Antibody-Drug Conjugate Field Expanding in Oncology

OncologyLive, Vol. 19/No. 6, Volume 19, Issue 6

Monoclonal antibodies that have the ability to selectively target cancer cells by binding to specific tumor-associated antigens have carved out an important role in anticancer therapy.

Monoclonal antibodies (mAbs) that have the ability to selectively target cancer cells by binding to specific tumor-associated antigens have carved out an important role in anticancer therapy. The idea of combining that specificity with the potency of cytotoxic chemotherapy in the form of an antibody— drug conjugate (ADC) has tempted oncology researchers for decades.

Yet, although the concept was embraced in laboratories, it has been a bumpy road for ADC development—until now. Initial excitement over the FDA’s approval of the first-in-class ADC gemtuzumab ozogamicin (Mylotarg) in 2000 was tempered by its subsequent withdrawal from the market. It took more than a decade for the successful clinical development of 2 more ADCs, ado-trastuzumab emtansine (T-DM1; Kadcyla) and brentuximab vedotin (Adcetris).

Since then, the field has been revitalized as researchers have used past failures to guide the development of newer drugs with improved designs. In recent years, the floodgates have opened; 2 ADCs were approved in 2017 and more than 50 are in various stages of clinical development. Several ADCs are in phase III trials and have the potential to broaden the range of approved indications for this drug class, particularly for the treatment of solid tumors.

Inotuzumab ozogamicin (Besponsa) became the third ADC on the market in August 2017 when it received regulatory approval for the treatment of patients with acute lymphoblastic leukemia (ALL), based on data from the phase III INO-VATE ALL trial.

Design Complexities

Revisiting the past also resulted in re-examination of the role of gemtuzumab ozogamicin, leading to the approval of a new dosing regimen in September 2017 for the treatment of pediatric and adult patients with acute myeloid leukemia (AML).ADCs are often described as targeted payloads, because the idea is to exploit the specificity of a mAb to allow precise tumor-targeted delivery of the cell-killing power of chemotherapy. The goal is to enhance therapeutic efficacy and reduce systemic toxicity (FIGURE 11).

Figure 1. Key Steps in Mechanism of Action of ADCs1

ADCs consist of 3 basic components: a tumor-targeted mAb covalently linked to a cytotoxic drug (often dubbed the “warhead”) via a linker. The mAb binds to a specific antigen on the surface of a cancer cell. This allows the ADC to be taken up into the cell in specialized compartments called endosomes that bud off from the cell membrane. The ADC is then trafficked to the lysosome, an organelle that serves as the cell’s digestive system, where the mAb is broken down into individual amino acids, thereby releasing the payload.

Although it is a relatively straightforward concept, designing a clinically effective ADC is incredibly complex and each of the 3 components has different properties and characteristics that can influence efficacy and safety (FIGURE 21).

Figure 2. Structure of an ADC

The mAb

The ideal target antigen should be highly expressed on cancer cells, with limited expression on healthy tissues, should be internalized upon mAb binding, and should undergo minimal shedding, so that it doesn’t mop up all of the ADC in the circulation before it reaches the target cell.

Another important consideration relating to the mAb component is that it can exert its own antitumor activity via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity, which may or may not be beneficial.

Finding an antibody that checks every box can be tricky and is further complicated by the heterogeneity of antigen expression on tumor cells and its evolution over time under the selective pressure of anticancer therapy

The Payload

Numerous studies have shown that only a very small amount of the ADC makes it into the cell. Therefore, the chemotherapy payload must be much more potent than would normally be tolerated.

The majority of payloads used in ADCs that have entered clinical development kill the target cell either by blocking mitosis or inducing DNA damage. These have predominantly involved 2 families of drugs: the auristatins, monomethyl auristatin E and F (MMAE and MMAF), and the maytansinoids, DM1 and DM4. Among the DNA-damaging drugs is calicheamicin, a highly potent antitumor antibiotic that causes doublestrand DNA breaks by binding to the minor groove of the DNA molecule.

