Efficacy

Jump to:

LOTIS-2 was a large registrational trial in r/r DLBCL therapy (N=145)1

Open-label, single-arm phase 2 study design1,2

Single-arm phase 2 study design

Key DLBCL inclusion criteria1,2

  • ASCT-eligible and -ineligible
  • DLBCL NOS
  • DLBCL arising from low-grade lymphoma
  • HGBCL with MYC and BCL2 and/or BCL6 rearrangements
  • ECOG 0-2

Key DLBCL exclusion criteria1

  • Bulky disease (≥10 cm)
  • Lymphoma with active CNS involvement
Permitted patients regardless of transplant eligibility and patients with prior CD19-directed therapy if CD19+2

aIn LOTIS-2, patients received 0.15 mg/kg for the first 2 cycles, then 0.075 mg/kg for subsequent cycles.1 The average weight was 77.1 kg, requiring 2 vials for the first 2 cycles, then 1 vial for subsequent cycles.3

bPET-CT evaluated by independent review committee using Lugano 2014 criteria.1

ASCT = autologous stem cell transplant; CNS = central nervous system; CR = complete response; DLBCL = diffuse large B-cell lymphoma; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; HGBCL = high-grade B-cell lymphoma; NOS = not otherwise specified; ORR = overall response rate; PET-CT = positron emission tomography-computed tomography; PR = partial response; r/r = relapsed/refractory.

LOTIS-2 included a broad range of heavily pretreated patients with difficult-to-treat disease1

Select baseline patient and disease characteristics (N=145)1

Tumor Characteristics1,2,5  
DLBCL NOS
DLBCL arising from low grade lymphomaa
88%
21%
HGBCLb 7%
GCBc 34%
ABCc 16%
Stage I-II 23%
Stage III-IV 77%
Refractoriness1,2,5  
Primary refractoryd 20%
Refractory to all prior treatments 17%
Refractory to most recent prior therapy 61%
Refractory to any treatment 63%
Patient Characteristics1  
Age, median (range: 23-94) 66
Age 75 or older 15%
Males 59%
Race: White 90%
Prior Therapies1-3  
Intensive salvage therapy failuree 71%
2 prior lines 43%
3-7 prior lines 57%
Prior Cellular Therapies1,5  
Prior SCT 17%
Prior CAR-T 10%

Broad study population reflects the disease’s heterogeneity

aData from 2-year follow-up; may differ from those in primary analysis.4

bAlternatively referred to in LOTIS-2 as transformed DLBCL; the diagnosis of DLBCL NOS included DLBCL arising from low-grade lymphoma.1,2

cHGBCL with MYC and BCL2 and/or BCL6 rearrangements.2

dABC and GCB were investigator-reported without independent testing; unknown 51%.2

ePrimary refractory defined as no response to front-line therapy.3

fAs defined by ADC Therapeutics, intensive salvage therapy includes one or more of the following: chemo-immunotherapy (ICE, GDP, DHAP, DHAX; all generally combined with rituximab), SCT, and/or CAR-T.3

ABC = activated B-cell; CAR-T = chimeric antigen receptor T cell; DHAP = dexamethasone, cytarabine, cisplatin; DHAX = dexamethasone, cytarabine, oxaliplatin; GCB = germinal center B-cell; GDP = gemcitabine, dexamethasone, cisplatin; ICE = ifosfamide, carboplatin, etoposide; SCT = stem cell transplant.

Meaningful response with ZYNLONTA® as a single agent1

Nearly half (48.3%) of patients achieved a response

 
 

Primary analysis 
(N=145)1,a

ORR 48.3% 

(primary endpoint)

(95% CI: 39.9, 56.7)

CR 24.1% 

(n=35) 
(95% CI: 17.4, 31.9)

PR 24.1% 

(n=35) 
(95% CI: 17.4, 31.9)

aMedian follow-up: 7.3 months (range: 0.3-20.2).1

2-year
follow-up5,b

bPatients were followed
for 2 years after study
completion. Median
follow-up, all patients:
7.8 mos (range: 0.3-42.6).5

cMedian follow-up, CR
patients: 35 mos
(range: 4.4-42.6.).5

CI = confidence interval; CR = complete response; ORR = overall response rate; PR = partial response.

Median time to response with ZYNLONTA® as a single agent1,3,5

 
 

Primary analysis
(N=145)1

OR 1.3 Months1,a

(n=70)

(range: 1.1-8.1)

CR 1.4 Months3,b

(n=35)
(range: 1.2-14.0)

During the treatment period, imaging was performed at 6 weeks and 12 weeks after Cycle 1, Day 1, then every 9 weeks until end of treatment.

2-year
follow-up3,5,c

cMedian follow-up, all patients:
7.8 mos (range: 0.3-42.6).5

dMedian follow-up,
CR patients: 35 mos
(range: 4.4-42.6).5

Median time to OR (n=70)

1.3 Months

(range: 1.1-8.1)

Median time to CRd (n=36)

1.5 Months

(range: 1.2-14.0)

aMedian follow-up time: 7.3 mos (range: 0.3–20.2).1

bExploratory data; LOTIS-2 was not designed or powered to evaluate rapidity of CRs. Consider small sample size when interpreting results.

