According to a report by the American Association for Cancer Research, advances in innovative therapies, medical research, preventive care, and early detection of cancer have reduced cancer deaths by 33% and saved more than 3.8 million lives over the past three decades. Recently, BioSpace reported 'Top 10 Potential Drugs for Refractory Tumors', focusing on new technologies such as monoclonal antibodies, ADCs, and tumor vaccines, etc. This article compiles and analyzes the current progress of these top 10 drugs for the industry's reference.
Lung cancer
1. Tagrisso Generic Name: osimertinib
Tagrisso is an oral, small molecule, third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that has been approved by the United States, Japan, China, and the European Union for first-line treatment of patients with locally advanced or metastatic EGFRm NSCLC; and second-line treatment of patients with locally advanced or metastatic NSCLC who are positive for the EGFR T790M mutation.
Data from the Phase III ADAURA study showed that Tagrisso significantly prolonged progression-free survival (PFS) and reduced the risk of disease recurrence or death by 80% compared to placebo as postoperative adjuvant therapy in patients with early-stage (Stage IB/II/IIIA) EGFRm NSCLC who had undergone complete tumor resection.
2. Tecentriq generic name: atezolizumab, atelizumab
Figure 2. Schematic representation of the mechanism of action of Tecentriq.
Tessage is an innovative monoclonal antibody for tumor immunotherapy. Unlike tumor immunotherapies specifically targeting PD1, by binding to the PD-L1 protein on the surface of tumor cells and on the surface of tumor-infiltrating immune cells, Tysage not only hinders the binding of PD-L1 to the PD-1 receptor, but also prevents the binding of PD-L1 to the B7.1 receptor, which not only helps the human immune system to recognize the tumor cells, but also further activates the T-cells of the human immune system to attack the tumor cells.On February 13, 2020, the NMPA formally approved Tysanchi in combination with chemotherapy for the first-line treatment of extensive-stage small cell lung cancer.
The results of the IMpower133 Phase III clinical study showed that at a median follow-up of 13.9 months, the median OS (overall survival) was 12.3 months and 10.3 in the atilizumab and placebo groups, respectively, and the median PFS was 5.2 months and 4.3 months, respectively. The IMpower133 study was terminated early due to the very good efficacy, with OS and PFS having reached positive results at the interim analysis.
Colorectal Cancer
Jemperli Generic Name: Dostarlimab-gxly, Dostarlimab
Figure 3. Schematic diagram of the mechanism of action of dobtalizumab
Dostarlimab-gxly is a humanized monoclonal antibody that binds with high affinity to the PD-1 receptor on T cells and prevents its interaction with PD-L1 and PD-L2 ligands, thereby blocking PD-1 activity and reducing tumor growth.
A single-arm, single-center Phase II clinical study evaluating the efficacy and safety of Dostarlimab in patients with stage II or III rectal cancer with dMMR (defective mismatch repair) was conducted with single-agent Dostarlimab given every 3 weeks for 6 months. The primary endpoints were sustained clinical complete remission 12 months after completion of Dostarlimab treatment or pathologic complete remission after completion of Dostarlimab treatment with or without radiotherapy, and overall remission to neoadjuvant Dostarlimab treatment with or without radiotherapy. A total of 12 patients completed treatment with Dostarlimab and were followed for at least 6 months. The results of the study showed that the 12 patients were in complete clinical remission, with no tumors detected on magnetic resonance imaging, 18F-deoxyglucose positron emission tomography, endoscopy, rectal biopsy, or biopsy. And no grade 3-4 adverse events were observed.
2.BOLD-100
Figure 4: Chemical structure of BOLD-100
BOLD-100 is a ruthenium-based potential "first-in-class" small molecule drug that induces G2/M cell cycle arrest, DNA synthesis blockade and apoptosis via the mitochondrial pathway.BOLD-100 has a high tumor-targeting potential, binds strongly to serum proteins such as albumin and transferrin and is activated in the reductive tumor environment. serum proteins such as albumin and transferrin that bind strongly and are activated in a reductive tumor environment.
Phase 1b/2 clinical trials conducted in multiple countries and regions evaluated BOLD-100 in combination with FOLFOX chemotherapy regimens in patients with advanced gastrointestinal cancer. The clinic showed a median progression-free survival of 5.5 months, an overall survival of 15 months, an overall remission rate of 22%, and a disease control rate of 89% in 13 patients with advanced gastrointestinal cancer (who had received a median of 4 lines of therapy).
