13 Anti-tumor drugs
Trastuzumab deruxtecan (Enhertu), an antibody drug conjugate (ADC) developed by Japan’s Daiichi Sankyo and authorized by AstraZeneca for co-development and commercialization, was approved by the FDA at the end of December 2019 (four months ahead of the PDUFA target date), and would be listed in the first week of 2020. Enhertu contains a humanized anti-HER2 antibody, conjugated to a topoisomerase I inhibitor via a tetrapeptide. It is suitable for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received at least two anti-HER2 regimens in the past. The FDA has accelerated the approval of the drug based on the treatment results (tumor remission rate and remission duration) of 184 patients in the DESTINY-Breast 01 study (NCT03248492). In addition, the FDA has previously granted special review qualifications for the drug’s fast track and breakthrough therapy. Whether more breast cancer indications can continue to be approved will depend on the verification of clinical benefits in confirmatory trials.
Phesgo, developed by Genentech, was approved by the FDA in June 2020 and listed in August for the treatment of HER-2 positive early and metastatic breast cancer patients. The drug is a fixed-dose compound preparation of Pattuzumab (Pertuzumab) and Herceptin (Trastuzumab) and hyaluronidase-zzxf. It is administered by subcutaneous injection and needs to be combined with intravenous chemotherapeutics. The new drug regimen for patients with breast cancer is one of the important progress in this therapeutic area. The initial loading dose of Phesgo takes about 8 minutes, and each administration time during the subsequent maintenance treatment takes about 5 minutes. In contrast, using standard intravenous preparations for sequential infusion of the loading dose of Patjet and Herceptin takes about 150 minutes, and during the subsequent maintenance treatment, the infusion time of the two drugs is 60-150 minutes. In addition, Phesgo can be administered by medical staff in medical institutions, and patients can also self-administer at home.
In 2019, the FDA’s Oncology Center of Excellence (OCE) and drug regulatory agencies in other countries jointly launched the Orbis program. This initiative provides a framework for international partners to submit and review anti-tumor drugs at the same time. The cooperation between international drug regulatory agencies can enable drugs to be approved for marketing faster in countries with slower registration approvals, and allow patients with malignant tumors to receive treatment earlier. Last year, the HER-2 inhibitor tucatinib (Tukysa; Seattle Genetics) was the first drug approved under the framework of the Orbis program. The drug is suitable for use in combination with trastuzumab and capecitabine to treat HER-2 positive breast cancer. The FDA conducted this review jointly with the Medicines Agency of Australia (TGA), Health Canada, the Health Sciences Agency of Singapore (HSA) and Swissmedic (SMC) of Switzerland. Tocatinib is currently awaiting approval from regulatory agencies such as the European Union.
Another anti-HER-2 monoclonal antibody Margetuximab (Margenza; MacroGenics) was approved by the FDA in mid-December 2020, and used in combination with chemotherapy to treat adult patients with HER-2 positive metastatic breast cancer who have previously received at least two anti-HER-2 therapies (at least one of which is used to treat metastatic tumors). Margetuximab is a monoclonal antibody that targets the HER-2 tumor protein and the Fc fragment has been engineered and optimized. Similar to trastuzumab, Margetuximab can inhibit tumor cell proliferation, reduce the shedding of the extracellular domain of HER-2, and mediate antibody-dependent cellular cytotoxicity (ADCC). However, the difference of Margetuximab is that its Fc fragment is engineered through MacroGenics’ Fc optimization technology to enhance the participation of the immune system. The binding force between modified Fc region of Margetuximab and the activated Fc receptor FCGR3A (CD16A) was enhanced, while the binding force between modified Fc region of Margetuximab and the inhibitory Fc receptor FCGR2B (CD32B) was decreased in vitro. These changes led to the enhancement of ADCC and natural killer cell activation ability in vitro. The manufacturer said that Margetuximab would be available in the spring of 2021.
