FOR THE TREATMENT of lymphoma, antibody-drug conjugates (ADCs) are becoming an important class of drugs, as described at the 2018 Pan Pacific Lymphoma Conference by Brad Kahl, MD, Professor of Medicine at Washington University School of Medicine, St. Louis.1
Brad Kahl, MD
“We have one ADC—brentuximab vedotin (Adcetris)—that’s had a major impact in Hodgkin lymphoma and CD30-positive non-Hodgkin lymphoma. Polatuzumab vedotin looks like it’s poised to also make an impact if current trials are positive. Many others are currently in development,” Dr. Kahl said.
The ABCs of ADCs
ADCS ARE DESIGNED to deliver cytotoxic agents more selectively to the tumor. “If you are able to achieve that, you can improve the therapeutic index, which would then, in theory, allow for the delivery of more potent cytotoxic agents that you could administer intravenously,” Dr. Kahl explained.
ADCs include an antigen-antibody combination and a payload that is attached via a linker. The antigen is tumor-specific and must be abundant in the tumor cell; the monoclonal antibody must be able to bind to that antigen. Target antigens for ADCs currently in development include CD19, CD22, CD25, CD30, CD37, and CD79b.
The linker, which has to be stable in the circulation, releases the drug upon internalization. “A lot of considerations go into making an ADC, and the linker technology and the conjugation strategy just may turn out to be the most important part of all of this to optimize the therapeutic index for ADCs,” Dr. Kahl said.
Payloads, so far, have included microtubule inhibitors, DNA-damaging agents, and toxins. Payloads—essentially “warheads”—must be potent, as only about 2% of the payload actually localizes to the tumor cell.
The ADC brentuximab vedotin is approved in patients with relapsed or refractory Hodgkin lymphoma (response rate = 75%) and CD30-positive anaplastic large cell lymphoma (response rate = 86%), post-remission high-risk Hodgkin lymphoma after autologous stem cell transplant (progression-free survival benefit), and relapsed cutaneous T-cell lymphoma and CD30-expressing myelofibrosis (response rate = 56%). It was also recently approved in combination with standard chemotherapy in the front-line setting for Hodgkin lymphoma (progression-free survival benefit). Further data for brentuximab vedotin are also expected in 2018 as front-line therapy for peripheral T-cell lymphoma and CD30-positive anaplastic large cell lymphoma.
Inotuzumab ozogamicin (Besponsa), which targets CD22 and is approved in B-cell precursor acute lymphoblastic leukemia, failed to show a benefit in lymphoma patients in clinical trials.
“A lot of considerations go into making an ADC, and the linker technology and the conjugation strategy just may turn out to be the most important part of all of this to optimize the therapeutic index for ADCs.”— Brad Kahl, MD
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Next Up: Polatuzumab Vedotin
“POLATUZUMAB VEDOTIN is probably the ADC that is the most poised right now to potentially make an impact in lymphoma,” Dr. Kahl commented. Polatuzumab vedotin targets CD79b, and its payload—the antineoplastic monomethyl auristatin E (MMAE)—is similar to that of brentuximab. Studies are evaluating it as a single agent; in combination with rituximab (Rituxan) and with bendamustine plus rituximab (BR); and in combination with rituximab plus cyclophosphamide, doxorubicin, and prednisone (R-CHP).
The phase I/II ROMULUS trial evaluated polatuzumab vedotin plus rituximab in relapsed or refractory diffuse large B-cell lymphoma (DLBCL).2 The median progression-free survival was 5.5 months, and response rates were about 55% for both the single agent and the combination.
“The waterfall plot showed that the majority of patients derived a clinical benefit. The progression-free survival curve showed a lot of drop-offs in the first few months, but then you saw a reasonably good tail to that curve, suggesting respectable activity for single-agent polatuzumab vedotin in relapsed large cell lymphoma,” he observed.
Patients with relapsed or refractory follicular lymphoma and DLBCL were then evaluated in a randomized phase II trial of polatuzumab vedotin plus BR (ClinicalTrials.gov identifier NCT02257567). Early findings, reported at the 2018 ASCO Annual Meeting, were that polatuzumab vedotin can be safely administered in combination with BR, and there is strong activity for its addition to BR in DLBCL (but not follicular lymphoma).3
In the DLBCL cohort, the combination improved progression-free survival, from 2.0 months to 6.7 months (hazard ratio [HR] = 0.31, P < .0001), and overall survival, from 4.7 months to 11.8 months (HR = 0.35, P = .0008), regardless of prior lines of treatment or refractoriness of disease. “There was a pretty substantial progression-free survival benefit and a statistically significant overall survival benefit, when compared to BR alone, in that population,” he noted.
The combination did increase the rate of serious adverse events (55% vs 33), the most common being infections and febrile neutropenia. “That’s probably an acceptable increase in toxicity for such an improvement in progression-free and overall survival,” Dr. Kahl suggested.
Polatuzumab vedotin is also being tested in combination with R-CHP (Polo-R-CHP), essentially substituting the ADC for the vincristine in R-CHOP. In an ongoing study of 45 previously untreated DLBCL patents, the Polo-R-CHP arm had a 91% positron-emission tomography response at the end of treatment and a 78% rate of complete responses.4 At 18 months, approximately 80% of patients were free of disease progression.
