Antibody Drug Conjugates

Antibody Drug Conjugates

Antibody drug conjugates (ADC) are a relatively recent approach to cancer treatment in clinical practice and many more are currently in clinical development.

What is an antibody drug conjugate?

As the name suggests it comprises a monoclonal antibody (mAb) and a drug (cytotoxic agent) that are linked by the chemical reaction of conjugation (Figure 1).

Figure 1: Structure of an Antibody Drug Conjugate

Source: Trail, P. A. (2013) (1)

Abbreviations: mAb: Monoclonal antibody

Development of ADCs maximises the therapeutic margin; binding a potent cytotoxic chemotherapy to a tumour antigen-specific mAb via a stable linker delivers treatment to the site of disease whilst minimising systemic toxicity. The cytotoxic agents are extremely potent and if delivered systemically would cause excessive toxicity to normal tissues. One of the first cytotoxic agents used to Investigate the development potential of an ADC was the poison ricin, made famous by the umbrella killing of Georgi Markov in 1978 (2, 3).

To be effective, an ADC must selectively bind, internalise, and deliver an intracellular concentration of drug that is sufficient to result in cell death (Figure 2).

Figure 2: Mechanism of antibody drug conjugate

Source: Trail, P. A. (2013) (1)

Improving the benefit risk balance of a medicine (maximising efficacy and reducing toxicity) is a continuing battle in most therapeutic areas, but particularly relevant to oncology. As with most therapeutic concepts, progress has been incremental over the last two decades. Initial development of ADCs was limited by systemic toxicity and a narrower therapeutic index than anticipated.

Tumour selectivity

The mAb should bind to a target that is only expressed by the tumour cells. The tumour selectivity and level of expression of a target antigen are critical in the design of safe and efficacious ADCs as the intracellular concentration of drug that can be achieved is determined both by the level of antigen expression and the efficiency of ADC internalization and intracellular trafficking (1).

Linker design

The design of the linker plays a key role in determining stability in the systemic circulation and intra-tumoral payload release, influencing pharmacokinetics (PK), efficacy, and safety. Multiple articles have been written on advances in linker chemistry, but non-specific release (that causes damage to normal tissues) needs to be reduced. Initial research showed that less than 1% of ADC doses accumulated in tumours.

So, the theory is great but what has happened in practice?

Several ADCs have been licenced by the FDA and EMA, initially for relapsed/ refractory haematological malignancies but, by early 2023, 6 of the 13 ADCs approved by the FDA targeted solid tumours (Table 1).

Interest in ADCs continues to grow and in 2022, 57 new ADCs entered Phase 1 clinical trials. There are several PD-L1 targeted ADC drugs in pre-clinical and Phase 1 stages.

Table 1: FDA (and EMA) Approved ADCs to April 2023

Abbreviations: FRα: folate receptor alpha; HER2: human epidermal growth factor receptor 2; HGBL: high-grade B-cell lymphoma; HR: Hormone receptor; MF: mycosis fungoides; NSCLC: non-small cell lung cancer; pcALCL: primary cutaneous anaplastic large cell lymphoma; PTCL: peripheral T-cell lymphomas; sALCL: systemic anaplastic large cell lymphoma.

Products in italics have been withdrawn in certain territories.

1. Mylotarg was withdrawn by the US FDA in 2010 due to toxicity concerns and was reapproved in 2017 with a lower indicated dose
2. EU orphan designation
3. For patients who have an International Prognostic Index (IPI) score of ≥2
4. For patients who are who are ineligible for cisplatin-containing chemotherapy
5. Where the cancer has spread or cannot be removed by surgery, and who have received a platinum-containing chemotherapy medicine and also received an immunotherapy medicine
6. Where patients have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting

Most are administered as single agents, but some ADCs, such as Polivy (with bendamustine and rituximab in DLBCL) and Mylotarg (with daunorubicin and cytarabine in AML) are authorised in combination with standard therapeutic agents in haematological malignancies.

Some ADCs, particularly those targeting haematological malignancies with orphan designation, received accelerated/conditional approval based on a single arm study with confirmatory studies completed post approval. Some products have additional indications in the USA compared to the EU. Trodelvy is authorised for treatment of urothelial cancer by the FDA with an overall response rate (ORR) of 27.7% in a single arm study, as accelerated and standard full marketing authorisations can co-exist on the same label in the USA.

Acknowledging this accelerated growth, the authorised ADCs have not totally fulfilled the promise of reduced systemic effects, as most have black box warnings for serious toxicities. Early dose optimisation is important, including investigating lower and/ or fractionated dosing schedules. Failure to adequately investigate dose may have contributed to some products being withdrawn from the market.

