ADC Reviews

The Main Representative ADC Drugs In The World

target drugs

1. Pfizer: Pioneer in the field of ADC, launched the world's first ADC drug Mylotarg

Mylotarg (Gemtuzumabozogamicin, gemtuzumab) was originally developed by Pfizer. It is a combination of a CD33-targeting monoclonal antibody and an anti-tumor antibiotic calicheamicin. It is the first drug to be delisted among all new drugs approved under accelerated approval, and it is also the first ADC drug to be marketed again after delisting. The FDA-approved indications include: (1) newly diagnosed CD33-positive adults and children with acute myeloid leukemia (AML) older than 1 month; (2) relapsed or refractory CD33-positive adults and older than 2 years of age childhood acute myeloid leukemia (AML).

The FDA approved Mylotarg in 2000 for “the treatment of first-time relapsed CD33-positive AML patients over 60 years of age who are unsuitable for cytotoxic chemotherapy,” but a post-marketing confirmatory phase III study (SWOGS0106) found that the drug was severely lethal In addition, the mortality rate in the combination group was higher than that in the chemotherapy group alone (5.7% vs 1.4%), and there was no apparent survival benefit. Pfizer took the initiative to withdraw Mylotarg from the market in June 2010, and optimized the “dosing regimen”: on the one hand, the toxic and side effects were reduced by reducing the single dose (from 9mg/㎡ to 3mg/㎡), and also Introduce “induction cycles” and “consolidation cycles” into the dosing regimen to ensure efficacy.

The clinical efficacy of Mylotarg has been improved thanks to the adjustment of the dosing regimen:
1) For first-line AML patients, a head-to-head phase III clinical trial of Mylotarg in combination with chemotherapy (daunorubicin and cytarabine) versus chemotherapy alone (daunorubicin and cytarabine) (ALFA-0701 ) data showed that the median event-free survival (mEFS) of patients in the Mylotarg group increased from 9.5 months to 17.3 months, and the risk of events was reduced by 44%.

2) For AML patients who have experienced one relapse, data from the MyloFrance-1 trial show that Mylotarg monotherapy can achieve a complete response rate (CR) of 26% of patients, and the median duration of response (mRFS) for all patients is 11.6 months . The twists and turns of Mylotarg highlight the importance of the “dosing regimen”. Currently, a trend in the design of ADCs is that the design of drug loading is becoming more and more toxic, but high toxicity is a double-edged sword, and the lessons of Mylotarg need to be learned. In short, Mylotarg has regained its strength after experiencing the market withdrawal storm, and it has pushed the AML indication from the original back-line drug to the first-line drug, accumulating valuable experience for the latecomers.

2. Roche: T-DM1 cements its dominance in breast cancer

Kadcyla (T-DM1, trastuzumab emmet) is a HER2 ADC drug developed by Roche. It is composed of HER2-targeting trastuzumab and the chemotherapeutic drug maytansine (DM1) that inhibits microtubule aggregation through non-cleavable The thioether linker MCC is connected, DAR=3.5, and there is no “bystander effect”.

T-DM1 is the world’s first ADC approved for use in solid tumors (breast cancer), and the FDA-approved indications include “adjuvant therapy for HER2-positive early breast cancer” and “adjuvant therapy for HER2-positive metastatic breast cancer” Second-line treatment”, but it did not achieve the expected effect in gastric cancer and NSCLC as in breast cancer, T-DM1 became the first ADC drug approved for marketing in mainland China in January 2020.

1) Adjuvant therapy for HER2-positive early breast cancer
For patients with HER2-positive breast cancer with residual infiltrating tumor cells after taxane and trastuzumab treatment, the results of a head-to-head trial of T-DM1 and trastuzumab (KATHERINE) showed that: T-DM1 arm The 3-year invasive tumor recurrence-free survival (iDFS) was significantly higher than the control group treated with trastuzumab alone (88.3% vs 77%, HR0.5, 95%CI0.39-0.64; P

2) Second-line therapy for HER2-positive locally advanced or metastatic breast cancer
Patients with locally advanced or metastatic HER2-positive breast cancer who have progressed after trastuzumab or taxane monotherapy or a combination of both, T-DM1 monotherapy and chemotherapy combined “lapatinib + cape The results of the head-to-head Phase III clinical trial (EMILIA) of Tabine showed that the median overall survival (mOS) of the two was 30.9 months vs. 25.1 months; the median progression-free survival (mPFS) was 9.6 months vs. 6 months. 4 months; objective response rate (ORR) 43.6% VS 30.8%; median duration of response (mDOR) 12.6 months VS 6.5 months, it can be said that T-DM1 beats chemotherapy combination therapy. Based on this trial, the FDA approved T-DM1 for the second-line treatment of HER2-positive metastatic breast cancer. Since then, T-DM1 has become the standard therapy for this indication. It is currently the world’s best-selling ADC drug, with global sales of $2.178 billion in 2021. T-DM1, together with trastuzumab and pertuzumab, completed the full range of HER2-positive breast cancer from “preoperative neoadjuvant therapy”, “postoperative adjuvant therapy” to “first- and second-line therapy for advanced metastatic disease” The treatment coverage has established Roche’s dominance in the field of breast cancer.

