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ADC药物竞争激烈？以HER2靶向ADC药物为例，看不同ADC药物的结构和数据差异。
近年来，新一代ADC药物的问世成为乳腺癌抗HER2治疗的突破，掀起抗肿瘤ADC药物的开发浪潮。 For a time, the research and development of ADC drugs was very popular, and many ADC drugs were in full swing. How to stand out became a hot topic. The key is still how to provide better efficacy and better safety for the clinical practice with unique drug design and innovative mechanisms of action. This paper sorts out the latest research progress of several domestic and foreign HER2-targeted ADC drugs such as DS-8201, T-DM1, SYD985, RC48, ARX788, MRG002, A166, etc. in the field of HER2-positive advanced breast cancer, and analyzes the differences in the efficacy of these different ADC drugs and the key differences in the structure of related ADC drugs.
HER2 targeted ADC drugs are fiercely competitive
clinical efficacy varies greatly
Breast cancer treatment has always been a pioneer field of innovative therapies, and ADC drugs are no exception. The first solid tumor ADC drug is used to treat breast cancer. As a classic tumor target, HER2 is highly expressed in tumor tissues and has less normal tissue expression. Moreover, HER2 can efficiently mediate the endocytosis of ADC drugs, so it is also an ideal target for ADC drug development. The ADC drug targeted by HER2 can be traced back many years ago. The first product to be launched was T-DM1. There are new ADC drugs in the future. The second one to be launched is the famous DS-8201. With the great success of DS-8201, the development of HER2-targeted ADC drugs has entered a new era of competition. However, how to distinguish these ADC drugs with the same targets and whether they still have clinical application value is increasingly questioned.
T-DM1 kicked off the prelude to ADC drugs for breast cancer, but the advanced second-line treatment of PFS is still less than 1 year
T-DM1 is the first ADC drug approved for HER2-positive advanced breast cancer indication. In its Phase III clinical study EMILIA[2], for HER2-positive advanced breast cancer patients who have received trastuzumab and paclitaxel , the median PFS in the T-DM1 group was 9.6 months, which was statistically different compared with the 6.4 months in the lapatinib + capecitabine group.同时，T-DM1 组中位OS为30.9个月，显著长于拉帕替尼+卡培他滨组的25.1个月。两组的ORR分别为43.6%和30.8%，缓解持续时间（DOR）分别为12.6和6.5个月。 The TH3RESA study [3] is a phase III clinical study of T-DM1 applied to post-stage treatment of HER2-positive breast cancer. Compared with the commonly used clinical options, both the median PFS (6.2 months and 3.3 months) and the median OS (22.7 months and 15.8 months) of T-DM1 were significantly extended.总体而言，虽然T-DM1在HER2阳性乳腺癌治疗领域有先发之势，但其晚期治疗获益仍有较大提升空间。
Figure 1. PFS results in EMILIA and TH3RESA studies. The
T-DM1 group was 9.6 and 6.2 months, respectively,
DS-8201 set off a new generation of ADC drugs. It broke through history from the back line to the second line
0 From the current global ADC research progress, DS-8201 is undoubtedly the leader. In the key research exploration of DS-8201, based on the initial treatment benefits of DS-8201 in breast cancer in the DS8201-A-J101 study, the researchers further carried out an open-label, multi-center, two-part phase II study DESTINY-Breast01 (DB01)[4]. Its results have been unveiled at the International Oncology Conference many times and have become the first major research of DS-8201 published in the New England Journal of Medicine (NEJM). 2021年ESMO大会公布的DB01最终数据显示[5]，针对既往平均接受过6线治疗的患者，DS-8201的客观缓解率（ORR）高达62.0%，中位PFS长达 19.4 个月，中位OS长达29.1个月。由于惊艳的疗效，FDA在2019年即批准了DS-8201用于HER2阳性晚期乳腺癌的三线及三线以后的治疗。
Figure 2. Final data of DB01 study:
ORR 62%, median PFS 19.4 months, median OS 29.1 months