Toxicity by cytotoxic payload

Calicheamicin derivatives

Mylotarg (gemtuzumab ozogamicin), the first authorised ADC, received accelerated approval from the FDA in 2000 for the treatment of relapsed AML. Later, in 2007, the application for treatment of CD33-positive AML patients in first relapse who are not candidates for other cytotoxic chemotherapy was refused by the CHMP, based on the modest proportion of complete responses (CRs: 13%) reported in the single arm studies and the identified risks, including severe and fatal cases of veno-occlusive disease (VOD), particularly when given in conjunction with a haematopoietic stem cell transplant (HSCT).

Mylotarg was withdrawn from the US market in 2010 when a confirmatory Phase 3 study in previously untreated AML showed that it was associated with a higher rate of fatal related adverse events compared to standard of care chemotherapy (5.8% vs 0.8%) with no improvement in efficacy. In 2017, Mylotarg was reapproved by the FDA based on additional studies with a lower dose and fractionated dosing schedule; it was approved in 2018 by the EMA. There remains a black box warning regarding fatal hepatic VOD.

Gemtuzumab ozogamicin is comprised of a humanized Immunoglobulin G 4 (IgG4) monoclonal antibody conjugated to a calicheamicin derivative via the bifunctional AcBut linker. Another ADC, Besponsa (inotuzumab ozogamicin), authorised for relapsed/refractory CD22 positive B cell ALL, is similarly comprised of a IgG4 antibody covalently attached to a calicheamicin derivative via an acid cleavable linker. Like Mylotarg, a major toxicity is severe, sometimes fatal hepatic VOD, particularly post HSCT. However, the response rate (CR/incomplete count recovery [CRi]) was high with Besponsa (81%, 95% CI 72, 88) compared to standard of care chemotherapy (29%, 95% CI 21, 39). The primary overall survival (OS) endpoint was not met (median 7.7 vs 6.2 months). Despite a higher frequency of early deaths post HSCT at Day 100, a late survival benefit was evident, making Besponsa an important treatment option for R/R B ALL (Figure 3).

Figure 3: Overall Survival (inotuzumab ozogamicin)

Source: Kantarjian et. al. 2019 (4)

Abbreviations: CI confidence interval; HR, hazard ratio; InO, inotuzumab ozogamicin; OS: overall survival; SoC, standard of care (intensive chemotherapy).

For 2- and 3-year survival, the 1-sided P value was based on the chi-square test or the Fisher exact test (if any cell count was <5). †One-sided log-rank test.

Truncated pseudomonas PE38 exotoxin

Lumoxiti, the only licenced product utilising the PE38 exotoxin, was authorised based on a single arm study in the US in 2018 and in the EU in February 2021 for treatment of adult patients with relapsed or refractory hairy cell leukaemia (HCL). Important toxicities with a black box warning were life threatening haemolytic uraemic syndrome (HUS) and capillary leak syndrome (CLS). Astra Zeneca withdrew Lumoxiti in the EU in July 2021, where the product had not been marketed, and intends to withdraw Lumoxiti from the US market in July 2023. The rationale was the low clinical uptake attributed to the availability of other treatment options and possibly to the complex administration, toxicity prophylaxis and safety monitoring.

Anti microtubule agents

Blenrep was authorised based on a single arm study with an ORR of 32% (95% CI 22, 44) for the treatment of relapsed/ refractory multiple myeloma in adult patients, who have received at least four prior therapies. The cytotoxic component (Monomethyl auristatin F: MMAF) disrupts the microtubule network and ocular toxicity is a major issue with ophthalmic examinations required at baseline and regularly throughout treatment. The confirmatory Phase 3 study (DREAMM-3), failed to show a progression-free survival (PFS) benefit compared with pomalidomide plus low-dose dexamethasone. GSK withdrew Blenrep from US the market in November 2022 but continues to evaluate its benefit in combination treatments and dosing optimisation to maintain efficacy while reducing toxicity.

Another agent that disrupts the microtubule network is Elahere (mirvetuximab soravtansin), which received accelerated approval from the FDA in 2022, based on an ORR of 32% (95% CI 23, 42) in a single-arm trial of 106 patients with folate receptor alpha (FRα) positive, platinum-resistant epithelial ovarian cancer. The small molecule, DM4 is an anti-tubulin agent and Elahere has a black box warning regarding ocular toxicity.

Tivdak, authorised by the FDA based on a single arm study with an ORR of 24% (95% CI 16%, 33%) in 101 patients with recurrent or metastatic cervical cancer who had received no more than two prior systemic regimens, including at least one platinum-based regimen, is a tissue factor-directed antibody and microtubule inhibitor conjugate. The toxic payload (MMAE) is a microtubule-disrupting agent attached to the antibody via a protease-cleavable linker and, again, product labelling includes a boxed warning for ocular toxicity.

Neither Tivdak or Elahere, with single arm studies showing ORRs of 24% and 32% in solid tumour populations have been approved (by April 2023) in the EU. Despite the wait for confirmatory Phase III studies, it is exciting to see products being developed for solid tumours, such as ovarian and cervical, where there have been limited new therapies authorised in the last decade. Where the initial efficacy was impressive, a single arm study was sufficient to allow accelerated/ conditional approval even in a disease with multiple therapeutic options, such as HER2 positive metastatic breast cancer.

