End points in clinical trials in diffuse large B-cell lymphoma: time for more dialogue?

Figures & data

Table 1. Primary end points, progression-free survival and event-free survival definitions as primary end points in completed and ongoing randomized phase III diffuse large B-cell lymphoma trials.

Trial name/Treatment arms	Year of reporting	Primary end point	PFS defined as time from randomization to …	EFS defined as time from randomization to …	Ref.
1st line trials
R-CHOP vs CHOP	2002	EFS	Disease progression, start of new therapy, treatment or disease-related death	Disease progression, start of new therapy or death	[7,8]
Phoenix trial, Ibrutinib+R-CHOP vs R-CHOP	2019	EFS	Disease progression or death	Disease progression, start of new therapy for PET–positive or biopsy-proven residual disease after six or more cycles of R-CHOP, death	[9]
DA-EPOCH-R vs R-CHOP	2019	EFS (=PFS^†)	Disease progression or death	Disease progression or death	[10]
Zuma-23 trial Axicabtagene Ciloleucel vs R-CHOP or DA-EPOCH-R	Ongoing	EFS	Disease progression, death	Disease progression, death, initiation of any non-protocol specified subsequent new lymphoma therapy for the treatment of residual disease or Biopsy-proven residual disease at the month 6 disease assessment or later, regardless of whether subsequent new lymphoma therapy is initiated or not	[11]
Bevacizumab-R-CHOP vs R-CHOP	2014	PFS	Disease progression, death	Not used	[12]
Epcoritamab-R-CHOP vs R-CHOP	Ongoing	PFS	Disease progression, death	Disease progression, start of new therapy or death	[13]
R-CHOP vs G-CHOP	2017	PFS	Disease progression or death	Disease progression, start of new therapy or death	[14]
Robust trial, Lenalidomide +R-CHOP vs R-CHOP	2021	PFS	Disease progression or death	Disease progression, start of new therapy or death	[15]
Polarix trial, Pola-R-CHP vs R-CHOP	2022	PFS	Disease progression or death	EFSeff (key secondary end point): disease progression, death, primary efficacy reason determined by the investigator other than disease progression/relapse, that leads to initiation of start of new antineoplastic therapy; if biopsy is obtained after treatment completion, and is positive for residual disease EFSall (secondary end point): disease progression, death, start of new therapy	[16]
Polar Bear trial, Pola-R-mini-CHP vs R-mini-CHOP	Ongoing	PFS	Disease progression, lack of response or death	Unknown (no secondary end points reported)	[17]
frontMind trial, Tafasitamab-Lenalidome-R-CHOP vs R-CHOP	Ongoing	PFS	Disease progression or death	Disease progression, start of new therapy or death	[18]
2nd line trials in transplant-eligible patients
Belinda trial, Tisa-cel vs transplant strategy	2021	EFS	Not used	Stable or progressive disease at or after the week 12 assessment or death at any time	[19]
Zuma-7 trial, Axi-cel vs transplant strategy	2021	EFS	Disease progression or death	Disease progression, start of new antineoplastic therapy^‡, death, best response of stable disease up to and including the response on the day 150 assessment after randomization	[20]
Transform trial, Liso-cel vs transplant strategy	2021	EFS	Disease progression or death	Disease progression, death, failure to achieve CR or PR by 9 weeks post-randomization, start of new antineoplastic therapy due to efficacy concerns	[21]
2nd line trials in transplant-ineligible patients
Pix-R vs Gem-R	2016	PFS	Disease progression, death	Not used	[22]
Lotis-5 trial, Lonca-R vs R-Gem-Ox	Ongoing	PFS	Disease progression or death	Not used	[23]
SUNMO trial, Mosunetuzumab+ Polatuzumab vs R-Gem-Ox	Ongoing	PFS	Disease progression or death	Not used	[24]
Selinexor-R-GDP vs R-GDP	Ongoing	PFS	Disease progression or death	Not used	[25]
B-MIND trial, Tafasitamab-Bendamustine vs BR	Ongoing	PFS	Disease progression, unacceptable toxicity, death or discontinuation for any other reason	Not used	[26]
R-InO vs BR or RG	2018	OS	Disease progression (including investigator's claim of clinical progression), death, start of new therapy	Not used	[27]
EPCORE-DLBCL-1 trial, Epcoritamab vs R-Gem-Ox	Ongoing	OS	Disease progression or death	Not used	[28]
POLARGO trial, Pola-R-Gem-Ox vs R-Gem-Ox	Ongoing	OS	Disease progression or death	Disease progression, death, start of new therapy	[29]
Glofitamab-Gem-Ox vs R-Gem-Ox	Ongoing	OS	Disease progression or death	Not used	[30]
Pola-R-ICE vs R-ICE	Ongoing	EFS	Disease progression or death	Disease progression, death, start of new therapy, failure to achieve metabolic CR at end of study treatment	[31]

† Per protocol in the Supplementary Material, EFS was the primary end point. However, as EFS was defined in the same way as traditional PFS, the reporting of the trial refers to PFS as primary end point.

‡ HSCT after CAR-T infusion was not considered an event in Zuma-7 trial.

Search was performed on 21 November 2022 on clintrials.gov website applying the filters ‘Phase III’, ‘Interventional Studies (except withdrawn and unknown status)’, ‘Adult, older adult’ and using the following search terms:

- relapsed refractory lymphoma: 85 studies found.

- untreated lymphoma: 89 studies found.

- newly diagnosed lymphoma: 78 studies found.

- first-line lymphoma: 49 studies.

Subsequently, trials were excluded for following reasons: not a global trial, other populations than DLBCL, maintenance trials in patients without measurable disease, no details reported on end points for an ongoing or terminated trial, trial investigated new formulation or a biosimilar.

CR: Complete Response; DLBCL: Diffuse large B-cell lymphoma; EFS: Event-free Survival; HSCT: Haematopoietic stem cell transplantation; PFS: Progression-free Survival; OS: Overall Survival, PET: Positron emission tomography..

Figure 1. Examples of patient journeys in diffuse large B-cell lymphoma trials.

PD: Progressive disease; R: Randomization; SD: Stable disease; CR: Complete Response.

Figure 2. Scheme of CAR-T and transplant treatment strategies.

Figure 3. Patient journeys and assessment of quality of life at 6 months.

CR: Complete Response; SD: Stable Disease; PRO: Patient-reported outcomes.

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