June 30, 2022

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Current status and future of ADC therapy in HER2-positive breast cancer

Current status and future direction of ADC therapy in HER2-positive breast cancer

Current status and future of ADC therapy in HER2-positive breast cancer. The development of anti-HER2 drugs is one of the most significant advances in the treatment of metastatic breast cancer (BC), which has significantly improved survival rates.

There are currently 8 approved HER2 targeted drugs with a median survival time of more than 5 years. The maximum anti-tumor activity of anti-HER2 drugs is achieved through combined chemotherapy. This effect may be related to the heterogeneity of HER2 expression and other primary drug resistance mechanisms. In addition, HER2 overexpressing cells have a high proliferation rate and are more responsive to cytotoxic therapies.

Antibody-conjugated drugs (ADC) are a class of therapeutic drugs that combine antigen-specific antibodies with effective cytotoxic payloads, which can increase the therapeutic index. The FDA has approved two anti-HER2 ADCs, which have different indications for HER2-positive breast cancer. Ado-trastuzumab emtansine (T-DM1) is the first HER2 targeted ADC.

It was initially approved in 2013 for use in patients with metastases previously treated with trastuzumab and taxane. The scope will be expanded in 2019 to include Adjuvant treatment of high-risk patients with residual disease after neoadjuvant treatment with taxane and trastuzumab.

In 2020, the second HER2 ADC: trastuzumabderuxtecan (T-DXd) was approved for patients who have received at least two anti-HER2 drugs under metastatic conditions.

The success of these two drugs has changed the treatment of HER2-positive breast cancer and injected new vitality into the field of ADC development. The new generation of HER2-targeted ADC has superior activity and may be effective in breast cancer patients with low HER2 expression, opening up a series of new possible clinical applications. The current challenges facing HER2 targeting ADCs include improving target specificity, optimizing toxicity characteristics, and identifying biomarkers for patient selection.

Approved HER2 targeting ADC

Trastuzumab emtansine

Trastuzumab emtansine (T-DM1) is the first HER2-targeted ADC approved for the treatment of advanced HER2-positive BC, and it was recently approved for early high-risk patients with residual disease after neoadjuvant therapy. T-DM1 contains the backbone of Trastuzumab, which is connected to mertansine (DM1) through a non-cleavable thioether linker (N-maleiminomethyl). Mertansine is an effective microtubule inhibitor with a DAR of 3.5. In addition to the anti-tumor effect of the payload, all cytotoxic functions of Trastuzumab, including ADCC and signal inhibition, have been preserved.

Clinically, according to the data from the key trials EMILIA and TH3RESA, T-DM1 is used as a second-line treatment for metastatic breast cancer. EMILIA is a phase III study that studied T-DM1 versus capecitabine and lapatinib in HER2-positive BC patients who had been treated with trastuzumab and taxane (n=911). The results are in favor of T-DM1, showing an improvement in overall survival (OS) (29.9 vs 25.9 months; HR 0.75, 95% CI 0.64–0.88), with a median follow-up of 47.8 months.

Similarly, in the TH3RESA trial, compared with the established standard of care treatment, the benefits and superior efficacy of T-DM1 were confirmed in patients with more severe HER2-positive metastatic breast cancer (MBC): progression-free survival (PFS) ) Improvement (6.2 vs 3.3 months; HR 0.53, 95% CI 0.42–0.66; P<0.0001), and OS was 22.7 vs 15.8 months.

Recently, according to the results of the KATHERINE trial, the benefits of T-DM1 have been extended to include early patients with residual disease after neoadjuvant therapy, and these patients are considered to be a group at high risk of recurrence. The 3-year noninvasive survival rate (IDFS) of the T-DM1 group was significantly higher than that of the control group treated with trastuzumab alone (88.3% vs 77%, HR 0.5, 95% CI 0.39~0.64; P<0.001).

In addition, the toxicity of T-DM1 is controllable. Adverse events include gastrointestinal toxicity and neuropathy, as well as decreased left ventricular ejection fraction (LVEF), and the severity is mostly 1/2. Thrombocytopenia and increased liver enzymes, including the risk of liver failure, are the most common high-grade toxicity reported in clinical trials.

Trastuzumab deruxtecan

Trastuzumabderuxtecan (T-DXd; DS8201a) is the second FDA-approved ADC for the treatment of advanced HER2-positive BC. These patients have used at least two HER2-targeted therapies. Like T-DM1, it consists of the backbone of trastuzumab, but there are many differences between the two ADCs. T-DXd has a DAR of 8 (T-DM1 is 3.5), and its cytotoxic payload is derived from exatecan, which is an effective topoisomerase I inhibitor, not a microtubule inhibitor. In addition, T-Dxd incorporates a cleavable linker that can be acted on by cathepsin (lysosomal enzyme), which is upregulated in many cancer cells. Related to this is that the payload is membrane-permeable, so it can exert a bystander effect. Theoretically, it can be active even in tumors with heterogeneity or low expression of HER2, which is not observed in T-DM1.

