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Lymphoid Malignancies: What’s Next for Antibody-Drug Conjugates?


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Antibody-drug conjugates are improving outcomes of patients with lymphoma, often those who have exhausted treatment options after chimeric antigen receptor (CAR) T-cell therapy. Four available antibody-drug conjugates are in the clinic, with brentuximab vedotin moving into the front-line setting—and others are in development. This treatment landscape was described at the 2021 Pan Pacific Lymphoma Conference by Brad Kahl, MD, Professor of Medicine at Washington University School of Medicine, St. Louis, and a medical oncologist at the Siteman Cancer Center.1

Building an Antibody-Drug Conjugate

Antibody-drug conjugates are constructed to selectively deliver potent cytotoxic agents to tumor cells and improve the therapeutic index. The antigen should be abundant on tumor cells and relatively tumor-specific; according to Dr. Kahl, “the more so the better.” It should be rapidly internalized upon binding, whereas the monoclonal antibody component needs to have high immunoaffinity for the antigen—such as CD19, CD22, CD25, CD30, CD37, and CD79b in lymphoma.


“It’s unlikely we will find meaningful new antigen targets, but there might be some room for improvement with linker technology and conjugation strategies.”
— Brad Kahl, MD

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“It’s unlikely we will find meaningful new antigen targets, but there might be some room for improvement with linker technology and conjugation strategies,” he said. Although linker technology is becoming increasingly “sophisticated,” Dr. Kahl suggested the clinical impact of such improvements will, however, be modest.

Dr. Kahl continued: “My guess is that the most room for improvement will be in the payload aspect. Cytotoxic agents that are selected for antibody-drug conjugate development are considerably more potent on a molar basis than traditional cytotoxic chemotherapy agents, and that is why they are selected for use.”

Antibody-drug conjugate payload options currently include microtubule inhibitors and DNA-damaging agents, usually monomethyl auristatin E (MMAE) or F, maytansine, ravtansine, p-phenylenediamine (PPD) dimer, calicheamicin, ricin, and pseudomonas toxin. However, this list may expand to include camptothecin analogs, cryptophycin-based tubulin inhibitors, RNA polymerase II inhibitors, RNA spliceosome inhibitors, and other toxins, Dr. Kahl noted. “There’s a ceiling on the efficacy of the current ‘warheads,’” he commented.

“Single-agent response rates are in the 40% to 50% range, and each antibody-drug conjugate has its own toxicity limitations. If antibody-drug conjugates are to break through the current ceiling, we need novel, better cytotoxic agents…that can be conjugated to antibodies to produce a quantum leap in antibody-drug conjugate activity,” suggested Dr. Kahl.

Four antibody-drug conjugates are in clinical use, and four are investigational. Dr. Kahl described the limitations and new directions for the available agents and what to expect from the investigational ones.

Antibody-Drug Conjugates Currently in the Clinic

the first antibody-drug conjugate to be approved was brentuximab vedotin (anti-CD30, MMAE payload), and it is now used in a variety of hematologic disorders. It is currently under study for limited-stage Hodgkin lymphoma, including in the front line, in combination, and in relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in combination with the R2 regimen (lenalidomide and rituximab).

Polatuzumab vedotin-piiq (anti-CD79b, MMAE payload) is approved for relapsed or refractory DLBCL, but it can also be useful as a bridge to CAR T-cell therapy. The drug is now being evaluated in the front-line setting with the combination of rituximab, cyclophosphamide, doxorubicin, and prednisone in the global phase III POLARIX trial, based on a 91% response rate and a 1-year progression-free survival of around 85% in the phase II study.2 “We expect to have top-line results later in 2021, which will let us know if we might have a new standard of care in front-line DLBCL,” commented Dr. Kahl.