Breast cancer
1.Dato-DXd generic name: datopotamab deruxtecan, datobotumab
Designed using Daiichi Sankyo's proprietary DXd ADC technology, Dato-DXd is one of the three core ADCs in Daiichi Sankyo's oncology field pipeline, and the most advanced program in AstraZeneca's ADC science platform.Dato-DXd is an antibody-coupled drug targeting TROP2 and consists of a humanized anti-TROP2 IgG1 monoclonal antibody linked, via a cleavable tetrapeptide linker, to a topoisomerase I inhibitor payload (a camptothecin derivative).
Triple-negative breast cancer (TNBC) accounts for approximately 15% of breast cancer cases and is associated with a higher rate of disease recurrence and poorer prognosis than other breast cancer subtypes.The results of the Phase I clinical study, TROPION-PanTumor01, demonstrated a 32% objective remission rate for Dato-DXd with a manageable safety profile . The results of Phase Ib/II clinical study showed that Dato-DXd in combination with duvarizumab showed a high objective remission rate of 73.6% in the first-line treatment of metastatic triple-negative breast cancer.
Recently, Daiichi Sankyo and AstraZeneca reported positive results from the Dato-DXd Phase III trial. Statistically significant and clinically meaningful improvements were shown in 733 previously treated patients with inoperable or metastatic hr-positive, her2-negative breast cancer. Detailed results will be presented at an upcoming medical conference.
2. DB-1303
DB-1303 consists primarily of a trastuzumab biosimilar, a stabilized enzymatically cleavable peptide junction, and a proprietary topoisomerase I inhibitor, P1003. Preclinical results show that DB-1303 exhibits potent inhibitory effects and antitumor activity in both HER2-positive and HER2-low-expressing cells and tumor models, and displays dose-dependent tumor growth inhibition and regression with a wide therapeutic window in tumor models. Currently, DB-1303 has been granted fast track status by the US FDA.
At this year's ASCO Annual Meeting, the latest Phase 1/2a clinical data for HER2 ADC (DB1303) showed that 85 patients were treated with six dose levels of DB-1303, and among all patients, the DCR for disease control rate was 88.5%; for patients with HER2+ BC and HER2 low-expressing BC, the DCR was 96.2% and 84.6%, respectively. The upcoming phase III trial will evaluate the efficacy and safety of DB-1303 as chemotherapy in approximately 466 patients.
Gastric Cancer
Zolbetuximab
Zolbetuximab is a first-in-class monoclonal antibody against Claudin 18.2 (CLDN18.2) for the first-line treatment of patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic adenocarcinoma of the stomach or gastro-esophageal junction (GEJ). on July 6, 2023, the Biologic License Application for Zolbetuximab (BLA) has been accepted by the FDA and granted priority review status. If this BLA is approved, Zolbetuximab will be the first CLDN18.2-targeted drug approved for marketing in the United States.
On March 23, 2023, Astellas announced positive data from a Phase 3 clinical trial of zolbetuximab in combination with chemotherapy for the first-line treatment of locally advanced unresectable or metastatic gastric cancer or adenocarcinoma of the gastroesophageal junction in patients who are Claudin18.2-positive and HER2-negative. Combination therapy with zolbetuximab and CAPOX, a two-drug combination regimen featuring capecitabine and oxaliplatin, reduced the risk of disease progression or death in patients by up to 31.3 percent compared to the placebo group. zolbetuximab combination therapy patients had a progression-free survival (PFS) of 8.21 months compared to the placebo group's PFS of 6.80 months. In addition, the zolbetuximab combination therapy also significantly prolonged overall survival (OS), with a median survival of 14.39 months in the zolbetuximab versus 12.16 months in the placebo group.
2. DKN-01
DKN-01 is a humanized monoclonal antibody analog that specifically binds to and inhibits signaling in the pathway of DKK1, an osteohormone on the skeleton involved in immune evasion of tumors and bone metastasis, and an immunosuppressive factor in gastric cancer.The FDA has granted DKN-01, an antagonist targeting the novel target DKK1 Fast Track status for the treatment of patients with gastric cancer and gastroesophageal junction (GEJ) adenocarcinoma with high DKK1 expression.
The Dickkopf-1 (DKK1) antibody DKN-01 was used in combination with tirilizumab and chemotherapy for the first-line treatment of patients with gastric and gastroesophageal junction cancers, with an objective remission rate of 68% in patients who received a full cycle of treatment. In particular, patients with high DKK1 expression had an objective remission rate of 90%.
