ADC Therapeutics SA

You should read the following discussion and analysis of our financial condition and results of operations together with our unaudited condensed consolidated financial statements, including the notes thereto, included in this Quarterly Report, as well as our audited consolidated financial statements, including the notes thereto, included in our Annual Report on Form 10-K. The following discussion includes forward-looking statements that involve risks, uncertainties and assumptions. Our actual results may differ materially from those anticipated in these forward-looking statements. See “Forward-Looking Statements.”

Business Overview

ADC Therapeutics is a leading, commercial-stage global pioneer in the field of antibody drug conjugates (“ADCs”).

Our goal is to be a leading ADC company that transforms the lives of those impacted by cancer. To achieve this, we are focused on unlocking the potential value of our robust ADC portfolio across two pillars of growth: hematology and solid tumors. We are a pioneer in the ADC field with specialized end-to-end capabilities unique to ADCs including a validated technology platform, a growing next-generation research & development toolbox and a proven track record that includes an approved and marketed product. We aim to expand our portfolio and accelerate the development of our pipeline through targeted investments and in collaboration with strategic partners. In this way, we plan to pursue multiple targets in parallel, enabling us to prioritize and ensure disciplined capital allocation strategy while advancing the most promising candidates in both hematology and solid tumors.

In the hematology space, our flagship product, ZYNLONTA, a CD19-directed ADC, received accelerated approval from the U.S. Food and Drug Administration (“FDA”) and conditional approval from the European Commission for the treatment of relapsed or refractory diffuse large B-cell lymphoma (“DLBCL”) after two or more lines of systemic therapy. We are seeking to continue expanding ZYNLONTA into international markets throughout the world, and into earlier lines of DLBCL and other indolent lymphomas, including follicular lymphoma (”FL”) and marginal zone lymphoma (“MZL”) as a single and combination agent of choice through our LOTIS-5 confirmatory Phase 3 clinical trial and LOTIS-7 Phase1b clinical trial as well as through investigator-initiated trials (“IITs”) at leading institutions. In addition, we are investigating a CD-22 targeted compound, ADCT-602, in a Phase 1/2 investigator-initiated study in relapsed or refractory B-cell acute lymphoblastic leukemia.

In the solid tumor space, our clinical-stage pipeline consists of ADCT-601 (mipasetamab uzoptirine) targeting AXL as a single agent and/or in combination in sarcoma, pancreatic, and NSCLC. Our pre-clinical stage pipeline includes a portfolio of next generation investigational ADCs targeting Claudin-6, NaPi2b, PSMA and ASCT2. In addition, we are advancing research with a range of payloads, linkers and conjugation technologies against undisclosed targets.

Recent Developments

In April 2024, the Company provided an update on the progress of the LOTIS-7 trial in hematology and on its technology platform capabilities, research and development activities and pipeline in the solid tumor space. In addition, in May 2024, IIT data was presented on ZYNLONTA in MZL.

Hematology

LOTIS-7

On April 4, 2024, The Company announced the completion of dose escalation in LOTIS-7, a Phase 1b open-label clinical trial evaluating ZYNLONTA® (loncastuximab tesirine-lpyl) in combination with bispecific antibodies glofitamab or mosunetuzumab in heavily pre-treated patients with relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL).

In the dose escalation portion (Part 1) of LOTIS-7, no dose-limiting toxicities (“DLTs”), no or low-grade cytokine release syndrome (“CRS”) and no immune effector cell-associated neurotoxicity syndrome (“ICANS”) were observed across all patients when ZYNLONTA was administered in combination with glofitamab or mosunetuzumab. Additionally, after the first investigator assessment, evidence of anti-tumor activity (complete response or partial response) was observed among the majority of patients, with mixed histologies including DLBCL, follicular lymphoma (“FL”) and marginal zone lymphoma (“MZL”). In addition, as of April 19, 2024, initial safety findings showed that the majority of CRS events seen were grade 1 (6 out of 18 patients) or grade 2 (2 of 18 patients), with no CRS greater than grade 2 observed in either combination arm. Furthermore, all grade 2 events responded to Tocilizumab/corticosteroids with no requirement for pressors or ICU management. Based on the data from Part 1, all three dose levels (90, 120 and 150 µg/kg) have now been cleared and enrollment in Part 2 dose expansion has been initiated with ZYNLONTA administered in combination with glofitamab at the 120 µg/kg and 150 µg/kg dose levels in 2L+ DLBCL.

The early data from Part 1 of the LOTIS-7 trial highlight the potential combinability of ZYNLONTA with bispecifics in lymphoma patients and continued progression of this trial in 2L+ DLBCL patients. The Company believes LOTIS-7 demonstrates the potential for ZYNLONTA plus bispecifics to enable broader accessibility in community settings, and based upon the current data and coupled with the potential for additive or synergistic efficacy with this combination, we are encouraged about the potential opportunity to expand the use of ZYNLONTA in DLBCL in the future where there remains high unmet need.

LOTIS-7 is a Phase 1b global multicenter, multi-arm study in patients with relapsed or refractory B-cell non-Hodgkin lymphoma including Part 1 (dose escalation) and Part 2 (dose expansion). The three dosing arms include ZYNLONTA plus polatuzumab vedotin, ZYNLONTA plus glofitamab, and ZYNLONTA plus mosunetuzumab T-cell-engaging bispecific monoclonal antibodies (“BsAbs”). Enrollment in LOTIS-7 includes Part 1 of the study with a 3+3 dose escalation in 3L/3L+ heavily pre-treated patients with ZYNLONTA doses starting at 90 µg/kg and then proceeding to 120 µg/kg and 150 µg/kg. The dose-limiting toxicity period has now been cleared across all three dose levels.