The FDA approved Sacituzumabgovitecan (Trodelvy; Immunomedics) in 2020. The drug is an ADC’s first innovative drug, which contains a monoclonal antibody targeting trophoblast cell surface antigen-2 (TROP-2) and is conjugated with a topoisomerase I inhibitor. TROP-2 is overexpressed on the cell membrane surface of a variety of epithelial tumors such as gastric cancer, prostate cancer, pancreatic cancer, lung cancer and triple negative breast cancer (TNBC).
Sacituzumabgovitecan is eligible for accelerated review based on the objective response rate (ORR) and duration of response (DoR) observed in a single-arm, multicenter, phase II study. The drug is used to treat patients with metastatic TNBC who have previously received at least two therapeutic drugs (for metastatic tumors). The study evaluated 108 adult TNBC patients who had received an average of 3 systemic treatments (for metastatic tumors) in the past. The results showed that the ORR of the Sacituzumabgovitecan group was 33.3%, and the median DoR was 7.7 months. The ADC would be listed within a few days after approval. However, whether it can expand the scope of approval depends on the results of verification of clinical benefits in its confirmatory phase III ASCENT study. Because the study showed convincing evidence of effectiveness at multiple endpoints, the Independent Data and Safety Monitoring Committee terminated the study early.
Relugoli (Orgovyx; Myovant Sciences) is the first and only oral gonadotropin-releasing hormone (GnRH) receptor antagonist, approved in the United States in late December 2020 for the treatment of advanced prostate cancer. The drug was approved by the FDA based on the effectiveness and safety data obtained in a phase III HERO study (NCT03085095) in male patients with advanced prostate cancer after obtaining FDA priority review. The study reached the primary endpoint: 96.7% of male patients in the Relugoli treatment group suppressed testosterone to castrate levels (<50ng/dL) for 48 weeks, while the proportion of the standard treatment group (receiving the current standard treatment drug leuprolide acetate injection) was 88.8%.The new indication for the drug was approved this time. The drug was first launched in Japan in 2019 and is indicated for uterine fibroids.
In March last year, Jiangsu Hansoh Pharma’s Ametinib (Amelox) was approved by China’s NMPA to treat EGFR T790M mutation-positive metastatic non-small cell lung cancer (NSCLC) patients with disease progression during or after receiving other epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy. Ametinib is the second third-generation EGFR TKI approved for the treatment of EGFR T790M-positive metastatic NSCLC patients. This approval provides an efficient and safe treatment plan for patients with advanced NSCLC. The approval of the drug is based on the results of APOLLO clinical studies. The APOLLO study was a multi-center, open-ended, single-arm phase II trial that evaluated the efficacy of ametinib in 244 patients with recurrent NSCLC who carry the EGFR T790M gene mutation. The primary endpoint of the study was the objective response rate (ORR) verified by a blinded independent center review committee review, while the key secondary endpoints include disease control rate (DCR), duration of remission (DoR) and progression-free survival (PFS) as assessed by overall survival (OS). The results of the APOLLO study showed that the ORR of patients with central nervous system (CNS) metastasis was 68.9%, the DCR was 93.4%, the median PFS was 12.3 months, and the ORR was 61.5%. Ameile would be listed in China in April 2020.
NMPA also took the lead in approving the anaplastic lymphoma kinase (ALK) inhibitor Ensatinib Hydrochloride (Bemena). The drug is suitable for second-line treatment of patients with ALK-positive locally advanced or metastatic NSCLC. In NSCLC patients, echinoderms microtubule-associated protein-like-4 (EML4) gene fused with the signal transduction region of ALK gene, resulting in the fusion protein EML4/ALK as a driving factor for tumor formation. Among lung cancer patients (usually non-smokers), 3%-13% of patients have carcinogenic ALK translocations. Ensatinib was jointly developed by Xcovery and Betta Pharmaceuticals, and Betta Pharmaceuticals retains all rights to the drug in the Chinese market. The drug was launched in China in December 2020.