DESTINY-Breast03 (DB03) study provides solid evidence for the advancement of the treatment line number of DS-8201. As a head-to-head comparison between the first ADC drugs, DS-8201 successfully challenged the existing second-line treatment standard T-DM1, becoming the new second-line treatment standard.The 2021 ESMO Conference released the DB03 blockbuster data with the first breakthrough summary (LBA1), and was subsequently published in NEJM in full. The results of the study showed that [6], PFS evaluated by the Blind Independent Center Review Committee (BICR), the median values of the two groups did not reach and 6.8 months respectively, and the risk of disease progression or death was reduced by 72%; the PFS evaluated by the investigator, the DS-8201 group lasted 25.1 months, while the T-DM1 group was only 7.2 months, and the risk of disease progression or death was reduced by 74%. Key subgroup analysis of PFS showed that regardless of hormone receptor status (HR+/HR-), whether the previous treatment with pertuzumab and , and whether visceral metastasis was performed, the DS-8201 group had significant benefits in PFS consistent with the overall population. In terms of OS, due to insufficient follow-up time, the two groups have not shown statistical differences, but DS-8201 has a clear trend of benefit from the survival curve. In addition, the disease control effect in the DS-8201 group was more significant, with an ORR of up to 79.7%, while the T-DM1 group was only 34.2%.
Figure 3. PFS evaluated by BICR in DB03 study, DS-8201 group has not yet reached the median value, T-DM1 group is 6.8 months
Figure 4. ORRs of the two groups in DB03 study: DS-8201 group 79.8%, and T-DM1 group 34.2%
With its outstanding performance in DB03 study, DS-8201 broke the previous treatment pattern of HER2-positive advanced breast cancer and became a new second-line standard treatment option. It is also worth stressing that 59% of Asian patients (Chinese patients account for about half of Asian patients) were included in the DB03 study, and the Asian subgroup patients had consistent benefits with the overall population, which also provides sufficient evidence-based support for the better application of DS-8201 to Chinese breast cancer patients.
other HER2 targeted ADC drugs are catching up. The clinical value requires efficacy data confirms that
ADC drugs have obvious advantages compared to traditional drugs, which has stimulated the R&D enthusiasm of major pharmaceutical companies and has almost become a battleground for military strategists. In addition to T-DM1 and DS-8201, a series of HER2-targeted ADC drugs are constantly emerging at home and abroad.
SYD985 is a research-based HER2-targeted ADC drug developed by Byondis in the United States. In the Phase III study, in TULIP[8], the median PFS in the SYD985 group was significantly longer than the chemotherapy (PC) group selected by doctors (BICR: 7.0 months and 4.9 months, P=0.002; investigator evaluation: 6.9 months and 4.6 months, P0.001), but there was no significant difference in OS, ORR and HRQoL between the two groups. Based on the TULIP study, SYD985 may be a postline treatment option after previous treatment with T-DM1, etc., so the drug has been submitted for marketing in the United States and has obtained the FDA's rapid approval channel qualification.
Figure 5. PFS results in TULIP study (2021ESMO)
RC48 is a HER2-targeted ADC drug developed by the Chinese biopharmaceutical company Rongchang Bio based on the VC linker and MMAE drug-loading technology of Seagen. C001 CANCER and C003 CANCER conducted in China for phase I and phase Ib clinical studies of HER2-positive or HER2-low-expressed advanced breast cancer, respectively (NCT02881138 and NCT 03052634). According to the summary analysis of these two studies released by the 2021 ASCO Annual Meeting, 118 female breast cancer patients were enrolled and received RC48 treatment, including 70 HER2-positive (59.3%) and 48 HER2-low-expressed (40.7%). In the HER2-positive subgroup, the ORRs of the 1.5, 2.0 and 2.5 mg/kg dose groups were 22.2%, 42.9%, and 40.0%, respectively. The median PFS for the 1.5, 2.0 and 2.5 mg/kg cohorts were 4.0 months, 5.7 months, and 6.3 months, respectively. Previous studies have shown that RC48 showed a better benefit risk ratio at a dose of 2.0 mg/kg, so 2.0 mg/kg was used in the ongoing dose of HER2-positive advanced breast cancer.