The pharmacokinetic properties are very important because they can affect the overall efficacy and safety of the ADC, notably whether the drug is readily exported from the cell by transporter proteins that mediate drug resistance and can lead to a phenomenon called “bystander killing.” Following export from the cell, the payload can have cytotoxic effects on other cells in the surrounding environment, with a potentially positive impact if it affects other cancer cells or a negative impact if it affects healthy cells.

The Linker

Arguably the most important aspect of ADC design, the properties of the linker can greatly affect the efficacy and safety of the ADC. Its most vital role is ensuring the correct timing of payload release. Too early and the cytotoxic drug can fall off in the circulation, causing off-target toxicity. Too late and the ADC may be disposed of by the cell without ever having an antitumor effect.

The linkers that are currently used are either cleavable or noncleavable. With a noncleavable linker, when the antibody is broken down in the lysosome, the payload is released, still attached to the linker and a single antibody amino acid. On the other hand, cleavable linkers are chemical motifs that are broken down in the presence of specific cellular enzymes or in the acidic environment of the lysosome, thereby releasing the cytotoxic drug without anything attached.

In addition to the type of linker, the location at which the linker attaches the drug to the antibody and the number of drug molecules loaded onto an antibody (known as the drug—antibody ratio [DAR]) are also important. Conventional methods, used to generate gemtuzumab ozogamicin and T-DM1, attach the payload to lysine residues on the antibody. IgG1 has 30 lysines available for conjugation, which means that this method is highly nonspecific and results in a heterogeneous mix of ADCs with different characteristics, including variable DAR.

The DAR is important because if too little payload is attached to the antibody, it will have limited therapeutic efficacy when it reaches its target. Too much payload can destabilize the ADC. Studies have demonstrated that the optimal DAR is highly specific to the type of payload and antibody being used.

The First Generation

More recently, ADCs have been generated by conjugating the payload to cysteine residues in the antibody, which limits the number of possible conjugation sites to 8 and results in increased homogeneity.2-6The first ADC to hit the market was gemtuzumab ozogamicin, in 2000, composed of a CD33- targeting mAb conjugated to a calicheamicin payload via a cleavable acid-sensitive linker. CD33 is expressed on 85% to 90% of AML cases.7 The approved indication, based on the demonstration of 30% remission rates in a phase II trial, was for patients with AML older than 60 years who were not candidates for cytotoxic chemotherapy.8

Unfortunately, phase III follow-up trials failed to confirm clinical benefit and demonstrated a higher risk of fatal adverse events (AEs). Gemtuzumab ozogamicin was voluntarily withdrawn from the market in 2010.9

Despite the setback, ADCs were pursued as a therapeutic strategy. Just a year later, brentuximab vedotin received regulatory approval for the treatment of patients with relapsed/refractory Hodgkin lymphoma (HL) following autologous stem cell transplant (ASCT) or in patients not eligible for ASCT who failed at least 2 other chemotherapy regimens. It was also approved as a second-line treatment for patients with anaplastic large cell lymphoma. Brentuximab vedotin consists of an anti-CD30 antibody (an antigen expressed on the characteristic Reed-Sternberg cells of HL) conjugated to MMAE with a protease-cleavable linker.10,11

In 2013, T-DM1 became the first ADC approved for the treatment of a solid tumor. Based on the renowned HER2- targeting mAb, trastuzumab (Herceptin), T-DM1 is composed of a DM1 payload conjugated to the antibody through a noncleavable linker. It was approved in the second-line setting, for the treatment of patients with HER2-positive breast cancer who had previously received treatment with trastuzumab and taxane chemotherapy, based on the results of the phase III EMILIA trial.12

New Approvals and a Comeback

When T-DM1 became available, expectations were high that it might replace trastuzumab in the frontline setting, but it has not proved more effective than dual blockade with trastuzumab and pertuzumab (Perjeta).13 It was also evaluated as a treatment for HER2-positive gastric cancer in the GATSBY trial, but recent results demonstrated that it was not superior to chemotherapy in patients with previously treated disease.14The approved ADCs were joined by a fourth drug in 2017 in the form of inotuzumab ozogamicin, an ADC with the same composition as gemtuzumab ozogamicin, but targeting CD22. The FDA granted approval for the treatment of patients with relapsed/refractory ALL, irrespective of Philadelphia chromosome status, on the basis of findings from a phase III trial in which the ADC was compared with chemotherapy.

