Zamtoacabtagene Autoleucel External Comparator Study

Objectif(s) de la recherche et intérêt pour la santé publique

Finalité de l'étude

Objectifs poursuivis

Domaines médicaux investigués

Bénéfices attendus

Public Health Interest:
Zamto-cel has been under investigation in two Phase 2 clinical trials (17,18). The first is DALY 2-EU [NCT04844866], which is a randomised, multi-centre, open-label study to evaluate the efficacy and safety of zamto-cel compared to SoC therapy with rituximab, gemcitabine and oxaliplatin (R-GemOx), in participants with R/R LBCL who are not eligible for high-dose chemotherapy (HDC) and ASCT (Part I). Note that this trial will also be supplemented with a cohort of patients who are eligible for HDC and ASCT and who progressed less than 12 months after the completion of 1L therapy (Part II). The second trial is DALY II USA [NCT04792489], which is a multi-centre, single arm study (SAT) to evaluate the efficacy, safety, and pharmacokinetics of zamto-cel in patients with R/R LBCL after receiving at least two prior lines of therapy (LoTs).
Owing to the rapidly evolving treatment landscape and limited comparisons with existing treatment options in the ongoing trials, Miltenyi are seeking high-quality real-world data (RWD) to generate external comparator evidence for the DALY 2-EU and DALY-2 USA trials. Such data will be used to bolster the evidence package for Miltenyi’s Joint Clinical Assessment (JCA) submission for regulatory and market access approval of Zamto within the European Union. The overarching aim of this external comparator (EC) study is therefore to compare the effectiveness of Zamto to existing SoC treatments in the patient populations covered by the referent DALY 2-EU and DALY-2 USA trials. An initial feasibility assessment will be conducted to identify suitable RWD sources, estimate patient counts and confirm completeness and quality of data recording prior to commencement of the full EC study. Subject to feasibility, this EC study will seek to generate evidence covering all Populations, Interventions, Comparators, Outcomes (PICOs) anticipated for JCA that are not supported by other Miltenyi research projects, in order to close existing comparative evidence gaps for the target label and reimbursement populations.

The primary objectives of the study are:
1. In patients with prespecified LBCL subtypes4 who failed one previous line of chemoimmunotherapy (2L R/R LBCL) who are eligible for ASCT and who progressed less than 12 months after the completion of 1L therapy, to compare effectiveness (superiority) with respect to progression-free survival (PFS) in patients from the DALY 2-EU trial (Part II) who underwent leukapheresis with the intent of zamto-cel treatment vs patients from the external comparator arm (ECA) who underwent stem cell apheresis with the intent of ASCT (see section 4.3.2).
2. In patients with prespecified LBCL subtypes4 who failed at least two previous lines of chemotherapy (3L+ R/R LBCL) and who have either failed ASCT or were ineligible, not intended or not consenting for ASCT, to compare effectiveness (non-inferiority) with respect to objective response rate (ORR) in patients from the DALY II USA trial who underwent leukapheresis with the intent of zamto-cel treatment vs patients from the ECA who underwent leukapheresis with the intent of CAR-T therapy (see section 4.3.2).

The secondary objectives of the study are:
1. In patients with prespecified LBCL subtypes 4 who failed one previous line of chemoimmunotherapy (2L R/R LBCL) and who progressed within 12 months after the completion of 1L therapy, to compare effectiveness (non-inferiority) with respect to ORR in eligible patients from the DALY 2-EU trial (Part I & II) who underwent leukapheresis with the intent of zamto-cel treatment vs patients from the ECA who underwent leukapheresis with the intent of CAR-T therapy (see section 4.3.2).
2. To repeat Primary Objective 1 (superiority zamto-cel vs. ASCT in 2L transplant-eligible R/R LBCL) with respect to the following effectiveness measures: • ORR • best objective response (BOR) • complete response rate (CRR) • event free survival (EFS)
3. To repeat Primary Objective 2 (non-inferiority zamto-cel vs. CAR-T in 3L+ R/R LBCL) with respect to the following effectiveness measures: • PFS • BOR • CRR • EFS
4. To repeat Secondary Objective 1 (non-inferiority zamto-cel vs. CAR-T in 2L transplanteligible and transplant-ineligible R/R LBCL) with respect to the following effectiveness measures: • PFS • BOR • CRR • EFS