In early 2020, Tepotinib Hydrochloride (Tepmetko; EMDSerono), an inhibitor targeting hepatocyte growth factor receptor (HGFR; MET), was approved in Japan, becoming the first compound targeting this specific target to be marketed in Japan. Tipotinib is an oral active compound designed to inhibit the oncogenic MET receptor signal transduction pathway caused by MET gene mutation. MET gene mutations include MET14 exon skipping mutation and MET amplification, or MET protein overexpression. The drug is suitable for the treatment of patients with unresectable advanced or recurrent NSCLC accompanied by jumping mutations in METex14 exon. About 3%-5% of NSCLC patients carry METex14, which are related to the aggressive behavior and poor prognosis of the tumor. In June 2020, Tibotinib announced its listing.
Capmatinib (Tabrecta; Novartis), the second oral MET inhibitor, received accelerated approval in the United States in May 2020 for the treatment of adult patients with metastatic NSCLC who carry the METex14 jumping mutation (confirmed by a FDA-approved test method). Capmatinib is approved for the first-line treatment of patients who have received previous treatment (regardless of any therapies), and will be marketed immediately after approval.
Selpercatinib (Retevmo; LoxoOncology) is the first innovative drug for a proto-oncogene tyrosine protein kinase receptor Ret (RET; CDHF12; PTC) inhibitor. The drug has received accelerated approval in the United States for the treatment of RET fusion-positive advanced NSCLC, RET mutant medullary thyroid carcinoma (MTC) and RET fusion-positive thyroid cancer. RET (rearrangement during transfection) has been found to be an important driver of certain malignancies, including NSCLC and thyroid cancer. Genomic changes in RET kinase, including fusion and activation point mutations, can lead to overactive RET signal transduction and uncontrolled cell growth. RET fusion was detected in about 2% of NSCLC and 10%-20% of thyroid papillary carcinoma, thyroid Hurthle cell tumor, anaplastic thyroid cancer, and poorly differentiated thyroid cancer. Selpercatinib was listed in the United States shortly after approval.
In September 2020, the second RET inhibitor Praalsetinib (Gavreto; BluePrint Medicines) was approved by the FDA for the treatment of adult patients with metastatic NSCLC who are positive for RET fusion (detected by an FDA-approved test method). This indication is based on the data from the Phase I/II ARROW study (NCT03037385) and was approved through the accelerated review channel of the FDA. Whether this indication can continue to expand its scope of approval will depend on the verification of clinical benefits in confirmatory trials. Pralsetinib is a precision targeted therapy that is taken orally once a day. Its mechanism of action is to selectively target RET gene mutations in various tissues, including fusions and mutations. The drug was jointly commercialized by Genentech in the United States, and was launched almost immediately after approval for the treatment of NSCLC. Later in the same year, the FDA also accelerated its approval for the following indications: adults with advanced or metastatic MTC and children ≥12 years of age who carry RET mutations and require systemic therapy, or adults and children ≥12 years with RET fusion-positive and advanced or metastatic thyroid cancer that require systemic treatment and are refractory to iodine.
Neuroendocrine tumors (NET) occur in cells that interact with the nervous system or glands that secrete hormones. NET can originate in various parts of the body, predominantly in the intestines or lungs, and can be benign or malignant. NET is usually divided into two types: pancreatic neuroendocrine tumor (pNET) or non-pancreatic neuroendocrine tumor (epNET). In late December 2020, the kinase inhibitor Sofatinib (Sutaida; Hutchison Medicine) was approved by China’s NMPA for the treatment of epNET. According to the company, there were an estimated 67,600 newly diagnosed NET patients in China in 2018, and the current number of patients is as many as 300,000. Sofatinib is an oral vascular immunokinase inhibitor that can selectively inhibit the activity of tyrosine kinases related to vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR). This inhibitory effect can inhibit angiogenesis and colony stimulating factor-1 receptor (CSF-1R), which has a regulatory effect on tumor-related macrophages and can enhance the body’s immune response to tumor cells. Hutchison Pharmaceuticals stated that it would plan to launch the drug in more markets as soon as possible.
