Breast cancer is one of the most common malignancies. Statistics show that the breast cancer mortality rate in China is as high as 4 per 100,000 population. In recent years, with a deepening understanding of cancer mechanisms and advancements in pharmaceutical technology, numerous novel anti-breast cancer drugs have been developed. Coupled with optimized prognosis for breast cancer, the mortality rate from this disease has shown a gradual downward trend.
Currently, there are over 150 breast cancer therapeutics in clinical development worldwide. Below, New Kangjie comprehensively evaluates and selects the top 10 most promising investigational breast cancer treatments based on their innovation, therapeutic efficacy, and commercial value. These ten agents include small-molecule signal pathway inhibitors, monoclonal antibodies, antibody-drug conjugates, and therapeutic anti-tumor vaccines, reflecting current hotspots and future directions in oncology R&D.
10
Oraxol
Oraxol is an oral formulation of paclitaxel. Paclitaxel is a natural antineoplastic agent extracted from yew trees and is widely used in clinical practice, with approved indications including HER2-positive metastatic breast cancer, ovarian cancer, and non-small cell lung cancer (NSCLC). However, currently marketed paclitaxel products all require intravenous administration, causing inconvenience to patients. Due to efflux by P-glycoprotein (P-gp) pumps in gastrointestinal cells prior to absorption, paclitaxel alone cannot be absorbed orally. Oraxol is an oral paclitaxel formulation developed by the US pharmaceutical company Athenex by combining paclitaxel with HM30181A, a specific P-gp inhibitor identified by Hanmi Pharmaceutical through its oral drug discovery platform. Oraxol is currently in Phase III clinical trials for the treatment of various types of breast cancer. Notably, this drug has already been submitted for clinical trial approval in China: on July 6, 2017, Chongqing HuiyuanPharmaceuticalsThe clinical trial application for paclitaxel capsules, jointly submitted by [Company Name] Co., Ltd. and Athenex, has been accepted by the Center for Drug Evaluation (CDE), with the registration category classified as 2.2.
09
Keytruda
Keytruda, with the generic name pembrolizumab, is a household name in the pharmaceutical industry. As the first PD-1 monoclonal antibody approved for market launch, it has accumulated approvals for nine indications, including common malignancies such as melanoma, non-small cell lung cancer, head and neck cancer, Hodgkin lymphoma, and gastric cancer. However, Keytruda remains an investigational drug for breast cancer. Since its target is PD-1 on T cells rather than directly targeting cancer cells, and given its strong performance in treating other cancers, it is theoretically expected to demonstrate favorable efficacy against breast cancer. In fact, Merck Sharp & Dohme (MSD) is conducting several clinical studies evaluating Keytruda as monotherapy or in combination with other agents. A Phase I clinical study showed that Keytruda achieved an overall response rate of 18.5% in patients with PD-L1-positive advanced triple-negative breast cancer. Another Phase II clinical study demonstrated that the combination of Keytruda and Eisai’s Halaven yielded an overall response rate of 33.3% in treating metastatic triple-negative breast cancer. It is anticipated that Keytruda will become available to breast cancer patients in the near future.
08
Margetuximab
Margetuximab is an Fc fragment-optimized monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2). Developed by MacroGenics, the drug was granted Fast Track designation by the FDA in January 2018 for the treatment of patients with metastatic or locally advanced HER2-positive breast cancer who had previously received anti-HER2 targeted therapy. The basis for this Fast Track designation primarily stemmed from the interim analysis of the Phase III SOPHIA clinical trial, a Phase III study comparing margetuximab plus chemotherapy versus trastuzumab plus chemotherapy for the treatment of metastatic breast cancer. The interim analysis revealed no safety concerns, and the progression-free survival (PFS) data supported the continuation of the SOPHIA trial, with the drug expected to reach the market in 2019.
07
Ipatasertib
Ipatasertib is a small-molecule pan-Akt inhibitor developed by Roche, capable of inhibiting all three Akt isoforms. Initially developed by Array Biopharma, the drug demonstrated significant efficacy in the multicenter, randomized, double-blind, placebo-controlled Phase II LOTUS trial, results of which were released in August 2017. The trial showed that ipatasertib significantly prolonged progression-free survival (PFS) in patients with triple-negative breast cancer (TNBC) compared to placebo. Conducted over a period of 18 months, the study enrolled 124 patients who were randomized in a 1:1 ratio to receive either paclitaxel plus ipatasertib (n=62) or paclitaxel plus placebo (n=62). Treatment was administered once every 28 days until disease progression or unacceptable adverse events occurred. These findings provided the first evidence that Akt inhibitors could be used for targeted therapy in breast cancer. Additionally, multiple clinical programs are currently investigating the efficacy of ipatasertib in combination with atezolizumab and taxanes for the treatment of triple-negative breast cancer.
06
Trastuzumab duocarmazine
Trastuzumab duocarmazine (SYD985) is an antibody-drug conjugate developed by the Dutch pharmaceutical company Synthon. Its antibody component is trastuzumab, a biosimilar of Herceptin—which generates annual sales exceeding USD 6 billion—and is a humanized monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER2). The cytotoxic payload is vc-seco-DUBA, a duocarmycin analog. This agent specifically recognizes and binds to cancer cells overexpressing HER2; the conjugated drug then binds to the minor groove of cellular DNA, causing irreversible alkylation, which disrupts nucleic acid structure and leads to tumor cell death. In November 2017, Synthon initiated the pivotal Phase III clinical trial named TULIP, a multicenter, open-label, randomized study comparing the efficacy and safety of SYD985 with conventional therapies in patients with HER2-positive, unresectable locally advanced or metastatic breast cancer. The trial is being conducted at 100 sites across the United States, Canada, Europe, and Singapore. In January 2018, based on preliminary data, the U.S. Food and Drug Administration (FDA) granted Fast Track designation to SYD985 for the treatment of patients with HER2-positive metastatic breast cancer (MBC). The drug was expected to be launched in 2020.