OR = overall response.

Durable responses in 2-year follow-up1,5,b,d

 
 

Primary analysis
(N=145)1,a

mDOR of OR (n=70)1

10.3 Months

(95% CI: 6.9, NE)

mDOR of CR (n=35)2,b,c

13.4 Months

(95% CI: 10.2, NE)

mDOR of PR (n=35)2,b

5.7 Months

(95% CI: 1.7, NE)

aMedian follow-up: 7.3 months (range 0.3–20.2). Of 70 patients with an OR, 25 (36%) were censored prior to 3 months; 26% of responders had a DOR of ≥6 months.1

durable-responses-in-2-year-follow-up

dMedian follow-up, all patients: 7.8 mos (range: 0.3-42.6).5

eMedian follow-up, CR patients: 35 mos (range: 04.4-42.6).5

bExploratory data; LOTIS-2 was not designed or powered to evaluate duration of CRs or PRs. Consider small sample size when interpreting results.

cOf 36 patients with a CR, 7 (19%) were censored prior to 3 mos; 56% of patients with a CR had a DOR of ≥6 mos.4

mDOR = median duration of response; NE = not estimable.

Onset and duration of complete response from time of first infusion: 2-year follow-up5,a

 
Onset and duration of complete response from time of first infusion

aExploratory data: LOTIS-2 was not designed or powered to evaluate duration of CRs. Consider small sample size when interpreting results.

bAll 11 patients with an ongoing CR at 2 years were censored due to their discontinuation of the study.5

CR = complete response.

Response in select patient subgroups3

Exploratory analyses of primary (ORR) and secondary (CR) endpoints in predefined subgroups.3

Subgroup analyses were not designed or powered to demonstrate an effect in patient subgroups. Consider small sample size when interpreting results.3

Patient and Disease Characteristics3 ORR % (n)a (95% CI) CR % (n)a (95% CI)
≥75 years (n=21) 52.4 (11) (28.8, 74.3) 38.1 (8) (18.1, 61.6)
DLBCL NOS (n=128) 50.4 (64) (41.4, 59.4) 24.2 (31) (17.1, 32.6)
HGBCL (n=10) 50.0 (5) (18.7, 81.3) 50.0 (5) (18.7, 81.3)
DLBCL arising from low-grade lymphoma (n=30) 43.3 (13) (25.5, 62.6) 23.3 (7) (10.3, 43.5)
GCB (n=49) 53.1 (26) (38.3, 67.5) 26.5 (13) (14.9, 41.1)
ABC (n=23) 47.8 (11) (26.8, 69.4) 21.7 (5) (7.5, 43.7)
Refractoriness3    
Primary refactory (n=29) 37.9 (11) (20.7, 57.7) 17.2 (5) (5.8, 35.8)
Refactory to all prior therapies (n=24) 37.5 (9) (18.8, 59.4) 16.7 (4) (4.7, 37.4)
Treatment Line3    
2 piror lines (n=63) 47.6 (30) (34.9, 60.6) 23.8 (15) (14.0, 36.2)
3-7 prior lines (n=82) 48.8 (40) (37.6, 60.1) 26.0 (21) (15.6, 35.1)
Treatment History3    
Prior CAR-T (n=14) 42.9 (6) (17.7, 71.1) 21.4 (3) (4.7, 50.8)
10% had prior CD-19-directed CAR-T
    
Prior SCT (n=24) 58.3 (14) (36.6, 77.9) 33.3 (8) (15.6, 55.3)
17% had prior SCT
    

68 patients received subsequent anti-cancer therapy, including2:

  • 12 patients who went on to consolidation with SCT
  • 16 patients who received CAR-T therapy after disease progression
    • In a retrospective subanalysis of LOTIS-2 patients who went on to CAR-T (n=14), 10 of 10 patients who were tested all had CD19 antigen expression after ZYNLONTA® treatment.2

The safety and efficacy outcomes for these patients have not been confirmed with a randomized clinical trial.2

an = responders.3

Back to Top

Indication and Usage

ZYNLONTA® is indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma.

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Important Safety Information

WARNINGS AND PRECAUTIONS

Effusion and Edema

Serious effusion and edema occurred in patients treated with ZYNLONTA®. Grade 3 edema occurred in 3% (primarily peripheral edema or ascites) and Grade 3 pleural effusion occurred in 3% and Grade 3 or 4 pericardial effusion occurred in 1%.

Monitor patients for new or worsening edema or effusions. Withhold ZYNLONTA® for Grade 2 or greater edema or effusion until the toxicity resolves. Consider diagnostic imaging in patients who develop symptoms of pleural effusion or pericardial effusion, such as new or worsened dyspnea, chest pain, and/or ascites such as swelling in the abdomen and bloating. Institute appropriate medical management for edema or effusions.

