20 Years of ADC Trials in Lymphoma Leave Many Questions Unanswered, Authors Say

The use antibody-drug conjugates (ADCs) in cancer care rose from being a rarity to commonplace, and with it, so have trials with these “smart bomb” delivery platforms for bringing powerful agents straight to a patient’s tumor.

But “success” is in the eye of the beholder, argue Zhang et al., in a recently published systematic review in Frontiers in Immunology.¹ The authors, from the School of Medical and Life Sciences at Chengdu University of Traditional Chinese Medicine in China, analyzed 410 interventional trials that evaluated evaluating ADCs in lymphoma. Drawn from the Trialtrove database through December 2025, the review maps trial growth, subtype distribution, target and payload platforms, combination strategies, inactive-trial patterns, and safety reporting to characterize the maturity of the ADC pipeline in lymphoma.

From Small Beginnings to a Burst After 2020

Trial initiation rose steadily, from 2 trials in 2006 to a peak of 41 in 2023, with nearly half of all trials (49%) launched between 2020 and 2025. Despite this growth, phase 2 trials have dominated, accounting for 47.1% of all studies. Single-arm designs represent 61.7% of the total, with only 18.5% randomized. The authors note that the share of trials that were randomized rose after 2010 but then plateaued, standing at 19.3% from 2021 to 2025.¹

“Thus,” they wrote, “the use of randomization increased compared with the earliest period but remained close to one fifth of trials after 2010, without a sustained upward trend.”

Of 50 unique ADC programs identified, 70% never advanced beyond phase 1 or 1/2. Diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL) together accounted for 41.6% of trial–subtype pairs and nearly all late-phase activity, while other subtypes, including follicular lymphoma, mantle cell lymphoma, and various T-cell lymphomas, remained largely confined to early-phase exploration.

The target landscape was concentrated around CD30 (181 trials), CD79b (104 trials), CD19 (47 trials), and CD22 (29 trials), with ROR1 emerging as a newer but still minor target. Tubulin inhibitors, especially MMAE, made up over 80% of payloads, and cleavable linkers predominated across virtually every subtype. Among 177 safety-evaluable trials, 61.6% reported at least 1 adverse event of grade 3 or higher, with neutropenia (55.4%), infection (44.6%), and peripheral neuropathy (39.0%) being the most common.

More Trials Than Diversity Seen in ADC Dataset

The authors argue that despite the growth in overall ADC trial activity in lymphoma, the rising number of studies is not yielding significant diversification in ADC architecture or the generation of randomized, survival-based evidence.

“This distinction is important,” Zhang and coauthors write, “because recent reviews describe a broad and increasingly sophisticated ADC pipeline, whereas the present trial-level analysis identifies where that apparent growth has—and has not—translated into mature lymphoma development.”

Clinical maturity, they write, clusters tightly around a handful of validated platforms:

• brentuximab vedotin (Adcetris; Pfizer): CD30, cHL and peripheral T-cell lymphoma;²
• polatuzumab vedotin (Polivy; Genentech): CD79b, frontline DLBCL via the POLARIX trial (NCT03274492);³
• loncastuximab tesirine (Zylonta; ADC Therapeutics); CD19, relapsed/refractory DLBCL.⁴

“These milestones explain much of the observed concentration around CD30, CD79b, and CD19,” the authors write. “They also show why success should be attributed to specific target–payload–linker–regimen combinations rather than generalized to ADCs as a uniform therapeutic class.”¹

The end point architecture reinforces this maturity gap, they explain. Early trials appropriately emphasize safety, dose-limiting toxicity, and maximum tolerated dose. Phase 2 shifts to overall response rate and complete response, and PFS dominates phase 3 (21 of 34 trials). But overall survival appeared as a primary endpoint in only 6 phase 3 trials; the authors call the almost total absence of biomarker or correlative end points a “missed opportunity.”

The authors argue this design pattern is well-suited to detecting early signals of activity but poorly suited to establishing durable comparative benefit, optimal sequencing, or biologically defined patient selection — and they call for future late-phase trials to incorporate meaningful time-to-event end points alongside duration of response, patient-reported outcomes, and prospectively specified biomarkers, particularly given how difficult it is to isolate an ADC's independent contribution within increasingly common combination regimens.