PharmaMar’s Rubicardine (Zepzelca) received accelerated approval from the FDA in June 2020 for the treatment of small cell lung cancer (SCLC). Rubicatine is an alkylating agent that binds to guanine residues in DNA. This process can trigger a cascade of events, reducing the activity of DNA-binding proteins (including some transcription factors) and damaging DNA repair pathways, leading to cell cycle arrest and ultimately cell death. The drug is used to treat adult patients with metastatic SCLC who have progressed during or after platinum-based chemotherapy. The drug was jointly developed by PharmaMar and its commercialization partner Jazz Pharmaceuticals, and it went on the market almost immediately after approval.
Mitomycin is an antibiotic isolated from Streptomyces capitis. It is activated in the body to produce bifunctional and trifunctional alkylating agents. The drug binds to DNA and can cause cross-linking reactions and inhibit DNA synthesis and function. Since the 1970s, intravesical mitomycin has always been used to treat bladder cancer, and it is still the standard treatment for postoperative chemotherapy for bladder cancer, especially for low-risk patients. In the spring of 2020, the FDA accelerated the approval of a new mitomycin preparation called Jelmyto pyelocalyceal solution for the treatment of low-grade upper urinary tract urothelial carcinoma (LGUTUC) in adults. Jelmyto is composed of mitomycin and sterile hydrogel. It uses UroGenPharma’s proprietary slow-release RTGel technology to extend the exposure time of urinary tract tissues to mitomycin, thereby making non-surgical treatment of tumors possible. After priority review, the drug was approved based on the results of the Phase III trial OLYMPUS study (NCT02793128). The results of this study indicated that Jelmyto has achieved clinically significant lesion eradication in adult patients with low-grade upper urothelial carcinoma (LGUTUC). Data showed that in the intention-to-treat population and the subgroup of patients who were judged to be unsuitable for surgical resection at the time of diagnosis, the complete response (CR) rate (primary endpoint) reached 59%. At the 12-month time point for assessing the durability of remission, 19 patients maintained CR, 7 patients had disease recurrence, and 9 patients continued to be followed up for 12 months to assess the duration of remission. Based on interim data, the 12-month remission persistence rate assessed by the Kaplan-Meier method was 84%. Most adverse events are mild to moderate and can be managed using conventional treatment methods. No treatment-related deaths occurred. Jelmyto was launched in the United States in August 2020 for the treatment of LG UTUC patients.
Avatinib (Ayvakit; BlueprintMedicines) is a potent and selective inhibitor of KIT and PDGFR-α mutant kinases. It was approved for marketing in the United States in early 2020 and was approved by the European Commission later in the same year. This kinase inhibitor is approved in the United States for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) carrying platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutations (including PDGFRAD842V mutations). Its indications approved in the EU are limited to patients with PDGFRA D842V mutation. Avatinib is recognized as an orphan drug in the United States and the European Union, and it has been certified as a breakthrough therapy in the United States.
The second KIT/PDGFRα inhibitor Repetinib (Qinlock; Deciphera) with a dual mechanism of action was approved a few months later and was immediately marketed in the United States. The drug’s approved indication in the United States is the 4-line treatment of gastrointestinal stromal tumors (GIST). After the drug has undergone priority review, it was approved based on the results of the US Oncology Product Real-time Review Program and a randomized, double-blind, placebo-controlled international multicenter study (INVICTUS study, NCT03353753). The study enrolled 129 patients with advanced GIST who had previously received other targeted therapies approved by the FDA (imatinib, sunitinib, and regorafenib). In this study, subjects received repetinib or placebo treatment, once a day, and repeated administration every 28 days until the patient developed disease progression or intolerable side effects. After disease progression, patients who were previously randomized to the placebo group can choose to switch to the study drug. The median PFS of Repetinib was 6.3 months, compared with 1.0 months in the placebo group, so Repetinib significantly reduced the risk of disease progression or death by 85%. In addition, the median OS of Repetinib was 15.1 months compared to 6.6 months in the placebo group, so Repetinib reduced the risk of death by 64% (35). As part of the Orbis program, the FDA, Australia’s TGA and Health Canada conducted a joint review of the application. The FDA granted the drug a series of special review qualifications, including orphan drug, fast-track and breakthrough therapy qualifications.