Loncastuximab tesirine-lpyl (anti-CD19, PPD payload) was recently approved in 2021 for relapsed or refractory DLBCL after two prior lines of treatment. Approval was based on the LOTIS-2 study, in which the response rate was 48% and the complete response rate was 24% in a population with a median of 4.6 prior lines of treatment.3 The duration of response was about 5 months for partial responders, but complete responders often had quite durable remissions. “It’s definitely a potent agent that I think clinicians will find useful to have in their toolbox,” Dr. Kahl noted. Loncastuximab tesirine is currently under study in a variety of combinations, including with ibrutinib and with rituximab, gemcitabine, and oxaliplatin.

A drawback for loncastuximab tesirine, however, is the potential for toxicity. Approximately 25% of patients discontinued therapy due to treatment-emergent adverse events. The most common grade 3 or 4 adverse events were neutropenia, thrombocytopenia, anemia, and increased gamma-glutamyl transferase; however, Dr. Kahl has found that more patients discontinue therapy because of side effects associated with the PPD payload: nonspecific vascular injury that can lead to third spacing of fluids (edema, effusion), skin reactions and nail disorders, and liver enzyme abnormalities. “These adverse events can be clinically significant and problematic for patients,” he said.

Moxetumomab pasudotox-tdfk (anti-CD22; pseudomonas exotoxin genetically attached to an antibody fragment) was approved for hairy cell leukemia after two prior lines of treatment. As monotherapy, the drug led to a response rate of 75% and a complete response rate of 41%, with one-third of patients achieving a durable response.4 “However, the toxicities are not trivial,” Dr. Kahl noted. There can be infusion reactions, significant capillary leak syndrome, and hemolytic uremic syndrome. “Obviously, close monitoring is warranted for these patients,” he added.

Dr. Kahl’s Take on Current Agents

“The single-agent activity of each of these antibody-drug conjugates is good, and I would say very good for brentuximab vedotin. Brentuximab vedotin has a first-line indication (in combination), and trials are underway looking for expanded indications,” Dr. Kahl commented.

“Polatuzumab vedotin has a potential front-line indication, and we will know more about that later this year. It’s not a bad strategy for bridging prior to CAR T-cell therapy and an option with bendamustine/rituximab as a palliative choice in DLBCL,” he continued.

“Loncastuximab tesirine is potent, and it’s a nice option to have now. It’s got a bit of a narrow therapeutic index, which makes its prolonged administration tricky, but dose reductions after two cycles make it safer. Targeting of CD19 may limit its use in the CAR T-cell era, but it could be an option for patients who are not candidates for CAR T-cell therapy or who still have CD19 after CAR T-cell therapy,” he said.

Investigational Antibody-Drug Conjugates in Clinical Trials

The toxicity Dr. Kahl described is a recurring theme with antibody-drug conjugates. In fact, excessive toxicity is the reason many investigational antibody-drug conjugates have not panned out, he said. “Though theoretically they are targeted agents, they are attached to chemotherapy or toxins and still have the potential for significant toxicity. A number of investigational antibody-drug conjugates have been dropped because of modest activity or modest activity coupled with unacceptable toxicity,” he explained. Fortunately, many are moving forward in development, including the following agents.

“Though theoretically antibody-drug conjugates are targeted agents, they are attached to chemotherapy or toxins and still have the potential for significant toxicity.”
— Brad Kahl, MD

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Camidanlumab tesirine (ADCT-301; anti-CD25, PPD payload): In a phase II study of 117 patients with relapsed or refractory Hodgkin lymphoma who had received a median of 6 prior therapies, the response rate was 66%, and the complete response rate was 27%.5 The toxicity profile was typical of agents with a PPD payload—skin reactions and third spacing of fluids—but the drug also poses a unique risk of Guillain-Barré syndrome. This was observed in seven patients (6%), with three cases resolved and four ongoing.

“Camidanlumab tesirine is a very active drug with nontrivial risks. Obviously, Guillain-Barré syndrome is a significant toxicity, and it creates a complex risk/benefit ratio. This toxicity often occurs in young patients who have exhausted treatment options, so this may be acceptable for certain individuals. We’ll have to see how the data mature and how the drug is advanced,” commented Dr. Kahl.