Among 326 patients, complete remission was observed in 35.8% and the median duration of response was 8 months among those treated with inotuzumab ozogamicin, compared with 17.4% and 4.9 months, respectively, with chemotherapy. The most common AEs included thrombocytopenia, neutropenia, infection, anemia, and fatigue.15

Meanwhile, researchers continued to probe the failure of gemtuzumab ozogamicin and other ADCs, in an effort to understand what went wrong. Recent studies have led to a revival of gemtuzumab ozogamicin, with a meta-analysis indicating that it likely does improve longterm overall survival (OS) and reduce the risk of relapse. The use of an intermittent dosing schedule helped to mitigate the potential for significant toxicity.16,17

In September 2017, gemtuzumab ozogamicin was approved in combination with chemotherapy for the treatment of adult patients with newly diagnosed AML and as monotherapy in adult and pediatric patients (2 years and older) with relapsed/refractory disease.

The first indication is based on the results of the ALFA-0701 trial in which 271 patients received induction therapy with daunorubin and cytarabine, with or without gemtuzumab ozogamicin at a dose of 3 mg/m2 on days 1, 4 and 7. The addition of gemtuzumab ozogamicin improved median event-free survival from 9.5 to 17.3 months.18

The monotherapy indication is based on 2 trials: MyloFrance-1, a single-arm phase II trial in which 57 patients were administered 3 mg/ m2 gemtuzumab ozogamicin on days 1, 4 and 7, followed by cytarabine consolidation therapy; and AML-19, a phase III trial involving 237 patients in which gemtuzumab ozogamicin (6 mg/m2 on day 1 and 3 mg/m2 on day 8) was compared with best supportive care.

Past Reveals Path Forward

In the phase II trial, gemtuzumab ozogamicin demonstrated a 26% complete remission rate and median recurrence-free survival of 11.6 months, while in the phase III trial, it improved OS from 3.6 to 4.9 months. The most common AEs included hemorrhage, infection, nausea, fever, vomiting, and constipation.19,20Revisiting past failures has also helped to shape the next generation of ADCs. New antibody designs are being investigated with enhanced or reduced effector functions targeting novel antigens, including those expressed on the cells of the tumor microenvironment or on cancer stem cells. More potent payloads are also being explored. Duocarmycin and pyrrolobenzodiazepine (PBD) dimers are DNA damaging agents, while tubulysins are a promising new class of tubulin inhibitors.

Additionally, advancements in conjugation technology are allowing more effective pairings of the antibody and payload. Most advanced is the development of site-specific conjugation, in which the payload is coupled to specifically defined or engineered sites within the antibody.2

With more than 50 drugs now in the pipeline and a global market predicted to reach more than $3 billion this year,21 the field has become increasingly competitive and some companies are choosing not to disclose the specifics of their ADC composition. More than 20 next-generation drugs have entered phase II and III clinical trials, including several agents that are being investigated in hard-to-treat malignancies (TABLE).

Table. The ADC Landscape: Approved and Later-Stage Agents

ADCs in Later Stages of Development

Additionally, at least 2 dozen novel agents are being explored in phase I trials, including several drugs with recently reported promising data.Sacituzumab Govitecan

Sacituzumab govitecan (IMMU-132) is generating excitement as a potential treatment for patients with triple-negative breast cancer (TNBC) based on findings from a single-arm study in patients with heavily pretreated metastatic disease.22

In results from the 110-patient trial, sacituzumab govitecan demonstrated an objective response rate (ORR) of 34%. Stable disease for ≥6 months was reached in 11% of patients, for an overall disease control rate of 45%. The median progression-free survival (PFS) was 5.5 months (95% CI, 4.8-6.6) and the median OS was 12.7 months (95% CI, 10.8-13.6).