In the first human phase 1 study of T-DXd, including 111 patients with advanced HER2-positive breast cancer after multiple treatments, the response rate of T-DXd monotherapy was 59.5%, and the median duration of response (DOR) 20.7 months. Based on these results, the Phase 2 study, DESTINY-Breast01, was subsequently launched, which is designed for HER2-positive MBC patients who have previously received T-DM1 treatment.

In a cohort study of 184 patients, the overall response rate was 60.9%, of which 6% of patients had a complete remission (CR), and the overall disease control rate (DCR) was 97.3%. Interestingly, the median time to response was 1.6 months, indicating rapid anti-cancer activity similar to classic chemotherapy drugs.

The latest situation recently announced shows that the DOR is more than 20.8 months, the median PFS is 19.4 months, and the median OS is 24.6 months. These results were finally awarded a breakthrough therapy by the FDA, and accelerated approval in December 2019.

The most common toxicities associated with T-Dxd include nausea and bone marrow suppression, which are mainly grade 1/2 in nature; however, there is also an important risk of pulmonary toxicity, which is broadly defined as interstitial lung disease (ILD), the severity of which is not Etc.

ADC in clinical development

Currently, many next-generation HER2-targeted ADCs are currently being studied in clinical trials. These new drugs are designed with different payloads and connection technologies to further improve their efficacy and tolerability.

Current status and future direction of ADC therapy in HER2-positive breast cancer

Trastuzumab duocarmazine

Trastuzumabduocarmazine (SYD985) is a HER2-targeted ADC, which is made up of the body of trastuzumab coupled with a cleavable linker and a payload of Ducamycin. The payload is membrane permeable, so regardless of HER2 expression, it is possible to enter neighboring cells. The Phase 1 study of this ADC showed acceptable toxicity and anti-tumor activity in HER2-positive and HER2-low-expressing breast cancers. In this extended study of patients with HER2-positive MBC, 33% of patients (16/48) obtained an objective response.

These results form the basis of the Phase III TULIP trial (NCT03262935), which included patients with HER2-positive MBC treated with T-DM1. The primary endpoint is the assessment of PFS. The results have not been reported. SYD985 is currently being studied in combination with paclitaxel (NCT04602117) and niraparib (NCT04235101). The combined application of SYD985 with adriamycin and cyclophosphamide is also being studied in the I-SPY trial (NCT01042379), which is a large-scale adaptive neoadjuvant trial designed to evaluate the pathological complete response (pCR) of different biological agents combined with chemotherapy. ) Rate.

A166

A166 is a combination of trastuzumab and duostatin-5 (an auristatin derivative). In 2020, the results of a phase I trial (NCT03602079) conducted on 27 evaluable patients showed that DCR was 59%, and PR was observed in 7 patients (26%) at dose levels of 3.6 mg/kg and 4.8 mg/kg. The research is ongoing.

XMT-1522

XMT-1522 is an ADC composed of the HT-19 antibody backbone. HT-19 is a human IgG1 anti-HER2 monoclonal antibody that binds to the domain IV of HER2 to form a table different from the binding site of trastuzumab The payload is an auristatin derivative (AF-HPA). Pre-clinical data show that XMT-1522 is effective against HER2-positive BC and gastric cancer cell lines, as well as xenograft models resistant to T-DM1. The preliminary results of a phase I study (NCT02952729) showed that in the 16 and 21.3 mg/m2 groups, the overall DCR was 83% (5/6), and there was 1 case of PR. Among patients, DCR was 25% (3/12).

RC48-ADC

RC48 is a new type of anti-HER2 ADC, which is composed of hertuzumab (a new anti-HER2 monoclonal antibody) coupled with MMAE through a cleavable linker. In a phase I study, RC48 showed acceptable toxicity characteristics and good anti-tumor activity in solid tumors. Among patients treated in the 2.0 and 2.5 mg/kg dose groups, the reported ORR was 33.3%, and the DCR was 53%. Another phase Ib study evaluated the activity of RC48-ADC in HER2-positive MBC. Among the 30 evaluable patients, the DOR was 96.7% (29/30), including 11 cases of PR and 18 cases of SD.

At present, RC48 has been marketed in China. It is used for HER2 overexpression locally advanced or metastatic gastric cancer that has received at least two systemic chemotherapy. It is the first ADC drug approved for marketing in China. Recently, RC48 was Licensed out with a total amount of US$2.6 billion, setting a new record for the transaction amount of a single Chinese innovative drug.

ALT-P7 (HM2/MMAE)

ALT-P7 is a new type of HER2-targeted ADC, which is formed by coupling a variant of trastuzumab and MMAE. The results of the first human study showed that among measurable patients, the DCR was 77.3% (17/22) and there were 2 PRs. Among patients with a median previous treatment of 6, the median PFS was 6.2 months. Currently, the second phase of the study is being planned.

