Innovations in cancer therapy: antibody-drug conjugates

Article by Sharmini Rajanayagam BSc (Hons), PhD; Senior Medical Writer at EPG Health

Anti-HER2 therapy

The monoclonal antibody trastuzumab was among the first targeted cancer therapies and the first human epidermal growth factor receptor 2 (HER2) inhibitor approved for the treatment of breast cancer^1,2. The development of trastuzumab was considered a breakthrough in the treatment of HER2+ breast cancers, as it was associated with significantly improved survival outcomes for a breast cancer subtype with a bleak outlook^1,2. The downside, though, is that trastuzumab is effective only in patients whose tumours overexpress HER2 at high levels, sufficient to register an immunohistochemistry (IHC) score of at least 3+ or IHC score of 2+ with gene amplification of ≥2 copies on fluorescence in situ hybridisation (FISH)^1,3. This excludes about 60% of patients whose tumours express HER2 at levels below this threshold⁴.

For the purpose of determining eligibility for anti-HER2 therapy, HER2+ status was defined as an IHC score of 3+ or IHC 2+ with gene amplification of ≥2 copies on FISH^3,5. IHC scores of 1+ or 2+ were not considered clinically relevant, given that they are typically unresponsive to anti-HER2 therapy, and tumours with these scores were relegated to HER2− status³. Clearly, breast cancers deemed HER2− by current guidelines are not necessarily devoid of these receptors. Indeed, more than half of metastatic HER2− breast cancers do express HER2 but at levels that evade standard anti-HER2 therapy⁴.

The current notion of HER2 status as binary, either positive or negative, is now undergoing a paradigm shift with the recognition of a third option – ‘HER2-low’ – found to be a viable treatment target of a new class of drugs^1,5. HER2-low encompasses tumours with IHC scores of 1+ and 2+ without gene amplification, which are unresponsive to standard anti-HER2 therapy but recently found to be sensitive to the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and trastuzumab duocarmazine^4–6.

Antibody-drug conjugates

ADCs are a recent innovation in cancer therapy and provide a unique means of fine-tuning the delivery of cytotoxic agents to tumour cells^7–9. ADCs consist of a monoclonal antibody, such as trastuzumab, bound to a chemotherapy drug via cleavable linker peptides (Figure 1).

Figure 1. Antibody-drug conjugate. Image adapted under CC BY-SA 4.0

The antibody binds to the target antigen on the tumour cell and is then internalised in the cell where the linker proteins are cleaved to release a cytotoxic payload^7–9. In this way, ADCs are capable of selectively delivering cytotoxic agents to specific cancer cell targets while minimising exposure to non-cancer cells^7–9. An additional key feature of T-DXd and trastuzumab duocarmazine is their ability to exert a so-called ‘bystander’ effect on neighbouring tumour cells, regardless of whether they express HER2¹⁰. Preclinical studies have shown that T-DXd has anti-tumour activity in a variety of tumour types, including those expressing low levels of HER2¹¹.

The ability of T-DXd and trastuzumab duocarmazine to selectively deliver potent cytotoxic payloads to HER2+ tumour cells, together with their unique bystander effect, broadens the reach of these agents to patients with HER2-low tumours, who are ineligible for standard anti-HER2 therapy

Trastuzumab deruxtecan

T-DXd is an ADC that consists of trastuzumab bound to the topoisomerase 1 inhibitor deruxtecan, an exatecan derivative. It was designed to deliver the potent topoisomerase 1 inhibitor to HER2-expressing cells^4,10. The linker peptides are stable in plasma but cleaved by lysosomal cathepsins, which are upregulated in cancer cells¹¹. Once released in the tumour cell, the topoisomerase 1 inhibitor, designed to be cell permeable, can exert its bystander effect to eliminate surrounding tumour cells, whether they express HER2 or not¹⁰.

In mid-2022, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the use of T-DXd for treatment of HER2+ metastatic breast cancer^12,13. Approval was based on the results of the DESTINY-Breast03 trial, which compared T-DXd with trastuzumab emtansine (T-DM1), an earlier version of an ADC combining trastuzumab with the cytotoxic anti-microtubule agent DM1¹⁴. DESTINY-Breast03 showed that the risk of disease progression was significantly lower in patients with HER2+ metastatic breast cancer who received T-DXd than in those who received T-DM1¹⁴.

DESTINY-Breast04 trial

Given the unique bystander effect of T-DXd, a subsequent clinical trial, DESTINY-Breast04, was undertaken to determine whether T-DXd would in fact prove effective against HER2-low breast cancer⁴. DESTINY-Breast04 was a randomised, multicentre, open-label, phase 3 trial that evaluated the efficacy and safety of T-DXd, compared with treatment of physician’s choice (TPC), in patients with HER2-low metastatic breast cancer⁴. Patients who had been treated previously with one or two lines of chemotherapy in the metastatic setting were recruited to the study. TPC included capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel¹⁵. At 18.4 months follow up, progression-free survival was significantly greater in patients on T-DXd than those on TPC (9.9 months vs 5.1 months; hazard ratio [HR] 0.50; 95% confidence intervals [CI] 0.40, 0.63; P<0.0001). T-DXd also increased overall survival (23.4 months vs 16.8 months; HR 0.64; 95% CI 0.49, 0.84; P=0.0010). This amounts to an impressive 50% reduction in the risk of disease progression and a 36% reduction in the risk of death⁴.

The incidence of adverse events was similar in the two treatment groups⁴. The most common side effects of T-DXd were nausea and neutropenia, but these could be managed with medication. An important risk associated with T-DXd treatment is interstitial lung disease, which occurred in 12% of patients in the DESTINY-Breast04 trial. Patients treated with T-DXd, therefore, require careful monitoring to ensure early detection and intervention to prevent or minimise serious outcomes⁴.

In August 2022, only two months after completion of DESTINY-Breast04, the FDA approved the use of T-DXd for the treatment of metastatic breast cancer in patients with the newly identified designation of HER2-low

Development of the anti-HER2 monoclonal antibody trastuzumab was rightly considered a breakthrough in the treatment of HER2+ breast cancer. The development of ADCs, including T-DXd, may well be considered a sophisticated advance in drug design for targeted cancer therapy.

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References

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3. Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol. 2018;36(20):2105-2122.
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11. Ogitani Y, Aida T, Hagihara K, Yamaguchi J, Ishii C, Harada N, et al. DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1. Clin Cancer Res. 2016;22(20):5097-5108.
12. FDA. @US_FDA. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer | FDA. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-nxki-breast-cancer.
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15. Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): Results of DESTINY-Breast04, a randomized, phase 3 study. J Clin Oncol. 2022;40(17_suppl):LBA3-LBA3.