Figure 6. Summary analysis of efficacy data of RC48 in two phase I studies. For people with HER2-positive advanced breast cancer, the ORR at the dose of 2.0 mg/kg was 42.9%, and the median PFS was 5.7 months
ARX788 is a HER2-targeted ADC drug developed by Ambrx, the United States, and is currently in the clinical phase II/III clinical research stage. Its phase I ACE-Breast-01 clinical study aims to explore the safety, pharmacokinetics and anti-tumor activity of ARX788 on HER2-positive breast cancer. According to the latest published research data, 69 patients were included in [10], with a median treatment line of 4 lines, and the ORR of all enrolled populations during the dose climb was 47.8%.Among the 29 patients receiving 1.5 mg/kg Q3W, the recommended recommended phase II clinical dose, the ORR was 65.5%, the median DOR was 14.4 months and the median PFS was 17.02 months. Currently, the Phase II/III study 9 [11], which evaluates the efficacy and safety of ARX788 compared with lapatinib + capecitabine in patients with HER2-positive advanced breast cancer, is underway.
Figure 7. ACE-Breast-01 study, the overall population ORR was 47.8%, and the 1.5mg/kg dose population ORR was 65.5%
MRG002 is a HER2-targeted ADC drug developed by Meiyake Company, a subsidiary of Lepu Bio. This product is also based on Seagen's VC linker and MMAE drug-loading technology. In 2021, ESMO announced the progress of the Phase I dose climbing trial of MRG002 [12], which is also the first time that MRG002 has appeared at the International Cancer Conference. A total of 25 patients were included in the study (median number of previous treatments was 5), including 19 breast cancer. The results showed that among the 22 patients who received at least one tumor efficacy evaluation, 17 were HER2-positive breast cancer, 9 of which were partial remission (PR), 4 were stable disease (SD), ORR was 53% (9/17), and disease control rate (DCR) was 76% (13/17).
Figure 8. MRG002 Tumor remission in phase I study, ORR is 53%
A166 is a HER2-targeted ADC drug developed by Kelun Botai Biopharma, a subsidiary of Sichuan Kelun, and is currently in the critical phase II clinical research stage. KL166-I-01-CTP (CTR20181301) is a single-arm, open, dose-escalating and dose-expansion phase I study evaluating the efficacy of A166 in patients with locally advanced or metastatic solid tumors expressing HER2. According to the study data [13] released by ASCO in 2022, a total of 58 patients with HER2-positive advanced breast cancer were included, and 100% of them have received anti-HER2 targeted therapy before, with a median treatment line of 4. During the dose amplification phase, the optimal ORRs for the 4.8 and 6.0 mg/kg cohort were 73.91% (17/23) and 68.57% (24/35), respectively, with median PFS of 12.3 months and 9.4 months, respectively.
Figure 9. A166's tumor remission in the Phase I study of the dose amplification stage. The ORR of 4.8 mg/kg dose was 73.91%, and the ORR of 6.0 mg/kg dose was 68.6%
ADC drug structure is complex, Me Better is difficult, and Me Too may not be easy
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0000 comprehensive analysis of the above-mentioned research progress of HER2-positive advanced breast cancer. It can be seen that although both HER2-targeted ADC drugs, their efficacy varies greatly. Although the patients enrolled in different studies are different, numerical, whether it is backline or second-line treatment, DS-8201 is almost the best and has a clear advantage among many ADC drugs. ARX788 also showed good potential in the future, but other drugs are relatively limited in competitiveness.
