Prof. Zhitao Ying: Research Progress of Antibody-Drug Conjugates in the Field of Hematology and Oncology 2021 China Oncology Congress

From 1910, when German immunologist Paul Ehrlich first proposed the idea of ​​antibody-drug conjugates (ADCs), to the 100 years since many ADC drugs have been approved and marketed, ADC drugs have played a pivotal role in the field of hematological tumors
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Compared with traditional cytotoxic drugs, the cytotoxic drug components of ADC drugs are combined with monoclonal antibodies through linkers, which improves the tumor specificity of ADC drugs and reduces their toxicity to normal tissue cells
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Furthermore, ADC drugs can deliver targeted and sufficient drugs to tumor cells expressing the corresponding antigen, thereby expanding the therapeutic window
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So, what is the current progress of clinical trials of ADC drugs? At the 2021 China Conference on Oncology (CCO) held online from April 14 to 17, 2022, Professor Ying Zhitao gave the title of "Research Progress of Antibody-Drug Conjugates in the Field of Hematology and Tumors", focusing on several types of Results and progress of clinical trials of ADC drugs
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Brentuximab vedotin (Brentuximab vedotin, BV) is an ADC drug of CD30 monoclonal antibody combined with a cytotoxic drug, methyl auristatin E (MMAE)
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The drug can bind to Hodgkin's lymphoma (HL) RS cells expressing CD30, release MMAE under the action of lysosomal proteases, and promote the death of RS cells
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Important clinical studies of BV approved by the FDA include SG35-0003 single-arm study, SG35-0004 single-arm study, ECHELON-1 study and ECHELON-2 study, etc.
The above studies have proved that BV can improve the remission of patients with various types of lymphoma rate and survival time
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In addition, the safety analysis showed that the most common adverse reactions in BV treatment were peripheral neuropathy, nausea, fatigue, diarrhea, and neutropenia, of which the most common grade ≥ 3 adverse event was neutropenia
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Prof.
Zhitao Ying then introduced the results of BV-related clinical trials in recent years
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The 63rd American Society of Hematology (ASH) in 2021 reported the results of a study of 718 patients with relapsed/refractory classical Hodgkin lymphoma (R/R cHL), comparing the salvage chemotherapy group alone, BV combined with salvage chemotherapy.
Chemotherapy can significantly improve the overall survival (OS) and progression-free survival (PFS) of patients; in addition, the 2021 ASH conference also announced another BV combined with CHEP regimen followed by BV consolidation in the treatment of patients with peripheral T-cell lymphoma (PTCL) As a result of efficacy, the patient objective response rate (ORR) was 91%, and the 18-month PFS rate and OS rate were 61% and 89%, respectively.
For safety results, adverse events of grade ≥3 were hematological toxic events: Neutral Neutropenia (37.
5%), febrile neutropenia (23%), lymphopenia (21%), anemia (19%) and thrombocytopenia (19%)
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In addition to HL and PTCL, BV-related clinical studies have also progressed in primary mediastinal large B-cell lymphoma (PMBCL)
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At the 16th International Conference on Malignant Lymphoma (ICML), the check-mate 436 study published the results of BV combined with nivolumab in patients with R/R PMBCL, with a CR rate of 37% and a follow-up of 33.
7 months , the median PFS reached 26 months, the PFS rate was 56% at 12 and 24 months, the median OS was not reached, the 12-month OS rate was 79%, and the 24-month OS rate was 76%
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Professor Ying Zhitao concluded that the above clinical trial results showed that BV can achieve good efficacy in patients with cHL, PTCL and PMBCL, and no special adverse events were reported; adverse events of grade ≥ 3 were hematological toxic events, which were Situations that cannot be avoided after the application of cytotoxic pharmaceutical ingredients
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Prof.
Zhitao Ying finally introduced the ongoing clinical studies related to BV, including the SGN35-032 study, the PACIFIC study, the ECHELON-3 study and the SGN35-027 study
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Currently, clinicians have doubts about the efficacy of BV in lymphoma patients with low CD30 expression
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Therefore, for the SGN35-032 study, Professor Zhitao Ying emphasized that this study explored the efficacy of BV combined with CHP regimen in the treatment of PTCL patients with CD30 expression below 10%.
reaction situation
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Polatuzumab Vedotin Polatuzumab Vedotin (Pola) is an ADC drug that combines CD79 mAb with MMAE
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The drug can bind to B cells expressing CD79, release MMAE under the action of lysosomal protease, and kill B cells expressing CD79
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An important registration study for Pola to receive FDA approval is the GO29365 study, which revealed Pola + bendamustine + rituximab (Pola + BR) in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) patients with better efficacy and safety
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In 2022, the journal Blood Advances published further follow-up data from the GO29365 study.
As of July 2020, the 2-year PFS rate of patients in the Pola+BR group was 28.
4%, and the 2-year OS rate was 38.
2%
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In the safety analysis, the incidence of peripheral neuropathy was high, reaching 31.