ADCs for breast cancer

The first ADC approved for treatment of a solid tumour was Kadcyla (T-DM1) in 2013 for patients with HER2 positive metastatic breast cancer and progressive disease following trastuzumab and a taxane. In the Phase III EMILIA trial, Patients who received Kadcyla had a median PFS of 9.6 months compared with 6.4 months for patients treated with lapatinib plus capecitabine (P < .0001). Median overall survival was 30.9 and 25.1 months for patients respectively (Figure 4). Kadcyla contains a black box warning reductions in left ventricular ejection fraction, fatal liver failure and embryo foetal toxicity.

Figure 4:     Kaplan-Meier curve of overall survival (T-DM1)

Source: Kadcyla (trastuzumab emtansine) SmPC (5)

Abbreviations: Cap: capecitabine; Lap: lapatinib; SmPC: Summary of Product Characteristics; T-DM1: trastuzumab emtansine

Hazard ratio is estimated based on a stratified Cox model; p-value is estimated based on a stratified log-rank test.

The second ADC to be approved for metastatic breast cancer was Enhertu (trastuzumab deruxtecan, T-DXd). This showed impressive efficacy in a single arm study of patients with HER2 positive metastatic breast cancer who had received two or more prior anti-HER2 therapies with an ORR of 60% (95% CI 53, 67). The US prescribing information (PI) includes a black box warning for interstitial lung disease and embryo foetal toxicity. Compared to T-DM1 in a randomised Phase III study (DESTINY-Breast03) involving patients with HER2 positive, previously treated advanced breast cancer, T-DXd resulted in significantly improved median PFS (NR vs 6.8 months; HR 0.28, p<0.0001).

https://www.ema.europa.eu/en/documents/product-information/enhertu-epar-product-information_en.pdf

Figure 5:     Kaplan-Meier plot of PFS per BICR (intent-to-treat analysis set

Source: Enhertu (trastuzumab deruxtecan) SmPC (6)

Abbreviations: BICR: blinded independent central review; PFS: progression-free survival; SmPC: Summary of Product Characteristics.

Topoisomerase inhibitors have also demonstrated efficacy in advanced/ metastatic breast cancer. Trodelvy (sacituzumab govitecan) consists of SN-38 covalently attached to a humanised antibody that recognises Trop-2 is authorised for previously treated triple negative breast cancer in the US and the EU. This is based on the Phase 3 ASCENT study with a significant improvement in median PFS of 4.8 months vs 1.7 months (HR 0.43, 95% CI 0.35, 0.54) compared to treatment of physician’s choice and an extended median overall survival of 11.8 compared to 6.9 months (HR 0.51; 95% CI 0.41, 0.62). Predictably, like irinotecan, Trodelvy causes severe neutropenia and diarrhoea, and the risk of Grade 3-4 adverse reactions is greater in subjects with reduced UGT1A1 activity (i.e. homozygous for the UGT1A1*28 allele).

Where next?

Future developments will continue to optimise linker design and cellular targeting, both antigen selection and optimisation of the therapeutic mAb. The aim is to reduce pre-release in the circulation and non-specific uptake of payloads in normal tissue. Modification of linker design (e.g., increased hydrophilicity) also may help to overcome tumour efflux that leads to ADC resistance.

A potential new approach is combining the ADC therapeutic concept with an antibody that targets the PD-1/PDL-1 immunotherapy pathway which could change the standard of care (SoC) in treatment of solid tumours. Authorisations to date have been in the advanced setting in relapsed/refractory patients or after at least 2 lines of systemic therapy. An important step will be to move ADCs to earlier in the treatment armamentarium, in the first line metastatic or adjuvant setting. To target this broader population ADCs will need to demonstrate significantly superior efficacy and an acceptable safety profile compared to current SoC and considering other emerging therapies.

Despite the challenges, ADCs provide enormous opportunities to improve outcomes for oncology patients in the future.

References

1. Trail PA. Antibody Drug Conjugates as Cancer Therapeutics. Antibodies. 2013;2(1):113-29.
2. Nelsson R. The poison-tipped umbrella: the death of Georgi Markov in 1978 – archive. Guardian. 2020.
3. Calvete JA, Newell DR, Charlton CJ, Wright AF. Pharmacokinetic studies in mice with ICI D0490, a novel recombinant ricin A-chain immunotoxin. Br J Cancer. 1993;67(6):1310-5.
4. Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019;125(14):2474-87.
5. Roche. Kadcyla (trastuzumab emtansine) SmPC. 2018 17 September 2018.
6. Daiichi Sankyo Chemical Pharma Co. L. Enhertu (trastuzumab deruxtecan) SmPC. 2022