LOTIS-2 was a large registrational trial in r/r DLBCL therapy (N=145)1
Open-label, single-arm phase 2 study design1,2
Key DLBCL inclusion criteria1,2
- Transplant-eligible and -ineligible patients
- DLBCL NOS
- DLBCL arising from low-grade lymphoma
- HGBCL with MYC and BCL2 and/or BCL6 rearrangements
- ECOG PS 0-2
Key DLBCL exclusion criteria1,2
- Bulky disease (≥10 cm)
- Lymphoma with active CNS involvement
aPatients received 0.15 mg/kg every 3 weeks for first 2 cycles, then 0.075 mg/kg for subsequent cycles.1
bPET-CT evaluated by independent review committee using Lugano 2014 criteria.1
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; PS = performance status; 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
aAlternatively referred to in LOTIS-2 as transformed DLBCL; the diagnosis of DLBCL NOS included DLBCL arising from low-grade lymphoma.1,2
bHGBCL with MYC and BCL2 and/or BCL6 rearrangements.2
cAs 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
dPrimary refractory defined as no response to front-line therapy.3
CAR-T = chimeric antigen receptor T cell; DHAP = dexamethasone, cytarabine, cisplatin; DHAX = dexamethasone, cytarabine, oxaliplatin; GDP = gemcitabine, dexamethasone, cisplatin; ICE = ifosfamide, carboplatin, etoposide; SCT = stem cell transplant.
48.3% of patients achieved a meaningful response with ZYNLONTA® as a single agent1,a
aMedian follow-up time was 7.3 months (range: 0.3-20.2).1
CI = confidence interval; NE = not estimable; ORR = overall response rate.
Half of responders achieved a CR with ZYNLONTA® as a single agent1,a
aMedian follow-up time was 7.3 months (range: 0.3–20.2).1
bExploratory data; LOTIS-2 was not designed or powered to evaluate rapidity/duration of CRs. Consider small sample size when interpreting results.
Response in select patient subgroups3
Subset analyses were predefined subgroups of primary endpoint (ORR) and secondary endpoint (CR)
Exploratory analyses; LOTIS-2 was not designed or powered to demonstrate an effect in patient subgroups. Consider small sample size when interpreting results
Sixty-eight patients received subsequent anti-cancer therapy, including 9 patients who went on to consolidation with SCT, and 15 patients who received CAR-T therapy after disease progression. The safety and efficacy outcomes for these patients have not been confirmed with a randomized trial.2
an = responders3.
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.
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.
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.
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.
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 9 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ZYNLONTA® and for 6 months after the last dose.
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.
DOSE DELAYS AND MODIFICATIONS
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. 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.
Please see the full Prescribing Information for additional Important Safety Information.
References: 1. ZYNLONTA® Prescribing Information. ADC Therapeutics SA; 2021. 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.