1%, but only 2% of grade ≥3 peripheral neuropathy
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From the results of further follow-up in 2022, R/R DLBCL patients can show durable benefits after receiving the Pola+BR regimen, and no special adverse events have been reported
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Professor Ying Zhitao then introduced the research results of Pola-related clinical trials in recent years
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In 2021, the Chinese Medical Journal published the results of a domestic clinical study of the Pola+BR regimen for R/R DLBCL patients.
Many domestic clinical hospitals participated in the study, including Henan Cancer Hospital and Jiangsu Cancer Hospital
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The results of this study showed that the CR and partial remission (PR) rate of patients could reach 80.
9%, and the most common adverse events were hematological toxicity events and peripheral neuropathy
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In 2022, the New England Journal published the results of the POLARIX study, which compared the efficacy of the Pola-R-CHP and R-CHOP regimens in treatment-naïve DLBCL patients, and showed that the Pola-R-CHP regimen compared with the R-CHOP regimen It can significantly improve the PFS of patients.
At 24 months, the PFS rate was 76.
7% in the Pola-R-CHP group and 70.
2% in the R-CHOP group.
There were no special adverse events between the two groups
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The 2021 American Society of Clinical Oncology (ASCO) announced the results of Pola combined with lenalidomide and rituximab (Pola+R2) in the treatment of R/R DLBCL patients.
The ORR reached 39% and the CR rate reached 29%
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At the 2021 ASH conference, some research data of the bispecific antibody Glofitamab combined with Pola for R/R DLBCL patients were announced.
Among 42 patients who were evaluable for efficacy and did not stop treatment, the CR+PR rate could reach 79.
6%, and the CR rate was 79.
6%.
The rate reached 51%; for adverse events, Cytokine Release Syndrome (CRS) occurred in 42.
4% of patients, only 1 patient with Grade ≥3 CRS, and 1 patient developed Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
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In addition, the 2021 ASH conference also released the clinical study results of the bispecific antibody Mosunetuzumab combined with Pola in patients with newly diagnosed DLBCL and follicular lymphoma (FL).
The ORR was 65% and the CR rate was 48.
3%; for adverse events , the incidence of CRS was 17.
5%, no CRS events of grade ≥ 3, and 2 cases of ICANS of grade ≥ 3 occurred
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Professor Ying Zhitao concluded that the above trial results showed that Pola, whether combined with BR or R-CHP, showed significant efficacy in R/R DLBCL patients, and no special adverse events occurred; in addition, bispecific antibody combined with Pola has shown good efficacy and safety in DLBCL patients.
Although CRS and ICANS occur, the incidence and grade are lower compared with CAR-T cell therapy
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Loncastuxima TesirineLoncastuxima Tesirine (Lonca) is an ADC drug of CD19 monoclonal antibody combined with cytotoxic drug-pyrrolobenzodiazepine (PBD)
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The main registration study for which the drug was approved by the FDA was the LOTIS-2 study, which evaluated the efficacy and safety of single-agent Lonca in patients with R/R DLBCL who received ≥2 lines of therapy.
The results showed that the ORR of the patients was 48.
3%, and the CR rate was was 24%, duration of response (DOR) was 10.
3 months, median PFS was 4.
9 months, median OS was 9.
9 months, and no specific adverse events were reported
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At the 2021 ASCO meeting, updated data from the LOTIS-2 study showed that in different subgroup analyses, Lonca was able to provide a sustained survival benefit for R/R DLBCL patients with ≥2 lines of therapy
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At the 63rd ASH Congress, the interim analysis results of the LOTIS-3 study were announced, which evaluated the efficacy and safety of Lonca combined with ibrutinib in the treatment of patients with R/R DLBCL.
The results showed that the ORR of the patients was 57.
1%, and the CR rate was was 34.
3%, and no special adverse events were reported
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Prof.
Zhitao Ying concluded that Lonca was approved by the FDA in 2021, and most of the drug's clinical trials are underway, such as the LOTIS-5 study
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From the LOTIS-2 and LOTIS-3 studies, we can see that Lonca has shown encouraging anti-tumor activity and manageable safety for R/R DLCBL patients, and we hope that future studies can use the drug clinically , to provide further data support
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Summary In the therapeutic exploration of hematological malignancies, ADC drugs are the third hot field after cellular immunotherapy and bispecific antibodies
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ADC drugs alone or in combination with traditional chemotherapy have brought new hope to patients with lymphoma, myeloma and leukemia
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In addition, including ADC drugs combined with bispecific antibodies, new ADC drug combinations are also being actively explored, which is expected to provide further data support for the clinical application of ADC drugs
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Expert Profile Prof.
Zhitao Ying, MD, Chief Physician, Peking University Cancer Hospital, Youth Committee Member, Hematology and Tumor Committee, China Anti-Cancer Association, Youth Committee Member, Chinese Geriatric Hematological Lymphoma Group, Chinese Medical Association Oncology Branch, Youth Committee Member, Chinese Society of Clinical Oncology (CSCO) Committee Member Member of the Professional Committee of Drug Clinical Research and Evaluation of China Elderly Health Care Association Graduated from Peking University School of Medicine in 2009 with a doctorate in oncology.
Started working in the Lymphoma Department of Peking University Cancer Hospital in 2009.
The main research direction is the standardized diagnosis and treatment of lymphoma Revision: Quinta Typesetting: XY Execution: XY