Systemic toxicity is a significant limitation of classical cytotoxic agents, with the efficacious dose often being close to the maximum tolerated dose. The concept of targeted cytotoxic drug delivery to reduce systemic toxicity was introduced by Paul Ehrlich, who believed that drugs could target cancer cells using a “magic bullet” approach. It was almost a century later when the first antibody-drug conjugate (ADC) gained regulatory approval. ADCs harness the specificity of monoclonal antibodies, which bind to antigens expressed on tumour cells to ensure selective uptake of highly cytotoxic payloads.

To date, there are 12 FDA-approved ADCs, with over 170 novel ADCs in the clinical stage of development, according to GlobalData’s Pharma Intelligence Center. Data presented at the ASCO 2023 conference demonstrated the potential of this therapeutic class across a broad range of tumour types. Daiichi Sankyo, arguably the major player in the ADC market, presented data for its lead ADCs, Enhertu (trastuzumab deruxtecan), datopotamab deruxtecan (Dato-Dxd), and patritumab deruxtecan (HER3-Dxd). Enhertu is a HER2-targeting ADC with regulatory approval for HER2-positive breast cancer, HER2-low breast cancer, HER2-positive gastric cancer, and HER2-mutant non-small cell lung cancer (NSCLC). Dato-Dxd, an-anti TROP2 ADC, and patritumab deruxtecan, an anti-HER3 ADC, are yet to gain regulatory approval but are currently in multiple clinical trials. Enhertu and Dato-Dxd are jointly developed by Daiichi Sankyo and AstraZeneca, with development and commercialisation agreements in place for both agents.

Enhertu in HER2-positive colorectal cancer (CRC) and other solid tumours

Data from the Phase II DESTINY-CRC02 two-stage study investigating Enhertu treatment in HER2-positive CRC was presented. In stage one, patients were randomly assigned to receive either 5.4mg/kg (n=40) or 6.4mg/kg (n=40) of Enhertu every three weeks. In stage two, a further 42 patients received the 5.4mg/kg dose every three weeks. All patients had advanced disease, with 72% of patients in the 5.4mg/kg cohort having liver metastases, and 3.7% having central nervous system metastases. In the 6.4mg/kg cohort, 65% of patients had liver metastases and 2.5% had central nervous system metastases. The median number of prior lines of therapy was three in the 5.4mg/kg group and four in the 6.4mg/kg group. All patients had received prior systemic chemotherapy, and most patients had received an anti-EGFR and an anti-VEGFR therapy. Only 20.7% and 25% of patients had received a prior anti-HER2 therapy in the 5.4mg/kg and 6.4mg/kg cohorts, respectively.

The confirmed objective response rate was 37.8% in the 5.4mg/kg cohort and 27.5% in the 6.4mg/kg cohort. There were no complete responses (CRs) at either dose, and the median duration of response (mDoR) was 5.5 months for both dose levels. The disease control rate (DCR) was comparable in both cohorts, at 86.6% in the 5.4mg/kg group and 85.0% in the 6.4mg/kg group. In the 5.4mg/kg cohort, the median progression-free survival (PFS) was 5.8 months, and the median overall survival (OS) was 13.4 months. In the 6.4mg/kg cohort, the median PFS was 5.5 months, and the median OS was not evaluable. This data demonstrates the efficacy of Enhertu in heavily pretreated HER2-positive CRC patients who have exhausted all therapeutic options.

Interim results were also presented for the Phase II DESTINY-Pan Tumor02 study investigating Enhertu in a broad range of HER2-expressing solid tumours. The study enrolled 267 oncology patients with HER2 immunohistochemistry (IHC)-positive disease (IHC 2+ or IHC 3+), including cervical cancer (40), endometrial cancer (40), ovarian cancer (40), biliary tract cancer (41), pancreatic cancer (25), bladder cancer (41), and other cancers (40). Patients received Enhertu at a dose of 5.4mg/kg every three weeks. Patients enrolled in the study had received a median of two prior lines of therapy.

The study reported an impressive overall response rate (ORR) of 37.1%, with 5.6% of patients achieving a complete response and 31.5% achieving a partial response (PR). A further 46.1% of patients had stable disease as the best response. Importantly, responses were durable, with a mDoR of 11.8 months. The results were even more dramatic for the subgroup of patients with IHC 3+ disease, with a confirmed ORR of 61.3% and a mDoR of 22.1 months. Data from this study demonstrates the potential for Enhertu to achieve a tumour-agnostic label, which would be a first for any ADC.