Cholangiocarcinoma is a rare malignant tumor that occurs in the bile duct. According to the anatomical origin, the disease can be divided into two types: intrahepatic cholangiocarcinoma (iCCA) that occurs in the intrahepatic bile duct and extrahepatic cholangiocarcinoma that occurs in the extrahepatic bile duct. In North America and Europe, the incidence of cholangiocarcinoma varies in different regions, ranging from 0.3-3.4/100,000. In April last year, the U.S. FDA approved Incyte’s Pemitinib (Pemazyre), which is a fibroblast growth factor receptor (FGFR)-1, -2, and -3 inhibitor. It is suitable for the treatment of unresectable locally advanced or metastatic cholangiocarcinoma adult patients with FGFR2 fusion or other rearrangement (detected by a detection method approved by the FDA) who have previously received treatment. FGFR2 fusion or rearrangement occurs almost exclusively in iCCA patients, and the incidence in such patients is 10%-16%. Pemitinib is the first and only FDA-approved therapeutic drug for this indication. The approval of the drug was based on ORR and DoR data, and was approved after obtaining the qualification for accelerated approval. Whether the drug can continue to expand its scope of approval will depend on the verification of clinical benefits in confirmatory trials. The drug was granted Orphan Drug, Priority Review and Breakthrough Therapy qualifications, and went on the market immediately after approval.
Boron neutron capture therapy (BNCT) is a specific type of tumor radiotherapy method. Its treatment principle is to use a neutron beam to irradiate the stable isotope boron 10 (10B) to produce high-energy alpha particles and recoil lithium-7 nuclei, thereby capturing neutrons and causing a fission reaction to destroy cancer cells. Due to the extremely short range of alpha particles (5-9 mcm), its destructive effect is limited to boron-containing tumor cells, and it is expected to have almost no effect on key normal tissues adjacent to the tumor. Research on BNCT has been conducted for decades, especially in the application of head and neck cancer and brain tumors (36). Borofalan (10B) (p-dihydroxyboranophenylalanine) is a boron-containing drug developed by Osaka Prefecture University and Stella Pharma using Stella’s boron isotope enrichment technology. In 2020, Borofalan (10B) (Steboronine; Stella Pharma) was approved to be marketed in Japan for the treatment of unresectable, recurrent local or advanced head and neck cancer, making it the world’s first BNCT to be marketed for any indication. Borofalan (10B) was awarded Sakigake qualification in Japan.
Cetuximabs arotalocan (Akalux; RakutenMedical) is an antibody-drug conjugate consisting of the EGFR-targeting antibody cetuximab and the phthalocyanine dye IRDye 700DX. Cetuximab sarotalocan (also known as ASP-1929) can bind to the epidermal growth factor receptor expressed in many types of solid tumors, including head and neck cancer, esophageal cancer, lung cancer, colon cancer, and pancreatic cancer. After ASP-1929 is combined with tumor cells, a non-caloric red light (690nm) emitted by an experimental infrared laser is used to irradiate local lesions to activate the pharmacological activity of ASP-1929. This product was approved in Japan in September 2020 for the treatment of unresectable locally advanced or recurrent head and neck cancer. Akalux was certified by Sakigake in April 2019. The company submitted an application for approval in accordance with the conditional advance approval system of the Japanese regulatory agency.
