As discussed in the first instalment of this series, antibody-drug conjugates (ADCs) have revolutionized the cancer treatment landscape. Harnessing the precision of monoclonal antibodies and the potent cytotoxicity of chemotherapy, they have the potential to minimize damage to healthy cells caused by systematic therapy. However, there are several challenges to overcome, including suboptimal delivery systems and capped efficacy. This raises the question: Should developers focus on optimizing available ADCs to ensure the maximum potential of current targets, or should they explore novel antigens?

The primary focus for the development of ADCs was originally on highly-expressed cancer antigens such as CD33 [MYLOTARG], HER2 [KADCYLA] or TROP2 [TRODELVY], driven by their known roles in the pathophysiology of specific tumors. Industry-sponsored clinical studies have now broadened beyond established antigens, with researchers now exploring novel targets applicable across various tumors.


Fast-tracked development in breast cancer unveils the potential of ADCs 

Breast cancer has been a frontrunner in ADC therapy, with HER-2 targeting ADCs proving highly successful in treating both early-stage and metastatic breast cancer. The commercial drive and research focus has likely been propelled by the rising prevalence and incidence of breast cancer, now the most frequently diagnosed tumor type. The breast cancer market is on a trajectory of continuous growth and is projected to reach a value of $73.68B by 2032. Genentech’s  KADCYLA  [ado-trastuzumab emtansine] was the first-in-class (FIC) FDA approval of a HER2-targeting ADC, approved in 2013 [2L HER-2+ metastatic]. KADCYLA later received a label expansion in 2019 [early-stage after neoadjuvant treatment] based on data from the Ph3 KATHERINE study. At a recent 8-year follow-up analysis, the study continues to demonstrate that the use of KADCYLA as neoadjuvant treatment for HER2+ breast cancer provides a sustained and significant improvement in invasive disease-free survival (IDFS).

First-generation ADCs such as KADCYLA were hindered by design flaws, including cytotoxic agents with limited potency and low tumor antigen expression, restricting effective therapeutic delivery. Additionally, unstable linkers often led to hepatoxicity and inaccurate tumor targeting, contributing to increased systemic toxicity. However, the emergence of a second generation of ADCs introduced technical advancements that yielded improved efficacy, even when targeting the same molecular site as their predecessors. Consequently, KADCYLA was displaced as standard of care (SoC) by ENHERTU [Initial FDA approval: Dec ’19 in 3L+ unresectable breast cancer] following data from the head-to-head Ph3 DESTINY-Breast03 trial which demonstrated almost double improved efficacy [61% vs 31%] and a steep improvement in OS.

TRODELVY [sacituzumab govitecan-hziy], another second-gen ADC targeting TROP-2, was granted accelerated FDA approval [Apr 2020] for the treatment of 2L+ metastatic triple-negative breast cancer, based on data from Ph1/2 TROPHY, which demonstrated a 33% ORR. However, TRODELVY established itself as SoC after the FDA granted full approval (Apr 2021) following a data readout from the Ph3 ASCENT trial, which demonstrated a 57% reduction in the risk of worsening and/or death [FDA approval, Apr 21] when compared to single-agent chemotherapy.

These second-generation ADCs represent a significant advancement as they exhibit activity across tumors with varying levels of target expression. Data from the Ph3 DESTINY-Breast04 and Ph3 TROPiCS-02 studies have demonstrated that ADCs can effectively target tumors with both medium and low levels of antigen expression, surpassing initial expectations.


Driving ADC innovation through pharmaceutical investment  

Currently, there are approximately 150 next-gen ADC drugs in the pipeline [Source: Citeline Biomedtracker]  most of which remain in the earlier stages of development, suggesting growing interest and funding. This interest is expected to surge as companies aim to capitalise on the high commercial potential, as ADCs are projected to reach $31 billion in sales within the $375 billion cancer market by 2028 [Source: Evaluate Pharma]. Notable acquisitions, like J&J’s $2 billion purchase of Ambrx Biopharma and Pfizer’s $43 billion acquisition of Seagen, along with big-pharma collaborations such as Merck’s $16.5 billion partnership with Daiichi Sankyo, highlight the growing confidence and funding of ADC development.