3. Seagen: Adcetris sets new benchmark in CD30-positive lymphoma treatment

Adcetris (Brentuximabvedotin, Velbutuximab) is composed of a human-mouse chimeric monoclonal antibody Brentuximab targeting CD30, a cleavable citrulline-valine dipeptide linker and a microtubule inhibitor MMAE, DAR is 4, and the molecular weight is 153 kDa.

As the most successfully commercialized ADC drug in the field of hematology (with global sales of US$1.306 billion in 2021, ranking second in the global ADC drug field). At present, Adcetris has been approved for six indications worldwide, mainly focusing on three cancer types: systemic anaplastic large cell lymphoma (sALCL), peripheral T-cell lymphoma (PTCL), and classic Hodgkin lymphoma (cHL). , focusing on these three cancer types, we have successfully moved from the back-line to the front-line, setting a benchmark for the first-line treatment of CD30 lymphoma.

1) First-line therapy for CD30-positive classical Hodgkin lymphoma (cHL)
Before Adcetris, the standard first-line treatment for CD30-positive classical Hodgkin lymphoma was the chemotherapy combination ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine). The results of ECHELON-1, a head-to-head randomized, open-label, multicenter phase 3 study of Adcetris previously combined with AVD (doxorubicin + vinblastine + dacarbazine) and chemotherapy combined with ABVD in the first-line treatment of advanced classical Hodgkin lymphoma (cHL) showed: With a median follow-up of 24.6 months, the primary endpoint analysis showed that the 2-year revised PFS rates as assessed by independent review committees in the Adcetris+AVD and ABVD groups were 82.1% and 77.2%, respectively, with the former reducing the risk of death or disease progression by 23%, the study said. The 2-year revised PFS rates were 81.0% and 74.4%, respectively, with the former reducing the risk of death or disease progression by 28%. Secondary endpoint analysis showed that, in Adcetris+AVD group VSABVD group, complete response rate (CR) was 73% vs 70%, 3% (95% CI: 2.3-8.4) objective response rate (ORR) was 86% vs 83%, respectively, 3.2% (95% CI: 2.2-8.6). The safety analysis showed that the safety of the Adcetris + AVD group was generally consistent with the known safety of the single drug. Based on the trial, the FDA approved Adcetris as a first-line treatment for classical Hodgkin lymphoma, ending more than 40 years of no new treatment options in the field.

2) First-line therapy for CD30-positive peripheral T-cell lymphoma (PTCL)
In the first-line treatment of peripheral T-cell lymphoma (PTCL), Adcetris combined with chemotherapy regimen CHP (cyclophosphamide + doxorubicin + prednisone) and the recognized first-line standard treatment regimen for PTCL CHOP (cyclophosphamide) The results of a head-to-head randomized, double-blind, international multi-center, phase III study of doxorubicin + vincristine + prednisone) showed that: with a median follow-up of 36.2 months, compared with standard first-line chemotherapy CHOP, Adcetris + CHP The treatment group can prolong the median progression-free survival (mPFS) of patients from 20.8 months to 48.2 months, reduce the risk of disease progression by 29%, increase the 3-year progression-free survival (mPFS) from 44.4% to 57.1%, and die With a 34% risk reduction, Adcetris in combination with chemotherapy regimen CHP sets a new benchmark in PTCL treatment.

4. AstraZeneca/Daichi Sankyo: DS-8201 beats the pack

Euhertu (T-DXd; DS-8201) was constructed from the humanized HER2 monoclonal antibody trastuzumab coupled to a topoisomerase I inhibitor camptothecin derivative (DXd) via a cleavable polypeptide linker , with a DAR of 8. Trastuzumab binds to the target HER2 on the surface of tumor cells and enters into tumor cells through endocytosis mediated by it. After entering the fusion medium, the polypeptide linker is cleaved, and the drug-loaded DXd is released to inhibit the activity of topoisomerase I. This leads to DNA damage and apoptosis.

