to 2 years Median follow-up 24.9 months	Investigator review: ORR: 65%, CR: 19% Blinded independent central review: ORR 58%, CR 19%, PR 39%, SD 23% 6 months OS: 100% 12 month OS: 87%	Positive study, median survival NR at >2 years
NCT02453594 Keynote-087	Phase II study of pembrolizumab in R/R cHL primary end point analysis Moskowitz et al^Citation129	210 patients, 3 cohorts: prior ASCT and BV (69), ineligible for ASCT and BV failure (81), and R/R to prior ASCT and no BV (60)	Pembrolizumab 200 mg intravenous every 3 weeks	Investigator review: ORR: 66.7%, 65.4% and 69.3% CR: 29%, 24.7%, 21.7% Blinded independent central review: ORR: 72.5%, 65.4%, 66.7% CR: 21.7%, 22.2%, 21.7% respectively, for the 3 cohorts	Positive study
Chronic lymphocytic leukemia
NCT02332980 MC1485	Phase II study of pembrolizumab alone or with idelalisib or ibrutinib in R/R CLL and RS. Ding et al^Citation130	25 patients: 16 with CLL and 9 with RS. Enrolled in the CLL arm of the study. Median age 69 years (46–81)	Pembrolizumab 200 mg intravenous q 3 weeks	RS: CR: 1 (11%) PR: 3 (33%) SD: 3 (33%) Progressive disease: 2 (22%)	Single agent pembrolizumab seems to have better activity in RS than in CLL, results being rather negative for the latter
		12 (48%) with del (17p)/monosomy 17/TP53 mutation. Median number of prior therapies: 4 (1–10)	Median number of doses: 3 (1–21)	CLL: No CR/PR 6-month OS: 73% for RS vs 59% for CLL
NCT02420912	Phase II study of nivolumab plus ibrutinib in CLL and RS. Jain et al^Citation131	Cohort 1: R/R CLL (5 patients) or RS (4 patients) Cohort 2: CLL in PR after min. 9 months of ibrutinib, N=3 pts Median age 63 years (42–78) Median number of prior therapies: 1 (1–3)	Nivolumab 3 mg/kg IV every 2 weeks, ibrutinib 420 mg/day For cohort 1: a first course of single-agent nivolumab followed by adjunction of ibrutinib	Cohort 1, CLL PR: 3 pts No response and withdrawal: 1 patient Non-assessable: 1 patient Cohort 1, RS: 2 patients with PR, 1 with PD, 1 non-assessable Cohort 2: no CR, all 3 patients showed decreased marrow infiltration	Early results are promising, study is ongoing
B-NHL
NCT01592370 CheckMate-039	Phase 1b study of nivolumab in R/R hematologic malignancy Lesokhin et al^Citation25	105 total 31 patients with R/R B-NHL (of which 11 DLBCL, 10 FL, 10 other) Median age 65 years (23–74)	Nivolumab 1 and 3 mg/kg at week 1, week 4, and then every 2 weeks until PD, CR, toxicity or for a maximum of 2 years	DLBCL: CR: 2 (18%), PR: 2 (18%), SD: 3 (27%), median PFS: 7 weeks FL: 4 (40%), CR: 1 (10%), PR: 3 (30%), SD: 6 (60%), median PFS: NR Other: CR: 0, PR: 0, SD: 7 (70%), median PFS: 11 weeks (3–39)	Acceptable safety profile and positive objective response rate leading to Phase II studies in DLBCL and FL
NCT01953692 Keynote-013	Phase 1b study of pembrolizumab in R/R PMBL Zinzani et al^Citation132	19 patients with PMBL Median age 30.5 years (22–62)	First 11 patients: pembrolizumab 10 mg/kg q 2 w (1 not treated – early PD) Subsequent patients: pembrolizumab 200 mg q 3 weeks	CR: 2 PR: 5 SD: 6 Median follow-up: 11.3 months (24–27.4), median duration of response NR	Manageable safety profile, promising antitumor activity
T-NHL
NCT01592370 CheckMate-039	Phase 1b study of nivolumab in R/R hematologic malignancy Lesokhin et al^Citation25	105 total of which 23 T-NHL: 13 MF, 5 PTCL, 5 other T-NHL Median age 61 years (30–81) 2–6 prior systemic therapies	Nivolumab 1 and 3 mg/kg at week 1, week 4, and then every 2 weeks until PD, CR, toxicity or for a maximum of 2 years	All T-NHL: CR: 0, PR: 4 (17%), SD: 10 (43%), median PFS: 10 weeks MF: CR: 0, PR: 2 (15%), SD: 9 (69%) Median PFS: 10 weeks PTCL: CR: 0, PR 2 (40%), SD: 0, median PFS: 14 weeks	Ongoing response in the two MF responders at 24 and 50 weeks, and for one patient with PTCL at 78 weeks
NCT01953692 Keynote-013	Phase 1b study of pembrolizumab in R/R PMBL Zinzani et al^Citation132	19 patients with PMBL Median age 30.5 years (22–62)	First 11 patients: pembrolizumab 10 mg/kg q 2 w (1 not treated – early progressive disease) Subsequent patients: pembrolizumab 200 mg q 3 w	CR: 2 PR: 5 SD: 6 Median follow-up: 11.3 months (24–27.4), median duration of response: NR	Manageable safety profile, promising antitumor activity
Multiple myeloma
NCT01592370 CheckMate-039	Interventional Phase I dose-escalation and expansion of nivolumab in R/R lymphoid malignancies Lesokhin et al^Citation25	81 patients with R/R lymphoid malignancies including 27 patients with MM Median age of 63 years (range, 32–81 years)	Dose escalation design (1 mg/kg and 3 mg/kg) of nivolumab administered every 2 weeks for up to 2 years	CR: 1 (4%) Median PFS: 10 weeks (5–15)	Negative study for MM patients
NCT02289222	Phase II study of pembrolizumab with pomaliodmide and dexamethasone in R/R MM Badros et al^Citation133	48 patients with MM Median age: 64 years (35–82) Median previous therapies: 3 (2–6)	Pembrolizumab 200 mg q 2 w (first 6 patients: 200 mg q 4 w) plus pomalidomide 4 mg q d 21 days plus dexamethasone 40 mg q w	Stringent CR: 4 Near CR: 3 VGPR: 6 PR: 14 MR: 7 SD: 9 Median duration of response ≥ VGPR: 10.7 months Median follow-up: 10 months (2–18)	Acceptable safety profile, promising therapeutic activity
NCT02036502 Keynote-023	Phase 1 study of pembrolizumab with lenalidomide and dexamethasone in R/R MM San Miguel et al^Citation134	34 patients; data available for 17 patients Median age 60 years (46–76) 53% had ≥3 previous therapies	4 patients: pembrolizumab 2 mg/kg q 2 w, lenalidomide 10 mg q d 13 patients: pembrolizumab 2 mg/kg or 200 mg and lenalidomide 25 mg All patients: dexamethasone 40 mg q w	VGPR: 4 PR: 9 Median follow-up: 287 days (48–476)	Preliminary results positive for safety and anti-myeloma activity. An international Phase III trial, KEYNOTE-183 (NCT02576977), is currently ongoing