Could ADCs potentially be shielded from biosimilar competition due to their intricate nature? The demanding structural characterization requirements for both novel ADCs and potential biosimilars mirror those of other biomolecules, needing a comprehensive understanding of primary and higher-order structures. Due to the intricate nature of replicating manufacturing processes and conducting similarity assays, the pool of sponsors willing to pursue biosimilar development is likely to be limited. Despite this, in May 2021, closely after KADCYLA’s loss of exclusivity (LoE) [EU, 2020], Zydus Cadila’s launched UJVIRA, the first biosimilar ADC of KADCYLA. Ujvira demonstrated equivalence to KADCYLA in efficacy, safety, pharmacokinetics, and immunogenicity. It’s worth noting that neither the European Commission nor the FDA has granted approval for UJVIRA or any other ADC biosimilar thus far. However, UJVIRA’s approval in India highlights the growing capabilities of biotech in developing biosimilars for complex therapies.

Expedited regulatory review mechanisms can accelerate the development of ADCs and enhance confidence within the field.  An example is the FDA’s breakthrough designation (BTD) for AbbVie’s Teliso-V [telisotuzumab vedotin], which targets c-Met, a pivotal protein considered a driver of tumour growth and often over-expressed in NSCLC. Although a promising agent in NSCLC, the MET/HGF axis had faced setbacks, elucidated by several trial failures evaluating protein inhibitors [Daiichi Sankyo’s Ph3, Kiowa Kyrin’s Ph3 ATTENTION]. However, in November 2023, AbbVie released top-line data from Ph2 LUMINOSITY, reporting a 35% ORR in c-MET high tumours and a lower 23% ORR in tumours with intermediate expression. Given its broad effectiveness in 2L and 3L settings, coupled with a BTD, Teliso-V is expected to receive approval in 2L+ NSCLC in 2024. AbbVie could additionally use data from its ongoing confirmatory Ph3 TeliMET-NSCLC-01 evaluating Teliso-V against docetaxel chemotherapy in c-Met+ non-squamous NSCLC to support accelerated approval.

Despite their longstanding use since the early 2000s, ADCs have gone through several successes and failures that highlight the need to optimise ADC delivery systems to minimise off-target events and systemic toxicity. A key example is Pfizer’s MYLOTARG, which was initially approved in the year 2000 as a standalone treatment for patients 60+ years old with CD33+ AML who had relapsed and were not eligible for alternative therapy. However, in 2010 MYLOTARG was voluntarily withdrawn from the market after a data readout from a confirmatory trial demonstrated uncertain clinical benefit and a higher rate of fatal toxicity. MYLOTARG was re-approved by the FDA in 2017 for adults with CD33+ AML and patients aged 2≥ with CD33+ AML who had relapsed or did not have initial response to treatment, this time with a lower dose and a black box warning for hepatoxicity and fatal hepatic veno-occlusive disease.

Third-generation ADC development holds promise for improved therapeutic efficacy, with a primary focus on site-specific conjugation to achieve targeted ADCs with well-defined drug-to-antibody ratios (DAR) and enhanced stability. Furthermore, ongoing research is dedicated to identifying payloads with new mechanisms of action (MoA) capable of targeting tumour-initiating cells to overcome resistance.

Through preclinical analysis, pathways of ADC resistance have been modelled, unveiling diverse mechanisms by which tumours develop resistance to ADC — spanning all delivery components of an ADC. Research suggests that navigating the complexity of targeted agent development to overcome resistance could find a solution in optimising sequential ADC treatments and combination therapies. However, this scenario can only materialise if there are multiple approvals in the field. Some studies even propose that swapping ADC targets in later lines of disease might demonstrate benefit. Although effective sequencing of chemotherapy has been broadly adopted, current data on ADC sequencing is constrained by the limited array of approved therapies. While ENHERTU and KADCYLA’s approval across different stages of disease might offer insight into effective sequencing for HER2+ breast cancer, the query of optimal sequencing lingers across other tumour types.


Evaluating the potential success of ADC-based combination therapies 

Toxicity and resistance to treatment remain significant limitations in realizing the full clinical potential of ADCs. As cytotoxic payloads gain potency, there’s an opportunity for effective treatment, but only when delivery is localized to minimize off-target effects.

Bucket trials offer a streamlined approach to assess the performance of an ADC on a molecular level across tumor types, evaluating activity in a short amount of time, which diminishes the investment risk associated with novel targets. Utilizing basket trials could streamline the approval process for expanding an already approved therapy into additional tumor types. For instance, KEYTRUDA gained approval for use in adults and children with TMB-H solid tumors, based on data from the Ph2 KEYNOTE-158 basket trial.  The success of these type of trials is also exemplified by AstraZeneca’s Ph2 DestinyPanTumor01 and DestinyPanTumor02 trials, both of which demonstrated ENHERTU’s effectiveness across diverse tumor types, resulting in two FDA Breakthrough Designations for the molecule in 2L+ settings across different solid tumors. At ESMO ’23 [abs #654O], AZ presented a primary analysis from the DestinyPanTumor01 trial, demonstrating a 29.4% ORR at 8.64 months follow-up. Meaningful responses were observed across HER2 protein expression levels, including HER2-low or HER2-zero expression, indicating the possibility of independence between mutation and expression as predictive biomarkers for response to T-DXd.