1) Post-line therapy for HER2-positive breast cancer (≥3rd line, DESTINY-Breast01 trial)
The open-label, single-arm, multicenter phase II clinical study DESTINY-Breast01 showed that 184 patients with HER2-positive breast cancer had been treated with two or more treatment regimens (median number of treatment lines was 6), and received DS- 820 After 15.4 mg/kg treatment, the median follow-up was 11.1 months, and the objective response rate (ORR) was 60.9% (n=111); 4.3% (n=8) of patients achieved a complete response rate (CR); 56% (n=103) patients achieved a local response (PR) with a median duration of response (mDOR) of 14.8 months and a median progression-free survival (mPFS) of 16.4 months. These patients had previously received T-DM1 therapy, and the median number of treatment lines was 6, which almost exhausted the treatment options for HER2-positive breast cancer, but still achieved dazzling clinical data, showing its huge clinical value. In terms of safety, the incidence of interstitial lung disease/pneumonitis (ILD) is 9%, of which 2.6% is fatal, and ILD and embryotoxicity are listed by the FDA as a black box warning. Based on this experiment, in December 2019, the FDA approved DS-8201 for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more HER2-targeted therapies.

2) Post-line therapy for HER2-positive metastatic gastric or gastroesophageal junction adenocarcinoma (≥3rd line, DESTINY-Gastric01 trial)
The open-label, multicenter, randomized DESTINY-Gastric01 study showed that in patients with HER2-positive gastric or gastroesophageal junction adenocarcinoma who had received at least second-line therapy (including trastuzumab), DS-8201 compared with control chemotherapy , objective response rate (ORR) (51.3% vs 14.3%), disease control rate (DCR) 85.7% vs 62.5%; median overall survival (mOS) 12.5 vs 8.9 months, 41% lower risk of death, 12-month OS rate: 52.2% vs 29.7%; median progression-free survival (mPFS) 5.6 vs 3.5 months, with a 53% reduction in the risk of disease progression. T-DXd-related interstitial lung disease (ILD; 13 grade 1/2, 2 grade 3, 1 grade 4, none grade 5) occurred in 16 patients (12.8%) but not in the chemotherapy group.

3) Second-line therapy for HER2-positive metastatic breast cancer (DESTINY-Breast03 trial)
DESTINY-Breast03, a randomized, open-label, head-to-head, phase III trial of DS-8201 and T-DM1 in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane Efficacy and safety in. The results showed that among the 524 randomized patients, the 12-month progression-free survival rates of the DS-8201 group and the T-DM1 group were 75.8% and 34.1%, respectively. At 12 months, overall survival was 94.1% and 85.9% in the DS-8201 and T-DM1 groups, respectively. The confirmed objective response rate (ORR) was 79.7% in the DS-8201 arm and 34.2% in the T-DM1 arm.

The confirmed objective response rate (ORR) was 79.7% for DS-8201 and 34.2% for T-DM1. Among patients who responded to DS-8201, 16.1% achieved complete remission (CR), 63.6% achieved partial remission (PR), 16.9% had stable disease (SD), and 1.1% had progressive disease (PD). The disease control rate (DCR) of the investigation and control groups were 96.6% and 76.8%, respectively.

Based on this trial, the FDA approved DS-8201 in May 2022 for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received prior anti-HER2 regimens. It can be said that DS-8201 completely disintegrates the status of T-DM1 as the standard therapy for second-line breast cancer treatment. The 2022 version of NCCN guidelines targets second-line systemic therapy for HER2-positive, recurrent unresectable (local or regional) or stage IV (M1) disease The recommended level of DS-8201 is already higher than T-DM1. In 2022, the National Breast Cancer Conference and the Chinese Society of Clinical Oncology Breast Cancer (CSCOBC) annual meeting added DS-8201 as a treatment for patients with breast cancer who failed trastuzumab. Class II recommendation for treatment, highest level of evidence 1A. Looking back, we can see that DS-8201 has a higher DAR than T-DM1, and the drug loading is not only more toxic, but also more uniform, which is an important reason for its victory.

4) Late-line therapy for HER2-mutated non-small cell lung cancer (≥3rd line, DESTINY-Lung01 trial)
The open-label, multicenter Phase II clinical trial (DESTINY-Lung01) study showed that for patients with metastatic HER2-mutant NSCLC who did not respond to standard therapy (median 2 prior therapy), as of May 2021, the median At 13.1 months of follow-up, the 91 patients treated with Enhertu had an independent review committee-confirmed objective response rate (ORR) of 55% (95% CI, 44-6

5), the disease control rate (DCR) was 92% (95%CI, 85-97), the median duration of response (mDOR) was 9.3 months (95%CI, 5.7-14.7), and the median progression-free survival was (mPFS) was 8.2 months (95%CI, 6.0-11.9) and median overall survival (mOS) was 17.8 months (95%CI, 13.8-22.1). DS-8201 showed durable antitumor activity in patients with advanced HER2-mutated NSCLC, with a safety profile largely consistent with previous studies. Drug-related adverse events of grade 3 or higher occurred in 49% of patients, with the most common event being neutropenia (19%). Drug-related interstitial lung disease occurred in 26% of patients and resulted in 2 deaths.