TRPH-222 (anti-CD22, maytansine payload): This antibody-drug conjugate uses a proprietary linker technology that achieves a specific drug-to-antibody ratio. In a phase I study of 22 patients, the response rate was 36%.6 Major toxicities were neutropenia, thrombocytopenia, neuropathy, and ocular toxicity. Dose-expansion studies are planned in follicular lymphoma and DLBCL.

VLS-101 (ROR1-targeted, MMAE payload): This is an oncofetal protein that often reappears in aggressive malignancies. In a phase I study of 32 patients, 80% of patients with DLBCL responded, as did 47% of patients with mantle cell lymphoma. Toxicities included neutropenia, neuropathy, and diarrhea.7 “This agent has been acquired by Merck, which has a robust development plan in store for it,” according to Dr. Kahl.

Naratuximab emtansine (anti-CD37, maytansine payload): In a phase II trial of 100 patients, naratuximab emtansine combined with rituximab produced responses in 50% of patients with DLBCL.8 Although follow-up was short, 75% of responders remained in remission at 12 months. Neutropenia occurred in 54%, and 10% of patients experienced a fatal adverse event. “This seems high, but there were a variety of causes, so it’s hard to detect a pattern, but I think this warrants attention as naratuximab emtansine is further developed.” 

DISCLOSURE: Dr. Kahl has served as a consultant or advisor to AbbVie, Acerta Pharma, ADC Therapeutics, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm Therapeutics, Kite/Gilead, MEI Pharma, MorphoSys, Molecular Templates, Pharmacyclics, Roche, and Teva; has received institutional research funding from Acerta Pharma, ADC Therapeutics, Celgene, and Genentech; and has been reimbursed for travel, accommodations, or other expenses by AbbVie, Celgene, Genentech/Roche, Juno Therapeutics, Millennium, and Seattle Genetics.

REFERENCES

1. Kahl B: What’s next for antibody-drug conjugates in lymphoid malignancies. 2021 Pan Pacific Lymphoma Conference. Presented August 10, 2021.

2. Tilly H, Sharman J, Bartlett N, et al: POLA-R-CHP: Polatuzumab vedotin combined with rituximab, cyclophosphamide, doxorubicin, prednisone for patients with previously untreated diffuse large B-cell lymphoma. 2017 European Hematology Association Congress. Abstract S106. Presented May 18, 2017.

3. 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 22:790-800, 2021.

4. Kreitman RJ, Dearden C, Zinzani PL, et al: Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia. Leukemia 32:1768-1777, 2018.

5. Zinzani PL, Carlo-Stella C, Hamadani M, et al: Camidanlumab tesirine efficacy and safety in an open-label, multicenter, phase 2 study of patients with relapsed or refractory classical Hodgkin lymphoma. Hematol Oncol 39(suppl 2):075, 2021.

6. Hernandez-Ilizaliturri FJ, Flinn IW, Kuruvilla J, et al: A phase I pharmacokinetic and safety study of Trph-222 in patients with relapsed/refractory B-cell non-Hodgkin lymphoma: Dose-escalation results. 2020 ASH Annual Meeting & Exposition. Abstract 701. Presented December 7, 2020.

7. Wang M, Barrientos JC, Furman RR, et al: VLS-101, a ROR1-targeting antibody-drug conjugate, demonstrates a predictable safety profile and clinical efficacy in patients with heavily pretreated mantle cell lymphoma and diffuse large B-cell lymphoma. 2020 ASH Annual Meeting & Exposition. Abstract 121. Presented December 5, 2020.

8. Levy MY, Grudeva-Popova Z, Trneny M, et al: Safety and efficacy of CD37-targeting naratuximab emtansine plus rituximab in diffuse large B-cell lymphoma and other non-Hodgkin’s B-cell lymphomas—A phase 2 study. 2021 European Hematology Association Congress. Abstract LB1903. Presented June 12, 2021.


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