Figure 10. Research progress of different HER2-targeted ADC drugs in the field of HER2-positive advanced breast cancer
From the research progress, such as RC48, ARX788, MRG002, and A166 are all in the Phase I trial stage. What is their anti-HER2 therapeutic potential? Further phase III clinical studies need to be verified. At the same time, considering that DS-8201 has replaced T-DM1 as the new second-line standard treatment, if these subsequent ADC drugs under development want to occupy a certain position in second-line or front-line treatment, whether to compare head-to-head with DS-8201 may be a key issue. In fact, only DS-8201 is currently compared with T-DM1.
On the other hand, SYD985 and T-DM1 have also shown certain application prospects in post-line treatment research. Studies have confirmed that the sequential use of different ADC drugs seems to have certain efficacy, which has brought important clinical implications for how to formulate effective treatment strategies in the future after the progress of front-line strong ADC drug treatment.
References:
[1] Strebhardt K, Ullrich A. Paul Ehrlich's magic bullet concept: 100 years of progress. Nat Rev Cancer. 2008 Jun;8(6):473-80.
[2] Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2 positive advanced breast cancer. N Engl J Med, 2012, 367(19):1783⁃1791.
[3] Krop IE, Kim SB, Martin AG, et al. Trastuzumab emtansine versus treatment of physical’s choice in patients with previously treated HER2 positive metastatic breast cancer(TH3RESA) :final overall survival results from a
randomised open!label phase 3 trial[J]. Lancet Oncol, 2017, 18(6):743-754.
[4]Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 2020;382:610-21.
[5]Saura C, Modi S, Ian Krop I, et al.Trastuzumab Deruxtecan (T-DXd) in Patients with HER2-Positive Metastatic Breast Cancer: Updated Survival Results from a Phase 2 Trial (DESTINY-Breast01).2021 ESMO. 279P.
[6] Cortés J, Kim SB, Chung WP, et al. DESTINY-Breast03 Trial Investigators. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022 Mar 24;386(12):1143-1154.
[7] Im SA, Xu BH, Kim SB, et al. Trastuzumab Deruxtecan vs T-DM1 in HER2+ mBC in Asian Subgroup: Results of the Randomized Phase 3 Study DESTINY-Breast03. 2022 JSMO. [PS2-1].
[8] C. Saura Manich, et al. Primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physical’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract LBA15. https://christie.openrepository.com/handle/10541/624730?show=full
[9]Wang JY, Liu YJ, Zhang QY, et al. RC48-ADC, a HER2-targeting antibody-drug conjugate, in patients with HER2-positive and HER2-low expressing advanced or metastatic breast cancer: A pooled analysis of two studies. | Journal of Clinical Oncology (ascopubs.org).2021 ASCO. Abstract 1022.
[10] Zhang J, Ji DM, Shen WN,et al. Safety and anti-tumor activity of ARX788 in HER2-positive metastatic breast cancer patients whose disease is resistant/refractory to HER2 targeted agents (trastuzumab, ADCs, TKIs, and bispecific antibodies): ACE-Breast-01 trial results. 2021 SABCS. PD8-04.
[11] Hu XC, Zhang J, Wang LP, et al. Abstract PS10-57: A randomized multicenter, open label phase Ⅱ/Ⅲ study of ARX788 vs lapatinib and capecitabine in patients with HER2 positive locally advanced or metastatic breast cancer(ZMC-ARX788-211)[EB/OL].
[12] Guo Y, Xue J, Peng W, et al. First-in-human, phase I dose escalation and expansion study of anti-HER2 ADC MRG002 in patients with HER2 positive solid tumors. 2021ESMO. 271P.
[13]Hu XC, Zhang J, Liu RJ, et al. Updated results and biomarker analyzes from the phase I trial of A166 in patients with HER2-expressing locally advanced or metastatic solid tumors.2022 ASCO. Abstract 1037.
https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.1037
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