ARX788

ARX788 is a site-specific ADC composed of anti-HER2 antibody coupled with a highly effective tubulin inhibitor AS269, using a unique unnatural amino acid coupling technology and a non-cleavable linker. The results of the first phase trial showed anti-tumor activity in HER2-positive BC. Among 48 evaluable patients, the ORR of the 1.3 mg/kg dose group was 56%, and the ORR increased to 63% when the dose was 1.5 mg/kg. Therefore, the FDA granted Fast Track designation in January 2021. ARX788 is currently undergoing a two-part phase 1 dose escalation trial (NCT03255070) for patients with HER2-positive solid tumors.

PF-06804103

PF-06804103 is formed by coupling a trastuzumab-derived antibody to AUR-06380101 (a new and effective auristatin derivative) through a cleavable linker. PF-06804103 has shown effectiveness in breast, stomach and lung tumor models with low HER2 expression. The preliminary results of the phase 1 dose escalation study (NCT03284723) showed that at a dose ≥ 3.mg/kg, the ORR was 52.4% (11/21). All patients had previously received HER2 targeted therapy, and the median number of previous treatments was 6.

A new generation of ADC

Several new-generation ADC drugs have shown encouraging results in preclinical studies, which show the future development direction of patients with HER2-positive solid tumors.

MRG002 and ZW49 are two kinds of ADCs. They both use auristatin as a payload to couple with different HER2 monoclonal antibodies. The former uses a humanized anti-HER2 IgG1 monoclonal antibody, and the latter uses ZW25, which recognizes trastuzumab and pertuzumab binding respectively. Site-specific anti-HER2 bispecific antibody. Two ADCs are currently undergoing phase I clinical trials (CTR20181778, NCT04492488, NCT04742153, NCT03821233).

BDC-1001 is formed by coupling a biological analogue of trastuzumab and a TLR 7/8 agonist through a non-cleavable linker. BDC-1001 can activate antigen-presenting cells while retaining antibody-mediated effector functions, such as ADCC. Preclinical data show that BDC-1001 induces effective immune-mediated anti-tumor effects in a xenograft model, and its safety has been demonstrated for the first time in a human study. The efficacy of BDC-1001 alone or in combination with anti-PD1 is still awaiting (NCT04278144).

Finally, a newly designed pertuzumab-based ADC has a lower affinity for HER2 at acidic endosomal pH. This design shows increased lysosomal transport and increased cytotoxicity in the HER2 low expression xenograft model, and is expected to enter further Clinical trials.

Toxicity characteristics

The toxicity characteristics of ADC seem to be related to the stability of the drug in the blood and the off-target effects of the payload. Compared with trastuzumab, the cardiotoxicity of the new ADC is mainly related to the monoclonal antibody component, which does not seem to be a problem.

A recent pooled analysis of the T-DM1 trial in metastatic patients showed that patients have a risk of congestive heart failure <1%. In addition, both T-DXd and SYD985 had a grade 3/4 drop in left ventricular ejection fraction of less than 1%.

Interstitial lung disease (ILD) is a risk associated with T-DXd treatment and requires vigilant and early intervention to prevent serious consequences. The DESTINY-Breast01 study reported that 15.2% (28/184) of patients had ILD cases of any grade. Although most cases were reversible grade 1 and grade 2 events, 5 cases of ILD died due to T-DXd treatment.

According to the FDA label, for patients with ILD grade 2 or higher, treatment should be permanently discontinued and any respiratory symptoms should be investigated immediately. The pathophysiology of T-DXd-related lung injury is unclear, and animal studies have shown the possibility of lung injury The mechanism is related to the target-independent uptake of T-DXd into alveolar macrophages. Further work is needed to clarify these findings and their clinical significance.

Ocular toxicity is considered to be a type of related toxicity, including a large number of ocular adverse events, usually low-grade and reversible, including conjunctivitis/keratoconjunctivitis, uveitis, corneal epithelial injury and optic neuropathy. Other ADC-related adverse events include bone marrow toxicity, nausea, fatigue, vomiting, and peripheral neuropathy, with varying frequencies, mainly due to specific payloads.

Current status and future direction of ADC therapy in HER2-positive breast cancer


Summary

ADC is one of the most successful developments in the treatment of HER2-positive breast cancer in the past decade. Innovative molecular structure, combined with antigen specificity and powerful cytotoxicity, gives ADC treatment unique pharmacodynamic and pharmacokinetic properties.

The efficacy of next-generation ADCs on poorly differentiated HER2 tumors may change the historical model of HER2 targeted therapy. New strategies are needed to define HER2 status to identify patients most likely to receive clinical benefit.

With the success of T-DM1 and T-DXd, a large number of new anti-HER2 ADCs with good activity are currently being studied.  These drugs will bring new hopes for the treatment of HER2+ breast cancer.

(source:internet, reference only)


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