Although HER2-targeted drugs have good effects in gastric cancer, HER2-positive gastric cancer patients in China only account for about 10%, so the scope of application is narrow. The performance of PD-1 immunotherapy in gastric cancer is also more general. There has not been much progress in the treatment of gastric cancer in the past three decades, and DKN-01 may become the biggest progress in the treatment of gastric cancer in the past three decades.
Tumor Vaccine
1. Tedopi
Tedopi is a neoepitope vaccine that uses a targeted approach to combat tumor heterogeneity by selecting well-expressed antigenic determinants found in multiple tumor types. From the five tumor-associated antigens CEA, p53, HER-2, MAGE-A2 and MAGE-A, which are known to be frequently expressed in lung cancer cells, scientists have selected and optimized nine new epitopes (CTL epitopes) plus one Pan-DR epitope to form a proprietary combination, i.e., the Tedopi vaccine, which induces and stimulates cytotoxic T-cells to recognize and attack the cancer cells, and enhances their response intensity and Duration.
Lung cancer is currently the number one cancer in the world in terms of morbidity and mortality, and despite the arrival of various new targeted drugs and immunotherapeutic agents, the treatment of lung cancer after drug resistance is even more tricky and desperate in actual clinical application.Tedopi has achieved positive positive results in a Phase III clinical trial (Atlante 1) in non-small cell lung cancer (NSCLC). All patients enrolled with the Tedopi vaccine in the second or third line after resistance or failure of immune checkpoint inhibitors achieved a one-year overall survival rate of 46%, far exceeding the pre-determined rate of 25%, and ten percentage points higher than that of patients who received standard chemotherapy regimens.
2. mRNA-4157
mRNA-4157 (Personalized Melanoma Vaccine) is a personalized de novo antigenic cancer vaccine encapsulated in lipid nanoparticles that encodes for up to 34 de novo antigens. mRNA-4157 vaccine is designed with the goal of stimulating an immune response by generating a T-cell response based on the mutational characteristics of the patient's tumor. 2023 March month, the mRNA vaccine received breakthrough therapy approval from the FDA.
Results from a Phase IIb clinical trial showed that in patients with stage III/IV melanoma at high risk of recurrence after complete resection, the combination therapy was able to reduce the risk of recurrence or death by 44% compared to PD-1 monoclonal antibody (Keytruda) alone. the 12-month progression-free survival (PFS) rate in the Keytruda combined with mRNA-4157 treatment group was 83.4% compared to 77.1% in the Keytruda alone treatment group. At 18 months, the figures were 78.6% and 62.2%, respectively. This result suggests that the combination of mRNA vaccine + immune checkpoint inhibitor may be a novel approach to prolonging the lives of patients with high-risk melanoma.
References：
1. 10 Promising Therapies for Hard-to-Treat Cancers , https://www.biospace.com.
2. FDA Approves First Adjuvant Therapy for Most Common Type of Lung Cancer， U.S. Food and Drug Administration，Dec 18, 2020.
3. tecentriq - Cancer Immunotherapy Treatment for NSCLC,https://www.tecentriq.com.
4. Jemperli (dostarlimab) RUBY phase III trial met its primary endpoint in a planned interim analysis in patients with primary advanced or recurrent endometrial cancer. https://www.gsk.com.
5. Bold Therapeutics Presents Positive Interim Phase 2 Results for BOLD-100 in Advanced Gastric and Biliary Tract Cancer at ASCO 2023. https://www.biospace.com .
6. Dent RA, Cescon DW, Bachelot T. TROPION-Breast02: Datopotamab deruxtecan for locally recurrent inoperable or metastatic triple-negative breast cancer. Future Oncol. Aug 1,2023.
7. Kathleen N. Moore, Dhanusha Sabanathan, Yiqun Du, Safety and efficacy of DB-1303 in patients with advanced/metastatic solid tumors: A multicenter, open-label, first-in-human, phase 1/2a study.Journal of Clinical Oncology 2023 41:16 3023.
8. A New Targeted Treatment Shows Promise for Select Patients with Stomach Cancer. https://news.weill.cornell.edu.
9. https://zhuanlan.zhihu.com.
10. OSE Immunotherapeutics Provides Regulatory Update on Tedopi®, a Cancer Vaccine at a Late-Stage Clinical Development in Lung Cancer After Failure to Immunotherapies. https://www.biospace.com.