The anti-PD-1 monoclonal antibody Prolgolimab (Forteca; Biocad) was approved in Russia last year for the treatment of metastatic or unresectable melanoma, making it the first domestically developed PD-1 inhibitor to receive regulatory approval in the country.
In November, the FDA approved the marketing application of the anti-GD2 monoclonal antibody Naxitamab (Danyelza; Y-mAbTherapeutics) for the treatment of relapsed or refractory high-risk bone/medullary nerves that have experienced partial remission, mild remission or stable disease during previous treatment in children ≥1 year old and adult patients. This approval was supported by clinical evidence from two key studies. The subjects included in these two studies were patients with refractory or relapsed high-risk neuroblastoma. Naxitamab is well tolerated. There were almost no treatment termination events in clinical trials, and all adverse events that occured can be managed by clinical methods. The FDA approved the drug with accelerated approval; the ongoing Study201 (NCT03363373) clinical study was a post-marketing clinical trial conducted at the request of regulatory agencies to verify and further characterize the clinical benefits. The study planned to enroll at least 80 Cases of patients. Naxitamab acts on the ganglioside GD2 (it exists in the plasma membrane of the cell and regulates the process of cell signal transduction). GD2 is highly expressed in a variety of tumors and sarcomas originating from neuroectoderm. Naxitamab has received FDA priority review, orphan drug, breakthrough therapy and rare pediatric drug designation.
Zeste gene enhancer homolog 2 (EZH2) is a gene transcription regulating enzyme and a member of the histone lysine methyltransferase family. EZH2 is involved in regulating chromatin structure formation and mediating DNA methylation. EZH2 is also responsible for initiating gene silencing during embryonic development, while maintaining the pluripotency of certain adult stem cells. In addition, EZH2 activity in most adult somatic cells is down-regulated to allow lineage-specific gene expression programs to be expressed. The amplification and overexpression of this protein is involved in the occurrence and progression of a variety of malignancies (including solid tumors and hematological malignancies). In January 2020, the FDA approved the first innovative drug EZH2 inhibitor Tazemetostat (Tazverik; Epizyme) for the treatment of metastatic or locally advanced epithelioid sarcoma (a rare soft tissue malignancy) in adults and children ≥16 years of age. In June, the FDA approved the Supplemental New Drug Application (NDA) for Tazemetostat for two different follicular lymphoma (FL) indications: for adult patients with relapsed or refractory FL who are positive for EZH2 mutations (using an FDA-approved test method) and have received at least two systemic treatments in the past, and for adult patients with relapsed or refractory FL who have no satisfactory alternative treatment options. The FDA also approved Roche Molecular Systems’ Cobas EZH2 mutation test as a companion diagnostic product. Based on the total remission rate and duration of remission achieved by each cohort in the Phase II study of Tazemetostat in patients with EZH2 mutation and wild-type EZH2FL, the FDA has given priority review and accelerated approval for the drug’s indications. The drug was launched in the United States shortly after approval. In Japan, Epizyme’s commercialization partner, Eisai, was submitting regulatory approval for the drug’s indications for the treatment of EZH2 mutation-positive FL.
Multiple myeloma (MM) is the most common adult hematological malignancy, and overall it is also the second most common hematological malignancy, accounting for about 10%-13% of such malignancies. In 2020, three new therapies for multiple myeloma were on the market for the first time.
In August 2020, the US FDA approved the first ADC for the treatment of multiple myeloma: Belanta mabmafodotin (Blenrep; GlaxoSmithKline). ADC is a first innovative drug targeting BCMA. It consists of a humanized anti-B cell maturation antigen (BCMA) monoclonal antibody that is coupled to the cytotoxic drug Auristatin F via an uncleavable linker. BCMA is a cell surface protein that plays an important role in the survival of plasma cells. It is preferentially expressed on mature B lymphocytes (Figure 8) and overexpressed in MM patients. In August of the same year, ADC obtained conditional marketing authorization in the European Union. The indications approved in both EU markets are: adult patients with multiple myeloma who have previously received at least 4 monotherapy (including proteasome inhibitors, immunomodulators and anti-CD38 monoclonal antibodies). Belantamabmafodotin went on the market immediately after it was approved in the United States, but it is only available to medical institutions that have joined the risk assessment and mitigation strategy plan.