Sacituzumab govitecan consists of SN-38, the active metabolite of irinotecan, linked with a humanized IgG antibody targeted against TROP-2, a cell-surface glycoprotein that is expressed in more than 90% of TNBC. In the study, 57 patients had moderate (2+) to strong (3+) TROP-2 expression by immunohistochemistry and 5 had weak or absent staining for the marker. Data were not available for the remaining patients.

Based on the promising results and high unmet need, Immunomedics, the company developing the drug, plans to submit the data for potential accelerated approval. The phase III randomized ASCENT study is currently enrolling participants and would serve as the confirmatory study for sacituzumab govitecan in metastatic TNBC (NCT02574455).

Rovalpituzumab Tesirine

Rovalpituzumab tesirine (Rova-T) targets the Notch ligand DLL-3 and uses the PBD dimer warhead SG3199 and a pegylated cleavable linker. The results of a phase I study demonstrated encouraging antitumor activity and manageable toxicity in patients with small cell lung cancer (SCLC). Among 60 evaluable patients, the ORR was 18% and 50% had stable disease, with responses limited to patients with a high level of DLL-3 expression. Grade 3 or higher treatment-related AEs occurred in 38% of patients and included thrombocytopenia, pleural effusion, and lipase elevation.23

A phase III trial testing the drug as a third-line and later treatment for patients with relapsed/ refractory DLL3-expressing SCLC is planned but not yet recruiting patients (NCT03334487).

Mirvetuximab Soravtansine

Mirvetuximab soravtansine (IMGN853) is being evaluated in a phase III clinical trial in patients with ovarian cancer. This ADC consists of a folate receptor (FR)-alpha—targeting mAb conjugated to DM-4 via a cleavable disulfide linker. In a pooled analysis from an ongoing phase I study, among patients with platinum-resistant ovarian cancer who had received 1 to 3 prior lines of therapy, the ORR was 30%, including 3 complete responses (CRs), according to data presented at the 2017 American Society of Clinical Oncology Annual Meeting. AEs were generally manageable and included diarrhea, fatigue, nausea, and blurred vision.24

The phase III FORWARDI trial I is recruiting patients with FR-alpha—positive advanced epithelial ovarian, primary peritoneal, and/ or fallopian tube cancer with platinum-resistant disease after 1 to 3 prior treatments. Participants will be randomized to mirvetuximab soravtansine or investigator’s choice of single-agent chemotherapy (NCT02631876).

Polatuzumab Vedotin

Polatuzumab vedotin is a CD79b-targeting ADC, in which the antibody is joined to MMAE via a cleavable linker. Results from an ongoing phase II study, presented at the 2017 American Society of Hematology Annual Meeting (ASH), demonstrated increased response rates for the ADC in combination with bendamustine and rituximab (BR) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), compared with BR alone.25

In the phase III POLARIX trial, patients with previously untreated DLBCL are being randomized to polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin hydrochloride, and prednisone (R-CHP) versus R-CHP plus vincristine (NCT03274492).

Vic-trastuzumab Duocarmazine

Another ADC under development in breast cancer is vic-trastuzumab duocarmazine (SYD985), a HER2-targeting ADC. In January 2018, the FDA granted a fast track designation for the drug as a treatment for patients with HER2-positive metastatic breast cancer that has progressed after at least 2 prior anti-HER2 regimens, according to Synthon Biopharmaceuticals, the company developing the agent.26 The drug elicited a 36% ORR among 14 evaluable patients with heavily pretreated HER2-positive disease, according to findings from a first-in-human phase I trial.27

In November 2017, Synthon launched the phase III TULIP trial to evaluate vic-trastuzumab duocarmazine versus physician’s choice of therapy in patients with progressive HER2- positive locally advanced or metastatic breast cancer (NCT03262935).

Earlier Stages of Pipeline

Vic-trastuzumab duocarmazine uses a linker drug technology, valine-citrulline-seco-duocarmycin-hydroxybenzamide-azaindole, based on synthetic duocarmycin analogs that promote cell death by causing DNA alkylation.The growing pipeline of ADCs in development for oncology indications includes numerous agents in phase I and II stages. Findings about several of these drugs have been presented at recent conferences.