Abbreviations: ASCT, autologous stem cell transplantation; BV, brentuximab vedotin; CLL, chronic lymphocytic leukemia; cHL, classical Hodgkin’s lymphoma; CR, complete response; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; FDA, US Food and Drug Administration; HL, Hodgkin’s lymphoma; MR, minimal response; MM, multiple myeloma; MF, mycosis fungoides; NHL, non-Hodgkin’s lymphoma; NR, not reached; ORR, objective response rate; OS, overall survival; PR, partial response; PTCL, peripheral T-cell lymphoma; PMBL, primary mediastinal large B-cell lymphoma; PD-1, programmed cell death receptor 1; PD-L, programmed cell death receptor ligand; PFS, progression-free survival; R/R, relapsed/refractory; RS, Richter syndrome; SD, stable disease; SCT, stem cell transplantation; VGPR, very good partial response.

AnsellSMLesokhinAMBorrelloIPD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphomaN Engl J Med2015372431131925482239

 PubMed Web of Science ®Google Scholar

AnsellSArmandPTimmermanJMNivolumab 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)Blood201512623583583

 Google Scholar

TimmermanJMEngertAYounesACheckmate 205 update with minimum 12-Month Follow up: a phase 2 study of nivolumab in patients with relapsed/refractory classical Hodgkin lymphomaBlood20161282211101110

 Web of Science ®Google Scholar

ArmandPShippMARibragVPembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: long-term efficacy from the phase 1b keynote-013 studyBlood20161282211081108

 Web of Science ®Google Scholar

MoskowitzCHZinzaniPLFanaleMAPembrolizumab in relapsed/refractory classical Hodgkin lymphoma: primary end point analysis of the phase 2 keynote-087 studyBlood20161282211071107

 Web of Science ®Google Scholar

DingWLe-RademacherJCallTGPD-1 blockade with pembrolizumab in relapsed CLL including Richter’s transformation: an updated report from a phase 2 trial (MC1485)Blood20161282243924392

 Google Scholar

JainNBasuSThompsonPANivolumab combined with ibrutinib for CLL and Richter transformation: a phase II trialBlood2016128225959

 Web of Science ®Google Scholar

LesokhinAMAnsellSMArmandPNivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib StudyJ Clin Oncol201634232698270427269947

 PubMed Web of Science ®Google Scholar

ZinzaniPLRibragVMoskowitzCHPhase 1b Study of Pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma: results from the ongoing keynote- 013tTrialBlood201612822619619

 Google Scholar

BadrosAZHyjekEMaNPembrolizumab in combination with pomalidomide and dexamethasone for Relapsed/Refractory Multiple Myeloma (RRMM)Blood201612822490490

 Google Scholar

San MiguelJMateosM-VShahJJPembrolizumab in combination with lenalidomide and low-dose dexamethasone for Relapsed/Refractory Multiple Myeloma (RRMM): keynote-023Blood201512623505505

 Google Scholar