The following table sets forth the Grade 3 and Grade 4 adverse events (AE), regardless of relatedness, for the LOTIS-7 Part 1 dose escalation as of April 19, 2024:

*A patient may have more than one adverse event.

The following table summarizes serious adverse events (SAE), regardless of relatedness, for the LOTIS-7 Part 1 dose escalation as of April 19, 2024:

*CRS expressed as number of patients with at least 1 CRS event. 2 patients experienced multiple Grade 1 CRS events. 5 of 8 patients experiencing CRS coded SAE based on whether hospitalization required and/or prolonged.

MZL

Initial data from an investigator-initiated Phase 2 clinical trial evaluating ZYNLONTA® (loncastuximab tesirine-lpyl) for the treatment of relapsed/refractory (r/r) MZL were presented on May 4, 2024, at the Lymphoma Research Foundation’s 2024 Marginal Zone Lymphoma Scientific Workshop by the trial’s lead investigator, Izidore Lossos, MD, Professor, Director, Lymphoma Program at the Sylvester Comprehensive Cancer Center, University of Miami. The 50-patient single-arm, open-label Phase 2 multicenter study is currently being conducted at the Sylvester Comprehensive Cancer Center at University of Miami and City of Hope, and led by Izidore Lossos. This study is evaluating the safety and efficacy of 6 cycles of ZYNLONTA across 18 weeks in patients with r/r MZL previously treated with ≥1 line of systemic therapy (www.clinicaltrials.gov identifier NCT05296070). As of the data cutoff date of March 30, 2024, 15 patients were evaluable. Of these 15 patients evaluated, 13 achieved a complete response (“CR”) and one patient achieved a partial response (“PR”). All patients who achieved responses had maintained them at the time of the data cutoff with the longest responder reaching approximately 20 months.

In this study, according to the lead investigator, ZYNLONTA was generally well tolerated and safety was consistent with the known profile with two patient discontinuations. One patient discontinued after cycle 2 and a second patient discontinued after cycle 4 due to a toxicity which fully resolved upon discontinuation of treatment. Both of these patients remain in CR at 10 and 6 months respectively.

MZL is a rare, indolent non-Hodgkin lymphoma (“NHL”) and the third most common NHL subtype. In the United States, there are an estimated 3,000 - 4,000 r/r MZL patients treated with systemic anti-cancer regimens annually. There are few FDA-approved therapies for MZL. With existing treatment options, despite patients achieving durable responses, high unmet medical need remains with <30% CR for 2L+ NCCN preferred treatments. Achievement of complete response to treatment represents the strongest predictor of positive outcomes in MZL. As this investigator-initiated trial progresses, with the expected number of sites expanding to 5 to help accelerate trial enrollment, assuming the results continue to be positive, the Company plans to potentially pursue a regulatory pathway and compendia strategy in parallel as soon as sufficient data are available. We believe the total addressable 2L+ MZL patient population has a potential peak market value of approximately $500 million, which assumes a total addressable population and average net price for ZYNLONTA in 2030 with a CAGR ~2% and ~3% respectively, and average cycles expected in MZL. The potential expansion in MZL contributes to the overall ZYNLONTA growth strategy in NHL.

Solid Tumors

Research Strategy, Platform and Pipeline

Our solid tumor research strategy is focused on three key elements. First, we have identified areas of high unmet need that currently feature high use of chemotherapy. Second, we are pursuing targets within these tumor types that are amenable to an ADC approach. And third, we are utilizing our deep knowledge and broad toolkit to optimize the design of ADCs that fit with our first two criteria.

On April 9, 2024, the Company hosted a virtual Research Investor Event featuring presentations from Ameet Mallik, Chief Executive Officer, and Patrick van Berkel, PhD, Chief Scientific Officer, sharing details on this strategy and highlighting recent updates and the Company’s novel exatecan-based antibody drug conjugate platform.

As shared during this event, our four lead candidates have a differentiated profile based on a novel, proprietary linker approach to tracelessly release exatecan and a high therapeutic index, which reflects the proprietary design of our ADCs.

Our Napi2b and Claudin-6 targeting ADCs are in IND-enabling studies and our PSMA and ASCT2 targeting ADCs are in drug candidate selection stage which we expect to complete this year. Details include:

•Claudin-6 and NaPI2b: As recently presented at the American Association for Cancer Research (“AACR”) Annual Meeting from preclinical studies supporting the future clinical development two of our lead candidates GB01-VA-PL2202 targeting Claudin-6 and NaPi2b-PL2202 targeting NaPi2b. These preclinical studies demonstrated the Company’s novel, exatecan-based ADCs, targeting Claudin-6 and NaPi2b, were well tolerated with potent and specific in vitro and in vivo anti-tumor activity. Based on these results, we believe a Claudin-6 directed ADC and a NaPi2b directed ADC have the potential for high impact in platinum-resistant ovarian cancer and non-small cell lung cancer.

•PSMA: With PSMA-PL2202, we are developing an optimized ADC directed against a validated target with high potential impact in metastatic castrate resistant prostate cancer.

•ASCT2: And with ASCT2-PL2202, we are designing an optimized ADC directed against a novel target with high potential impact in many indications including - but not limited to - colorectal cancer and non-small cell lung cancer.

Beyond this, we are further diversifying our toolbox with drugs with other Mode of Actions, including other DNA damaging agents and immunomodulators and focus on conjugation technology to develop dual conjugate ADCs based on two different drugs with orthogonal modes of action.