Trastuzumab Deruxtecan

One ADC of particular note is trastuzumab deruxtecan (DS-8201), a HER2-targeted compound that uses a novel enzyme-cleaved peptide linker and a potent, topoisomerase I inhibitor as the payload. As a result of its unique design characteristics, DS-8201 is reported to be effective against cancers with low HER2 expression and in T-DM1— resistant cancer cells, setting it apart from T-DM1.

The results of an ongoing phase I dose-escalation and expansion trial were presented at the 2017 San Antonio Breast Cancer Symposium (SABCS). Patients with a variety of HER2- expressing cancers have been enrolled in the trial, but the results from 146 patients in the breast cancer cohorts were presented. There were no dose-limiting toxicities up to 8 mg/kg and the confirmed ORR was 41%, including 1 CR. The most common AEs were nausea, decreased appetite, vomiting, alopecia, and diarrhea.28

DS-8201 has been granted a breakthrough therapy designation for the treatment of patients with HER2-positive, locally advanced or metastatic breast cancer who have previously been treated with trastuzumab, pertuzumab, and T-DM1.

Ladiratuzumab Vedotin

Another breast cancer ADC that has attracted interest in the field is ladiratuzumab vedotin, which targets the transmembrane protein LIV-1. In phase I study results presented at 2017 SABCS, ladiratuzumab vedotin demonstrated a median PFS of 11.6 weeks in heavily pretreated patients with TNBC who received the drug as monotherapy.29

Ladiratuzumab vedotin is composed of a humanized IgG1 and anti—LIV-1 mAb, an MMAE, and a protease-cleavable valine-citrulline maleimidocaproyl linker. After activation by the STAT3 pathway, LIV-1 promotes an epithelial-to-mesenchymal transition. LIV-1 is expressed in more than 90% of breast tumors and has limited expression in normal tissues.

Glembatumumab Vedotin

Glembatumumab vedotin (CDX-011) targets glycoprotein NMB (gpNMB), which is overexpressed by multiple tumor types. The drug has shown efficacy in uveal melanoma and breast cancer. In a phase II study, the drug induced a disease control rate of 61% in patients with metastatic uveal melanoma, despite a low a low ORR of 6%. There were no complete responses, 2 (6%) partial responses, and 17 patients (55%) with stable disease.30

In advanced breast cancer, the drug elicited a 30% ORR among patients whose tumors expressed gpNMB in the phase II EMERGE trial.31 Glembatumumab vedotin is being evaluated in patients with TNBC in the phase IIb METRIC study (NCT01997333).

GSK2857916

In the realm of hematologic malignancies, GSK2857916, an ADC targeting B-cell maturation antigen (BCMA), induced an ORR rate of 60% among 21 patients with heavily pretreated multiple myeloma, including 2 CRs and 1 stringent CR, according to phase I results presented at 2017 ASH.32

In November 2017, the FDA granted GSK2857916 a Breakthrough Therapy Designation for the treatment of patients with relapsed/refractory multiple myeloma who have failed at least 3 prior lines of therapy, including an anti-CD38 antibody, and who are refractory to a proteasome inhibitor and an immunomodulatory agent.

GSK2857916 is a humanized IgG1 anti-BCMA antibody conjugated to MMAF via a stable, protease-resistant maleimidocaproyl linker. The treatment exhibits enhanced ADCC resulting from afucosylation of the fragment crystallizable domain, which increases affinity to FCγRIIIa expressed on immune effector cells.

Depatuxizumab Mafodotin

Depatuxizumab mafodotin (ABT-414) targets the epidermal growth factor receptor variant III (EGFRvIII) mutation that is highly expressed in patients with glioblastoma. The mAb is bound to MMAF via an acid-cleavable linker. The results of a phase I dose-escalation and expansion study were recently published. Among 66 patients treated at a dose of 1.2 mg/kg every 2 weeks, all of whom had previously been treated with temozolomide and radiotherapy, the ORR was 6.8%, the 6-month PFS was 28.8%, and the 6-month OS was 72.5%. AEs included blurred vision, dry eye, keratitis, and photophobia.33

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