In July 2020, DCGI of India granted the anti-CD6 monoclonal antibody Itolizumab (Alzumab; Biocon) “Limited Emergency Use” authorization. Itolizumab has been approved for the treatment of psoriasis in the past, and this time it is authorized to treat cytokine release syndrome in patients with acute respiratory distress syndrome caused by COVID-19.
In November 2020, the FDA granted the JAK1/JAK2 dual inhibitor Baritinib (Olumiant; Eli Lilly) EUA for the treatment in suspected patients or hospitalized patients with COVID-19 confirmed by laboratory tests that required oxygen inhalation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. The dual inhibitor is approved for use in adults and children (age ≥ 12 years old and weight ≥ 40 kg) patients.
The anti-CD38 monoclonal antibody Darlimumab was launched in 2015 and quickly became a conventional drug for the treatment of MM. In 2020, the FDA approved Darzalex Faspro, a new type of subcutaneous injection of Darzalex Faspro containing recombinant human hyaluronidase PH20 (rHuPH20). The administration time can be shortened from a few hours of traditional formulations to 3-5 minutes. Darzalex Faspro is approved for the treatment of adult MM patients, including: combined with bortezomib, melphalan and prednisone, for the treatment of newly diagnosed patients who are not suitable for autologous stem cell transplantation (ASCT); combined with lenalidomide and dexamethasone for the treatment of newly diagnosed patients who are not suitable for ASCT and patients with relapsed or refractory MM who have previously received at least one other treatment; combined with Bortezomib and dexamethasone for the treatment of patients who have received at least one other treatment in the past; monotherapy for patients who have previously received at least 3 lines of therapy [including proteasome inhibitors (PI) and immunomodulators] or are resistant to both PI and immunomodulators. This new formulation was developed by the Danish company Genmab and later authorized to Janssen for global development and commercialization. The drug has been on the market in May.
Another anti-CD38 monoclonal antibody, Isatuximab (Sarclisa; Sanofi) was approved in the United States, the European Union, Australia, Japan and Canada last year. The drug is suitable for use in combination with pomalidomide and dexamethasone (pom-dex). It is used to treat adult patients with relapsed or refractory multiple myeloma who have previously received at least two treatments (including lenalidomide and proteasome inhibitors). In the ICARIA-MM study (NCT02990338), the combination of Isatuximab and Pom-dex can significantly increased the progression-free survival (PFS), with a median PFS of 11.53 months, while the PFS of Pom-dex monotherapy was 6.47 months. Compared with Pom-dex monotherapy, the ORR of the combination of Isatuximab and Pom-dex was also significantly improved, which were 60.4% and 35.3%, respectively. Isatuximab was first launched in Canada in July; it has been granted orphan drug designation in the United States and the European Union.
In July, Health Canada and the US FDA approved Inqovi, which is a fixed-dose compound preparation consisting of the demethylating drug decitabine and the cytidine deaminase inhibitor Cedazuridine. It can inhibit the degradation of decitabine in the gastrointestinal tract and liver, so that it can be absorbed by oral administration. Inqovi is the first and only oral demethylation drug suitable for the treatment of patients with moderate to high risk of myelodysplastic syndrome (MDS), including adult patients with previously treated and untreated, new and secondary MDS accompanied by the following French-U.S.-UK subtypes (refractory anemia, refractory anemia with ring sideroblasts, excessive blastsIncluding previously treated and untreated, new and secondary MDS with the following French-U.S.-UK subtypes (refractory anemia, refractory anemia with ring sideroblasts, hyperblastic refractory anemia and chronic myelomonocytic leukemia CMML). The drug has been reviewed and approved under the framework of the Orbis program, and its developer has also submitted new drug marketing applications in the United States, Canada and Australia. The FDA also granted the product orphan drug and priority review qualifications. Inqovi went public in the United States in September.