DS-8201 has now received FDA Breakthrough Therapy Designation for the treatment of patients with metastatic NSCLC harboring a HER2 mutation who have progressed during or after platinum-based therapy. In addition, DS-8201 is exploring the combination of immunotherapy such as anti-PD-1 antibody on the one hand, and is also expanding its indications on the other hand. Currently in clinical trials in colorectal cancer, triple-negative breast cancer, bladder cancer and other cancers, the strong clinical efficacy and expanding indications make DS-8201 out of the limelight for a while, which is why NatureReviewsDrugDiscovery predicts that the drug will In 2026, global sales will reach US$6.2 billion, accounting for nearly 40% of the world’s first 10 ADC drugs. In the Chinese market, in December 2020, DS-8201 was granted a breakthrough therapy designation by CDE. It is a single drug for HER2-positive locally advanced or metastatic gastric or esophagogastric junction (EGJ) patients who have received one or more previous treatment regimens. GEJ) Treatment of adult patients with adenocarcinoma. On March 21 this year, the domestic listing application of DS-8201 was accepted by NMPA.

5. Gilead: Trodelvy is the world's first approved ADC for TROP-2

The original research company of Trodelvy (Sacituzumabgovitecan, Goxatuzumab) is Immunomedics, which was acquired by Gilead for $21 billion. The drug consists of a humanized IgG1 antibody targeting the TROP-2 antigen through a cleavable linker and drug loading It is the only ADC drug targeting TROP-2 in the world.

1) Post-line treatment for triple-negative breast cancer (≥ third-line, ASCENT trial)
ASCENT, a global, open-label, randomized phase III trial, compared Trodelvy with chemotherapy single agents (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer Efficacy and safety. The median progression-free survival (mPFS) in the Trodelvy group was 57% lower than that in the chemotherapy group, 4.8 months vs 1.7 months, and the median overall survival (mOS) was 11.8 months vs. 6.9 months. Death The risk of progression was reduced by 49%, and the objective response rate (ORR) was 31% vs 4%.

Based on the results of the ASCENT trial, Trodelvy was approved by the FDA in April 2020 for the treatment of adult patients with metastatic triple-negative breast cancer (TNBC) who have received at least 2 prior therapies. It is also the first FDA-approved treatment for metastatic triple-negative breast cancer. The patient’s antibody-drug conjugate targeting TROP-2 provides a new treatment option for TNBC patients.

2) Later-line therapy for urothelial carcinoma (≥second-line, TROPHY-U-01 trial)
The results of the multi-cohort, open-label, phase II registration study IMMU-132-06 show that Trodelvy is aimed at patients with locally advanced or metastatic urothelial carcinoma who have received platinum-containing chemotherapy combined with PD-1 inhibitors or PD-L1 inhibitors. At 9.1 months of follow-up, the objective response rate (ORR) was 27% (95% CI, 19.5 to 36.6), and the median duration of response (mDOR) was 7.2 months (95% CI, 4.7-8.6 months) , the median progression-free survival (mPFS) was 5.4 months (95% CI, 3.5-7.2 months), and the median overall survival (mOS) was 10.9 months (95% CI, 9.0-13.8 months).

Based on the TROPHY-U-01 trial, in April 2021, Trodelvy was granted accelerated approval by the FDA for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma treated with platinum-based chemotherapy in combination with PD-1 inhibitors or PD-L1 inhibitors. On March 7, 2022, Gilead announced the clinical phase 3 TROPiCS-02 study of Trodelvy in HR+/HER2- metastatic breast cancer patients who had previously received endocrine therapy, CDK4/6 inhibitor, 2 to 4 line chemotherapy regimens ( NCT03901339) Results: The study met its primary endpoint with a statistically significant improvement in progression-free survival (PFS) in the Trodelvy-treated arm compared to the chemotherapy arm. The primary endpoint results are consistent with those observed in the Phase 1/2 IMMU-132-01 study, and the safety results are also consistent with previous studies. Detailed clinical data will be announced at a follow-up academic meeting. The TROP-2 antigen targeted by Trodelvy is abundantly expressed in a variety of tumor cells (such as breast cancer, cervical cancer, colorectal cancer, kidney cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer, etc.). These solid tumors have therapeutic potential. At present, Trodelvy has carried out a number of clinical trials for metastatic non-small cell lung cancer and other solid tumors, either as a single drug or in combination with anti-PD-1 monoclonal antibody and other drugs, and there is great room for imagination in the future.