The exploratory objectives of the study are:
1. To assess the non-inferiority of zamto-cel compared to CAR-T therapy with respect to ORR in 2L R/R LBCL early progressors (i.e., those who progressed within 12 months after the completion of 1L therapy) among patients who underwent leukapheresis with the intent of zamto-cel treatment in the DALY 2-EU Part I vs patients from the ECA who underwent leukapheresis with the intent of CAR-T therapy (transplant-eligible and ineligible).
2. To assess the non-inferiority of zamto-cel compared to CAR-T therapy with respect to ORR in 2L R/R LBCL early progressors (i.e., those who progressed within 12 months after the completion of 1L therapy) among transplant-ineligible patients only (DALY 2-EU Part I vs transplant-ineligible patients from the CAR-T ECA).
These exploratory analyses will help understand the effectiveness of zamto-cel in distinct patient subgroups relevant to clinical practice and future regulatory discussions.

1. To evaluate the comparative effectiveness (superiority) of Zamto vs SoC in DLBCL patients that have R/R disease after first-line chemotherapy and are ineligible for ASCT overall, and in subgroups of patients who progressed within 12 months, or more than 12 months, after the start of first line therapy. The following SoC treatments will be considered:
a) All SoC which is expected to consist of the following: Polatuzumab vedotin + bendamustine + rituximab (Pola-BR), tafasitamab+lenalidomide, R-GemOx, rituximab + cyclophosphamide + etoposide + prednisolone + vincristine (R-CEOP), R-gemcitabine, polatuzumab vedotin+RGemOx, epcoritamab, bendamustine +/- R, gemcitabine monotherapy, lenalidomide monotherapy, rituximab monotherapy
b) Pola-BR
c) Tafasitamab+lenalidomide

2) To evaluate the comparative effectiveness (non-inferiority) of Zamto vs SoC for 2nd line R/R DLBCL patients that are ineligible for ASCT, and who progressed within 12 months after the start of first line therapy. The following SoC treatments will be considered:
a) Any CAR-T therapy: Axi-cel or liso-cel

3) To evaluate the comparative effectiveness (non-inferiority) of Zamto vs SoC for 2nd line R/R DLBCL patients who are eligible for ASCT, and who progressed less than 24 months after the start of first line therapy. The following SoC treatments will be considered:
a) Induction therapy followed by high dose chemotherapy (HDC) and ASCT, where induction therapy is expected to include any of the following: Rituximab/ofatumumab + dexamethasone + cytarabine + cisplatin (R-/O-DHAP), rituximab/ofatumumab + ifosfamide + carboplatin + etoposide (R-/O-ICE), rituximab + gemcitabine + dexamethasone + cisplatin (R-GDP), rituximab + dexamethasone + cytarabine + cisplatin + oxaliplatin (R-DHAOx), rituximab + etoposide + solu-medrone + cytarabine + cisplatin (R-ESHAP), Axi-cel or Lisocel

4) To evaluate the comparative effectiveness (non-inferiority) of Zamto vs SoC in DLBCL patients that have R/R disease after two or more lines of chemotherapy and are ineligible for ASCT. The following SoC treatments will be considered:
a) Any CAR-T therapy: Axi-cel or Liso-cel or Tisa-cel.

Research Method:
This is an EC study to generate evidence on the comparative effectiveness of Zamto versus the SoC in adult patients with R/R DLBCL. This study will involve 12 comparisons in 5 real-world (RW) cohorts/ external comparator arms (ECAs). The data for trial (Zamto) patients will be obtained from two referent trials: DALY 2-EU and DALY 2-USA. Data for the SoC patients will be obtained from RWD sources.

Study Population:
1. A.R/R DLBCL with progression at any time after one line of therapy and transplant-ineligible
2. B.R/R DLBCL with progression ≤12m after one line of therapy and transplant-ineligible
3. C.R/R DLBCL with progression >12m after one line of therapy and transplant-ineligible
4. B.R/R DLBCL with progression ≤12 months after one line of therapy or primary refractory disease and transplant-ineligible.
5. D.R/R DLBCL with progression <24 months after 1st line of therapy and transplant-eligible
6. E.R/R DLBCL after at least 2 lines of therapy