On payload and linker platforms, the near-total reliance on monomethyl auristatin E (MMAE)-based tubulin inhibition and cleavable linkers reflects substantial manufacturing and clinical experience but also creates shared liabilities, including neuropathy, myelosuppression, off-target exposure, and cross-resistance. The authors highlight SHR-A1912, a CD79b-directed ADC using a topoisomerase I inhibitor payload now in phase 3 for relapsed/refractory DLBCL, as a genuine diversification signal, while cautioning that its advancement is not yet evidence of superiority, since no phase 3 data were available at the database cutoff.

Importantly, the authors argue against equating trial status with therapeutic success or failure. Among 92 inactive (terminated/closed) trials, the most frequently cited reasons were recruitment/feasibility problems and unspecified causes—not efficacy or safety failures, which were each explicitly cited in only 5 records. High inactive-trial counts for CD30, CD79b, and CD19 programs, they stress, simply reflect these targets' longer development histories and greater trial volume, not elevated failure rates.

The discussion also situates ADCs within a fast-shifting competitive landscape. The S1826 trial's demonstration that the combination of nivolumab with doxorubicin, vinblastine, and dacarbazine, known asAVD, outperformed brentuximab-AVD in advanced cHL,⁵ and survival benefit in the STARGLO trial (NCT04408638) for glofitamab plus gemcitabine and oxaliplatin (GemOx) in transplant-ineligible DLBCL,⁶ both show that ADC regimens can be displaced by newer immune-based strategies.

The authors suggest ADCs' durable advantages of immediate availability, no cell-manufacturing requirement, and established administration position them as complementary options or an alternative for cell-therapy-ineligible patients, rather than a universal first choice.

“Sequencing should be individualized according to disease tempo, target preservation, prior toxicities, organ function, access, and the intended next therapy,” the authors write. “There is not yet sufficient evidence for a universal sequence among ADCs, CAR-T cells, T-cell engagers, checkpoint inhibitors, small-molecule targeted agents, and transplantation.”

Drawing on lessons in other cancers from gemtuzumab ozogamicin (Mylotarg; Pfizer) and trastuzumab deruxtecan (Enhertu; AstraZeneca), the authors argue lymphoma ADC development must treat dose, schedule, linker stability, and organ-specific toxicity as an integrated development package rather than assuming new payloads will simply sidestep MMAE-related toxicities.

The authors cited the proprietary nature of the database as a limitation.

Future Directions

The authors call for the following:

• A shift from broad histologic eligibility toward subtype- and biomarker-defined target selection, with reassessment of antigen expression after prior targeted therapy;
• Payload diversification paired with genuine resistance-mechanism evidence;
• More interpretable pharmacologic evaluation of linker/conjugation innovations;
• Faster transition of early signals into randomized, comparator-based trials with survival and translational endpoints; and
• Stronger academic-industry partnerships to push biologically novel programs past phase 2.

The authors conclude that the field's future value lies not in identifying a single "best" target or payload, but in better-matched target–payload–linker combinations. “A subtype-specific, biomarker-rich, and safety-conscious development strategy is more likely to produce durable clinical value than further expansion in trial numbers alone,” they conclude.

References

1. Zhang H, Yan H, Liu Y. Antibody–drug conjugate development in lymphoma: a systematic clinical trial landscape analysis. Front Immunol. 2026;17:1855476. doi:10.3389/fimmu.2026.1855476
2. Horwitz S, O’Connor OA, Pro B, et al. The ECHELON-2 trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma. Ann Oncol. 2022;33:288–98. doi: 10.1016/j.annonc.2021.12.002
3. Morschhauser F, Salles G, Sehn LH, et al. Five-year outcomes of the POLARIX study comparing Pola-R-CHP and R-CHOP in patients with diffuse large B-cell lymphoma. J Clin Oncol. 2025;43:3698–705. doi:10.1200/JCO-25-00925
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 II LOTIS-2 study. Haematologica. 2024;109:1184–93. doi: 10.3324/haematol.2023.283459
5. Herrera AF, LeBlanc M, Castellino SM, et al. Nivolumab+AVD in advanced-stage classic Hodgkin's lymphoma. N Engl J Med. 2024;391(15):1379-1389. doi:10.1056/NEJMoa2405888.
6. Abramson JS, Ku M, Hertzberg M, et al. Glofitamab plus gemcitabine and oxaliplatin (GemOx) versus rituximab-GemOx for relapsed or refractory diffuse large B-cell lymphoma (STARGLO): a global phase 3, randomised, open-label trial. Lancet;404(10466):1940-1954. doi:10.1016/S0140-6736(24)01774-4.