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The safety profile of Enhertu in both studies presented was consistent with previous studies, with no new safety signals reported.

Dato-Dxd in NSCLC

Updated data from the Phase Ib TROPION-Lung02 trial investigating Dato-Dxd in combination with Merck’s Keytruda (pembrolizumab) in NSCLC was presented. In total, 120 patients were treated in this study, spread over six experimental cohorts. Two cohorts received only Dato-Dxd in combination with Keytruda every three weeks, while the remaining four cohorts received a triple combination, including Dato-Dxd, Keytruda, and chemotherapy. Patients received the experimental treatment as either a first-line (1L) or second-line (2L) therapy. The PR rate was higher for the triplet therapy versus the doublet therapy, at 38% and 49%, respectively. In patients being treated in 1L, the ORR was 50% for patients treated with the doublet (n=34), and 57% for those treated with the triplet (n=53). The DCR was similar for both cohorts, in 1L and 2L, with the DCR for the doublet being 87% in 1L and 91% in 2L, and the DCR for the triplet being 84% in 1L and 91% in 2L. Preliminary PFS for patients in the doublet arm was 8.3 months, compared to 7.8 months for the triplet arm. No new safety signals were observed for Enhertu in this study. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 61% of patients, with the most common being neutrophil count decrease (8%) and amylase increase (8%). No treatment-related deaths occurred.

While this data is highly encouraging, no comparator arm was included in the study design. The doublet and triplet therapy are currently being investigated as 1L therapy in the Phase III TROPION-Lung07, which is set to enrol 975 patients with a PDL1-positive score <50%. The doublet is currently in the Phase III TROPION-Lung08 study as 1L therapy in patients with a high PDL1 score (≥50%). These trials will determine whether this ADC is added to the standard of care (SOC) for this lucrative oncology indication. However, the NSCLC treatment landscape is highly crowded, with a rich pipeline for this disease setting. Indeed, data for two further anti-TROP2 ADCs in the NSCLC setting has also been presented, including for Merck’s asset MK2870, which was developed by the Chinese company Kelun, and Gilead’s Trodelvy (sacituzumab govitecan).

Patritumab deruxtecan in estrogen receptor-positive and triple-negative breast cancer

Results from a study investigating patritumab deruxtecan for the treatment of locally advanced or metastatic HER2-negative breast cancer were also presented at the conference. Part A of the study enrolled 60 patients with HER2-negative breast cancer, and included patients who were hormone receptor-positive and hormone receptor-negative. All patients were treated at a dose of 5.6mg/kg every three weeks. Patients were heavily pretreated, with a median of three prior lines of therapy. The ORR was 35%, with these all being PRs. The clinical benefit rate, which included CRs, PRs, and patients with stable disease, was 43.3%. The DoR was greater than six months in 47.6% of patients. Responses were seen in patients irrespective of HER3 expression, with the relationship between HER3 expression and response being evaluated in Part B of the study.

In terms of safety, grade ≥3 drug-related TEAEs occurred in 31.7% of patients, with no grade 5 drug-related TEAEs reported. The most common grade ≥3 drug-related TEAEs were fatigue (6.7%), diarrhoea (5%), and a decreased neutrophil count (5%). This data demonstrates the clinical activity of patritumab deruxtecan in heavily pretreated HER2-negative breast cancer patients irrespective of HER3 expression level. This therapy has the potential to enter the therapeutic landscape of breast cancer across subtypes, with arm Z of the trial investigating patritumab deruxtecan in HER2-positive patients following progression on Enhertu, which has become the SOC in this setting. However, this novel ADC will face competition from already marketed Trodelvy, which is the SOC in the HER2-negative setting, and from other agents within the oncology pipeline.

Concluding comments

ADCs continue to demonstrate efficacy across different tumour types, and their use is expected to expand across indications as more suitable target antigens are identified and technology advances. According to GlobalData’s Intelligence Center, global sales for ADCs reached close to $7.7bn in 2022, and are expected to reach $38.7bn by 2029, with an impressive compound annual growth rate (CAGR) of 26%. Daiichi’s three lead assets, two of which are being jointly developed and commercialized with AstraZeneca, are expected to hold a significant chunk of the ADC market, with the consensus forecast predicting combined global sales of close to $13bn by 2029.