ADC Therapeutics (NYSE:ADCT) executives used a recent fireside chat at the H.C. Wainwright conference to outline the company’s strategy to expand the reach of its CD19-directed antibody-drug conjugate ZYNLONTA (loncastuximab tesirine) beyond its current third-line-plus diffuse large B-cell lymphoma (DLBCL) approval.
Company focus: expanding ZYNLONTA beyond third-line DLBCL
Chief Executive Officer Ameet Mallik described ADC Therapeutics as a commercial-stage company focused on antibody-drug conjugates, with ZYNLONTA as its core asset. ZYNLONTA is currently approved as a monotherapy for third-line-plus DLBCL, and the company’s strategy is “maximizing the value of ZYNLONTA” by moving into earlier lines of DLBCL and into indolent lymphomas.
- LOTIS-5, a Phase III confirmatory trial evaluating ZYNLONTA plus rituximab versus R-GemOx (rituximab, gemcitabine, oxaliplatin) in second-line, transplant-ineligible DLBCL.
- LOTIS-7, a Phase Ib study combining ZYNLONTA with the CD20xCD3 bispecific glofitamab in second-line-plus DLBCL.
Sales outlook: stability in 2026, growth tied to earlier-line expansion
ADC Therapeutics does not provide annual net revenue guidance, Mallik said, but he expects 2026 ZYNLONTA sales to be “broadly in line” with recent quarters, citing relatively stable performance under the third-line-plus monotherapy label. He noted quarterly variability driven by ordering patterns at large centers (inventory fluctuations for a low-volume product) and patient flow variability in community practices.
In the discussion, fourth-quarter ZYNLONTA sales were referenced at $22.3 million, compared with $15.8 million in the prior quarter and $18.1 million in the quarter before that. Mallik said variability is likely to continue, while annual sales should remain roughly consistent with the past couple of years.
Mallik emphasized that “the real growth opportunity starts when we move into the second-line setting,” with growth expected following a potential LOTIS-5-based approval path.
LOTIS-5: upcoming top-line readout and regulatory path
Mallik said LOTIS-5 is a 420-patient, 1:1 randomized study with progression-free survival (PFS) as the primary endpoint, agreed with the FDA. He stated the trial is powered at 90% to demonstrate a hazard ratio of 0.67, meaning a hazard ratio of 0.67 or lower would be required for the primary endpoint to be considered positive.
As context, Mallik described R-GemOx as a commonly used comparator across Phase III studies in relapsed/refractory DLBCL, with median PFS in comparator arms generally in the 2.3–5 month range and “typically between 3–4 months” in more recent studies. He offered an example that if R-GemOx delivered a 4-month median PFS, the ZYNLONTA-rituximab arm would need to show about a two-month difference to meet the hazard ratio threshold.
He also reviewed results from a required 20-patient safety run-in (presented previously), where the combination produced an 80% overall response rate and 50% complete response rate, with median duration of complete responses not reached after two years of follow-up. He said no new safety signals were observed and the safety profile appeared manageable.
The company expects LOTIS-5 top-line data in the second quarter, with plans to share PFS and mature secondary endpoints along with key safety tables. Mallik said there is no crossover in the trial. If results are positive, he anticipates filing a supplemental BLA roughly four to five months after the readout, followed by an expected 10-month standard review—timing that would imply a potential approval around mid-2027.
Mallik said confidence in LOTIS-5 is supported by trial design and historical R-GemOx performance, as well as the fact that an interim futility analysis in the second quarter of 2024 passed a pre-specified efficacy boundary and the independent data monitoring committee recommended continuing without modification. He added that the committee has also reviewed safety multiple times, including most recently last fall, and also recommended continuing as-is.
LOTIS-7: high response rates and CRS reduction highlighted
On LOTIS-7, Mallik described the rationale as combining two potent agents that have each been approved as single agents in DLBCL (glofitamab and ZYNLONTA). He said updated data in the first 49 efficacy-evaluable patients with at least six months of follow-up showed a 90% overall response rate and a 78% complete response rate. He added that 38 patients achieved complete responses, and 33 of those remained in complete response at the data cutoff, with some patients followed for nearly two years.