ADCs and IOs have promising synergy which arises from their impact on both the immune system and the tumour microenvironment. ADCs have shown greater efficacy in immunocompetent animal models compared to immunodeficient ones, indicating a significant immunomodulatory effect. The ADC’s antibody, beyond delivering the cytotoxic agent, can also modulate innate immune responses via its Y-shaped structure. Specifically, its crystallizable fragment interacts with immune cells and regulates the antibody’s bioavailability in the bloodstream. ADCs can bolster the cancer-killing abilities of IOs, as most cytotoxic payloads used in ADCs can induce cancer cell death through immunogenic activation. However, we should note that this synergy may be limited to specific combinations of ADCs and IOs. Concerns may arise regarding rapid ADC clearance potentially reducing overall efficacy, or the release of cytotoxic payloads within the tumor microenvironment (TME), which may harm local T-cells and impair the efficacy of immune checkpoint inhibitors (ICIs). Nevertheless, the synergy between chemotherapeutic agents + IOs has been extensively investigated, as IOs such as KEYTRUDA and Tecentriq are frequently administered in combination with chemotherapy, though ADCs might offer an improved safety profile.

Preliminary findings from Gilead’s Phase 2 EVOKE-02 trial evaluating TRODELVY + KEYTRUDA in 1L metastatic NSCLC have shown significant clinical efficacy across all PD-L1 subgroups and histologies. This highlights TRODELVY’s potential as a foundational element for IO combinations, surpassing historical responses to anti-PD1 monotherapy in this context. However, in Jan 2024 Gilead announced that the Ph3 EVOKE-01 trial had failed to reach its PEP of OS in metastatic NSCLC patients who progressed after treatment with chemotherapy + ICIs. Nevertheless, the trial showed a numerical improvement in OS with TRODELVY in both squamous and non-squamous histology, particularly notable in a subgroup of patients who had not responded to anti-PD-L1 monotherapy previously. Data from the Ph3 EVOKE-03 study, focusing on TRODELVY + KEYTRUDA in 1L metastatic NSCLC with PD-L1 TPS ≥ 50%, will provide further insight into the role of TRODELVY as an addition to treatment with KEYTRUDA, given the trial’s pembrolizumab monotherapy comparator.

Given their ability to block downstream signalling pathways and curb cell proliferation in cancerous cells, Tyrosine Kinase Inhibitors (TKIs) represent a pivotal treatment in cancer therapy. Pre-clinical evidence suggests the combined application of ADCs with TKIs could introduce an additional layer of blockade, potentially demonstrating increased selectivity, particularly in cancers characterized by specific biomarkers. A pre-clinical study evaluating a novel ADC [20D9-ADC] in combination with midostaurin [TKI] demonstrated potent antileukemic activity. The study was supported by previous data that demonstrated that TKI treatment increased surface expression of FLT3 on FLT3-ITD+ AML cell, sensitising them to bispecific FLT3 x CD3 antibodies. 20D9-ADC targets FLT3, a common driver mutation with high leukemic burden, which usually leads to poor prognosis in patients with AML. In April 2017, the FDA approved midostaurin + cytarabine + daunorubicin induction and cytrabine consolidation for the treatment of adults with AML who are FLT3+, demonstrating that FLT3 is already an established target for TKIs in AML. Companies investing in FLT3-targetting ADCs, such as Astellas Pharma with XOSPATA [gilteritinib, Ph1 NCT02864290], could leverage historical data to move to evaluate the combination across AML settings, which could provide a first-in-market advantage in indications with high unmet need where current SoC consists of chemotherapy with or without targeted therapy.

ADCs continue to represent one of the most promising frontiers in oncology, further streamlining a targeted approach in the treatment of hard-to-treat tumours. Although the pursuit of new, potent targets for ADCs shows promise, it’s crucial to prioritise the refining of current ADC systems to maximise the utility of current biomarkers. By adopting a combined treatment approach that integrates ADCs with established therapies, we may improve efficacy and overcome resistance to ADC monotherapy. In our next instalment, we will explore both the opportunities and challenges of treatment avenues beyond ADCs, focusing on the potential of radioligands and the utility of pan-tumour solutions.




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