CD19 is a cell surface transmembrane protein and a positive regulator of B cell receptor signal transduction. CD19 receptors are specifically expressed on the surface of B lymphocytes, and are expressed on the surface of most non-Hodgkin’s lymphoma (NHL), acute lymphoblastic leukemia and chronic lymphocytic leukemia cells. Tafasitamab (Monjuvi; MorphoSys/Incyte) is a humanized oncolytic anti-CD19 monoclonal antibody optimized for Fc fragments, which was approved by the FDA in July. It was used in combination with Lenalidomide for the treatment of adult patients with non-specific relapsed or refractory diffuse large B-cell lymphoma (DLBCL) (including DLBCL caused by low-grade lymphoma) and patients who are not suitable for autologous stem cell transplantation. DLBCL is the most common type of NHL, accounting for about 1/3 of the total global cases. Tafasitamab obtains accelerated review based on ORR data; whether it can expand the scope of approval for this indication would depend on the verification of clinical benefits in confirmatory trials. The drug is the first second-line treatment approved by the FDA for adult patients with disease progression during or after the first-line treatment of DLBCL. The monoclonal antibody was launched in the United States in the third quarter of 2020 and is currently undergoing review by EU regulatory agencies.
In the summer of 2019, the FDA also granted Brexucabtagene autoleucel (Tecartus; KitePharma) accelerated approval qualification. The drug is an anti-CD19 chimeric antigen receptor T cell (CAR-T) therapy for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL, another NHL). The FDA approved the one-time treatment after priority review based on the results of the ongoing pivotal study ZUMA-2 (NCT02601313). The single-arm, open-label study enrolled 74 adult patients with relapsed or refractory MCL who had previously received chemotherapy with anthracyclines or bendamustine, anti-CD20 antibody drug, and Bruton’s tyrosine kinase inhibitor (ibrutinib or acalabrutinib). In the study, 87% of patients (60 patients who can be evaluated for efficacy analysis) responded to a single infusion of brexucabtagene autoleucel, and 62% of patients achieved complete remission. In all patients, follow-up begins at least 6 months after the patient reaches the first objective remission. The drug had not yet reached the median DoR when it was approved. Later in the same year, Tecartus was first launched in the United States (the first market), and EMACHMP gave a positive evaluation of the product for the same indication.
Bruton’s tyrosine kinase (BTK) is a key signal transduction molecule of the B cell signal transduction complex, which plays an important role in the development and maturation of malignant B cells. This molecule mediates the signal transduction process initiated by the B cell receptor and IL-5 receptor. Studies have found that BTK is also a factor that plays a dual regulatory role in cell apoptosis. BTK inhibitors can bind to BTK and block the activity of the latter, thereby blocking B cell activation and B cell-mediated signal transduction, and can inhibit the growth of malignant B cells that are overexpressed in many hematological malignancies. The BTK inhibitor Tibrarutinib Hydrochloride (Velexbru; Ono) was approved in Japan last year for the treatment of three different types of NHL: primary central nervous system lymphoma, Waldenstrom’s macroglobulinemia, and lymphoplasmacytic cells lymphoma.
At the end of December, another new BTK inhibitor, Obutinib (Enokai), received priority review by China’s NMPA and was approved for the treatment of two indications: relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and relapsed or refractory MCL.
The anti-PD-1 monoclonal antibody tislelizumab (Bezian; BeiGene) was launched in China early last year and is suitable for the treatment of patient with classic Hodgkin’s lymphoma (cHL) that has received at least two treatments in the past. Later in the same year, the second indication of the drug was approved and marketed for the treatment of previously treated patients with locally advanced or metastatic urothelial cancer.