He also said the dataset included eight patients previously treated with CAR-T therapy, with six complete responses among them. The combination was described as generally well-tolerated with a manageable safety profile, with side effects consistent with known effects of the individual agents and no new side effects observed.
Mallik discussed physician expectations for bispecific combinations, noting that preferred bispecific combinations in NCCN guidelines have complete response rates “anywhere between 51%–61%.” He said physicians have suggested that response rates in the 60% range are differentiating and 70% or above could be transformative. ADC Therapeutics expects to share results from a 100-patient dataset by the end of the year.
He also highlighted a reduction in cytokine release syndrome (CRS) compared with glofitamab’s label profile, stating that at the 150 dose of ZYNLONTA (the approved dose and the dose being expanded), the company reduced CRS to 25% all-grade in the 49-patient dataset discussed.
Market opportunity and additional indications
Mallik estimated the current third-line DLBCL market at about 6,000 patients, saying ADC Therapeutics has about a 10% share and that, with an average of three cycles, translates to roughly $70–$75 million. He said adding the second-line opportunity would introduce an additional 12,000 patients, and that maintaining a similar share with longer average treatment duration (five cycles in the LOTIS-5 safety run-in versus three cycles for monotherapy) could translate to about $300 million. He added that, conservatively, achieving 5%–10% share in second line (while maintaining 10% in third line) could yield $200–$300 million.
Beyond DLBCL, Mallik pointed to investigator-initiated trials in indolent lymphomas:
- Follicular lymphoma: ZYNLONTA plus rituximab in 55 efficacy-evaluable, high-risk relapsed/refractory patients showed a 98% overall response rate and 84% complete response rate.
- Marginal zone lymphoma (MZL): ZYNLONTA monotherapy in the first 26 efficacy-evaluable patients showed an 85% overall response rate and 69% complete response rate.
He said both programs showed manageable safety and could support Compendia inclusion following publication. He added the company is evaluating regulatory strategies—particularly for MZL—citing that some approvals in the category have been based on datasets of roughly 60–70 patients, and noting the company has a 50-patient MZL study ongoing. He said data from indolent lymphoma studies are expected to read out and be presented at medical congresses between the end of the year and mid-next year.
On commercial adoption, Mallik said Compendia listings can provide access but typically result in less uptake than full FDA approval because the company cannot promote off-label uses, particularly affecting awareness in community settings.
Financing update and cash runway
Mallik also discussed an amended agreement with HealthCare Royalty. He said the original deal involved a $300 million investment in exchange for a royalty that is currently 7% and could increase up to 10% depending on revenue, with a prior change-of-control provision of $750 million.
Under the amendment, he said the change-of-control payment was reduced to $150 million if a transaction occurs between now and the end of 2027 (and $200 million thereafter). In exchange, HealthCare Royalty would continue to receive the same royalties until the original royalty cap is reached. Mallik also said ADC Therapeutics granted warrants to purchase approximately $9.8 million of common shares at an exercise price of $3.81, exercisable through the end of 2030 and subject to a lockup through the end of 2027.
On liquidity, Mallik said the company raised about $160 million last year and ended the year with $261 million in cash, which he expects to fund operations “at least into 2028.” He framed the upcoming clinical milestones—LOTIS-5 and LOTIS-7 data this year and indolent lymphoma data into next year—as key events that could “significantly de-risk” the growth opportunity the company sees starting in 2027.
About ADC Therapeutics (NYSE:ADCT)
ADC Therapeutics SA is a clinical-stage biopharmaceutical company focused on the discovery and development of highly targeted antibody-drug conjugates (ADCs) designed to treat hematological malignancies such as non-Hodgkin lymphoma and acute myeloid leukemia. By marrying the specificity of monoclonal antibodies with potent cytotoxic payloads, the company aims to maximize tumor cell eradication while limiting off-target toxicity.
At the core of ADC Therapeutics’ portfolio is loncastuximab tesirine-lpyl, a CD19-directed ADC that received accelerated approval from the U.S.