Myelosuppression

Treatment with ZYNLONTA® can cause serious or severe myelosuppression, including neutropenia, thrombocytopenia, and anemia. Grade 3 or 4 neutropenia occurred in 32%, thrombocytopenia in 20%, and anemia in 12% of patients. Grade 4 neutropenia occurred in 21% and thrombocytopenia in 7% of patients. Febrile neutropenia occurred in 3%.

Monitor complete blood counts throughout treatment. Cytopenias may require interruption, dose reduction, or discontinuation of ZYNLONTA®. Consider prophylactic granulocyte colony-stimulating factor administration as applicable.

Infections

Fatal and serious infections, including opportunistic infections, occurred in patients treated with ZYNLONTA®. Grade 3 or higher infections occurred in 10% of patients, with fatal infections occurring in 2%. The most frequent Grade ≥3 infections included sepsis and pneumonia.

Monitor for any new or worsening signs or symptoms consistent with infection. For Grade 3 or 4 infection, withhold ZYNLONTA® until infection has resolved.

Cutaneous Reactions

Serious cutaneous reactions occurred in patients treated with ZYNLONTA®. Grade 3 cutaneous reactions occurred in 4% and included photosensitivity reaction, rash (including exfoliative and maculo-papular), and erythema.

Monitor patients for new or worsening cutaneous reactions, including photosensitivity reactions. Withhold ZYNLONTA® for severe (Grade 3) cutaneous reactions until resolution. Advise patients to minimize or avoid exposure to direct natural or artificial sunlight including exposure through glass windows. Instruct patients to protect skin from exposure to sunlight by wearing sun-protective clothing and/or the use of sunscreen products. If a skin reaction or rash develops, dermatologic consultation should be considered.

Embryo-Fetal Toxicity

Based on its mechanism of action, ZYNLONTA® can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (SG3199) and affects actively dividing cells.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZYNLONTA® and for 10 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ZYNLONTA® and for 7 months after the last dose.

ADVERSE REACTIONS

In a pooled safety population of 215 patients (Phase 1 and LOTIS-2), the most common (>20%) adverse reactions, including laboratory abnormalities, were thrombocytopenia, increased gamma- glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

In LOTIS-2, serious adverse reactions occurred in 28% of patients receiving ZYNLONTA®. The most common serious adverse reactions that occurred in ≥2% receiving ZYNLONTA® were febrile neutropenia, pneumonia, edema, pleural effusion, and sepsis. Fatal adverse reactions occurred in 1%, due to infection.

Permanent treatment discontinuation due to an adverse reaction of ZYNLONTA® occurred in 19% of patients. Adverse reactions resulting in permanent discontinuation of ZYNLONTA® in ≥2% were gamma- glutamyltransferase increased, edema, and effusion.

Dose reductions due to an adverse reaction of ZYNLONTA® occurred in 8% of patients. Adverse reactions resulting in dose reduction of ZYNLONTA® in ≥4% was gamma-glutamyltransferase increased.

Dosage interruptions due to an adverse reaction occurred in 49% of patients receiving ZYNLONTA®. Adverse reactions leading to interruption of ZYNLONTA® in ≥5% were gamma-glutamyltransferase increased, neutropenia, thrombocytopenia, and edema.

DOSAGE MODIFICATIONS AND DELAYS

Recommended Dosage Modifications for Adverse Reactions

For any Grade 3 or greater nonhematologic toxicity, ZYNLONTA® should be held until the toxicity resolves to Grade 1 or less. For neutropenia: if absolute neutrophil count is <1 x 109/L, withhold ZYNLONTA® until the neutrophil count returns to 1 x 109/L or higher. For thrombocytopenia: if platelet count is <50,000/mcL, withhold ZYNLONTA® until the platelet count returns to 50,000/mcL or higher. For Grade 2 or greater edema or effusion, ZYNLONTA® should be held until the toxicity resolves to Grade 1 or less.

Recommendations for Dosage Delays

If dosing is delayed by more than 3 weeks due to toxicity related to ZYNLONTA®, reduce subsequent doses by 50%. If toxicity reoccurs following dose reduction, consider discontinuation. Note: If toxicity requires dose reduction following the second dose of 0.15 mg/kg (C2D1), the patient should receive the dose of 0.075 mg/kg for Cycle 3.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to ADC Therapeutics at 1-855-690-0340.

Please see the full Prescribing Information for additional Important Safety Information.

References: 1. ZYNLONTA® Prescribing Information. ADC Therapeutics SA; 2022. 2. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS 2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021; published online May 11, 2021. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(21)00139-X/fulltext. 3. Data on file. ADC Therapeutics SA. 4. Caimi PF, Ai WZ, Alderuccio JP, et al. Loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma: long-term efficacy and safety from the phase 2 LOTIS-2 study. Haematol. Published online August 31,2023. doi: 110.3324/haematol.2023.283459. 5. Caimi PF, Ai WZ, Alderuccio JP, et al. Long-term responses with loncastuximab tesirine: updated results from LOTIS-2, the pivotal phase 2 study of patients with relapsed/refractory diffuse large B-cell lymphoma. Poster presented at: European Hematology Association 2023 Hybrid Congress. Frankfurt, Germany and virtual, June 8-11, 2023.