These encouraging findings led to the initiation of the phase III POLARIX trial, evaluating Polo-R-CHP vs R-CHOP in 875 previously untreated DLBCL patients (NCT03274492). In 2017, the U.S. Food and Drug Administration granted Breakthrough Therapy designation to polatuzumab vedotin for relapsed or refractory DLBCL, and the European Medicines Agency granted it a Priority Medicines designation.
“If polatuzumab vedotin were to receive approval, it would certainly be an attractive option for patients with relapsed large cell lymphoma who are in palliative mode and unable to be treated with curative intent anymore,” Dr. Kahl commented.
Novel ADCs in Early-Phase Trials
A NUMBER OF other ADCs are in early-phase development. Loncastuximab tesirine (ADCT-402) is a CD19-targeting product currently being evaluated in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NCT02669017).
“This [loncastuximab tesirine] is an ADC that was interesting because of the payload that it uses—a pyrrolobenzodiazepine (PBD) dimer, which is a highly potent cytotoxic agent.”— Brad Kahl, MD
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“This is an ADC that was interesting because of the payload that it uses—a pyrrolobenzodiazepine (PBD) dimer, which is a highly potent cytotoxic agent,” Dr. Kahl said. “The [pharmaceutical company developing loncastuximab tesirine] believes that because a stochastic conjugation technology was used, it can more tightly control the number of payload molecules per antibody, and this can result in better pharmacokinetic properties and a better safety profile.” In particular, this nontubulin approach could be of benefit to patients who have been previously exposed to agents causing peripheral neuropathy.
At the 2017 American Society of Hematology Annual Meeting & Exposition, Dr. Kahl presented early data on loncastuximab tesirine from a first-in-human trial, showing strong antitumor activity as a single agent in a population with essentially no other treatment options.5 In 68 evaluable patients treated with loncastuximab tesirine at 120 μg/kg, the response rate was 60%, with 35% being complete responses, he reported, noting, “We saw a lot of patients responding, despite chemotherapy refractoriness.”
Treatment-related adverse events observed in this phase I dose-escalation study of loncastuximab tesirine include skin-related changes, fatigue, nausea, increased gamma-glutamyl transferase, anemia, and peripheral edema. The peripheral edema caused some concern in the trial, Dr. Kahl acknowledged, since some patients developed pleural effusions that required repeated drainage over the course of months, before abating. The study investigators did, however, find a dosing schedule that appears to mitigate this side effect.
The same company is also developing ADCT-301, a CD25 monoclonal antibody with a protease cleavable linker PBD dimer. The drug is being investigated in an ongoing phase I/II trial in 47 patients with Hodgkin lymphoma and non-Hodgkin lymphoma (NCT02432235). In preliminary analyses, the overall response rate observed with this agent was 71% in Hodgkin lymphoma patients and 33% in patients with peripheral T-cell lymphoma.6 The toxicities observed were rash, edema, and gamma-glutamyl transferase elevation. Two patients in the study developed Guillain-Barré syndrome, which the researchers plan to investigate further.
Other novel ADCs under investigation include TRPH-222, VLS- 101, Resimmune (A-dmDT390-bisFv(UCHT1), coltuximab ravtansine, denintuzumab mafodotin, pinatuzumab vedotin, moxetumomab pasudotox, and naratuximab emtansine. ■
DISCLOSURE: Dr. Kahl is a consultant for Genentech, Seattle Genetics, and ADC Therapeutics and has received research support from Genentech and ADC Therapeutics.
REFERENCES
1. Kahl B: New antibody-drug conjugates. 2018 Pan Pacific Lymphoma Conference. Presented July 18, 2018.
2. Palanca-Wessels MC, Czuczman M, Salles G, et al: Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: A phase 1 study. Lancet Oncol 16:704-715, 2015.
3. Shen LH, Kamdar M, Herrera AF, et al: Randomized phase 2 trial of polatuzumab vedotin with bendamustine and rituximab in relapsed/refractory FL and DLBCL. 2018 ASCO Annual Meeting. Abstract 7507. Presented June 3, 2018.
4. Hervé Tilly H, Flowers C, Friedberg JW, et al: A phase 3 study comparing polatuzumab vedotin plus R-CHP versus R-CHOP in patients with DLBCL (POLARIX). The 2018 European Hematology Association Congress. Abstract 80. Presented June 14, 2018.
5. Kahl BS, Hamadani M, Caimi P, et al: Encouraging early results from the first-in-human clinical trial of ADCT-402 (loncastuximab tesirine), a novel pyrrolobenzodiazepine-based antibody drug conjugate, in relapsed/refractory B-cell lineage non-Hodgkin lymphoma. 2017 ASH Annual Meeting and Exposition. Abstract 187. Presented December 9, 2017.
6. Horwitz SM, Hamadani M, Fanale MA, et al: Interim results from a phase 1 study of ADCT-301 (Camidanlumab tesirine; Cami-T) show promising activity of a novel pyrrolobenzodiazepine-based antibody drug conjugate in relapsed/refractory Hodgkin/non-Hodgkin lymphoma. 2017 ASH Annual Meeting and Exposition. Abstract 624.