05
DS-8201
DS-8201 is a key antibody-drug conjugate (ADC) under development by the Japanese pharmaceutical company Daiichi Sankyo. The antibody component of DS-8201 is Daiichi Sankyo’s proprietary humanized HER2 antibody, which is linked via a tetrapeptide linker to a novel topoisomerase I inhibitor payload. In August 2017, the U.S. Food and Drug Administration (FDA) granted DS-8201 Breakthrough Therapy Designation. Phase I study results were presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting held in early June. This study evaluated the efficacy of DS-8201 in patients with advanced, unresectable, or metastatic solid tumors who were resistant to or intolerant of standard therapies. The primary endpoints of the dose-escalation phase were to assess the safety and tolerability of DS-8201 and to determine the maximum tolerated dose (MTD). The results showed that among 34 patients with HER2-low metastatic breast cancer, the overall response rate (ORR) was 50.0%, and the disease control rate (DCR) was 85.3%. Subgroup analysis of 99 patients with HER2-positive metastatic breast cancer who had previously been treated with T-DM1, trastuzumab, and pertuzumab revealed an ORR of 54.5% and a DCR of 93.9% with DS-8201 treatment. These Phase I findings are remarkably impressive; however, further clinical studies are needed to validate its therapeutic value.
04
Taselisib
Taselisib is a PIK3CA inhibitor developed by Roche. PIK3CA is an isoform of PI3K. PIK3CA mutations can be found in hormone receptor-positive (ER+), human epidermal growth factor receptor 2-positive (HER2+), and triple-negative breast cancers. Preclinical studies have shown that Taselisib has greater potential than other PI3K inhibitors for the treatment of breast cancer. Preliminary results from Phase Ib studies indicated that Taselisib combined with fulvestrant was effective and well-tolerated in HR-positive breast cancer. The latest Phase III clinical trial demonstrated that combining Taselisib with standard hormonal therapy effectively delayed the progression of advanced breast cancer and reduced the risk of disease worsening by 30%. This Phase III study enrolled 516 patients with locally advanced or metastatic breast cancer who were ER-positive and HER2-negative, and whose disease had progressed or recurred after initial aromatase inhibitor therapy. The study showed that patients receiving the combination therapy had a 30% reduction in the risk of cancer progression. Furthermore, Taselisib treatment extended the time to disease progression by an additional 2 months (7.4 months in the treatment group vs. 5.4 months in the control group). The objective response rate was 28% in the treatment group, compared to 11.9% in the control group. Currently, there are no PI3K inhibitors approved on the market for the treatment of breast cancer, primarily because PI3K plays a crucial role in normal cellular physiological functions, and general inhibitors often cause significant side effects. As a specific isoform inhibitor, Taselisib may offer a solution to this challenge.
03
Sacituzumab govitecan
Sacituzumab govitecan is an antibody-drug conjugate developed by Immunomedics. The antibody component is a humanized monoclonal antibody targeting Trop-2 (trophoblast cell-surface antigen 2), while the drug payload, SN-38, is the active metabolite of irinotecan. Each antibody molecule carries an average of six SN-38 molecules. Administration of SN-38 alone would result in significant toxicity; however, antibody-mediated targeting of Trop-2-expressing cancer cells theoretically mitigates this issue effectively. In December 2017, results from a Phase I/II basket trial presented at the San Antonio Breast Cancer Symposium demonstrated that sacituzumab govitecan monotherapy was effective in treating heavily pretreated (third-line or beyond) recurrent or refractory metastatic triple-negative breast cancer (mTNBC). This study, which spanned over four years and enrolled 110 patients, reported an objective response rate (ORR) of 34%, including three complete responses and 34 partial responses. The clinical benefit rate was 46%. The median duration of response was 7.6 months, median progression-free survival (PFS) was 5.5 months, and median overall survival (OS) was 12.7 months. These findings indicate that sacituzumab govitecan monotherapy is an effective treatment for heavily pretreated (third-line or beyond) recurrent or refractory mTNBC, with potential approval anticipated as early as 2018.
02
Talazoparib
Talazoparib is an orally available multi-poly(ADP-ribose) polymerase (PARP) inhibitor. PARP is involved in the repair of single-strand DNA breaks, and cells with BRCA1/2 mutations are particularly sensitive to the cytotoxic effects of PARP inhibitors. Compared with olaparib, a marketed PARP inhibitor, talazoparib is theoretically more potent in its antitumor activity due to an additional mechanism known as “PARP trapping,” which immobilizes PARP molecules on DNA, thereby blocking DNA replication. The drug is currently owned by Pfizer and has a notable development history: it was initially developed by Lead Therapeutics, a small startup; acquired by BioMarin in 2010 for up to $97 million, after which Lead Therapeutics ceased operations per the agreement; advanced by BioMarin from preclinical studies to Phase III clinical trials over five years; transferred to Medivation in August 2015 for up to $570 million; and ultimately became part of Pfizer’s portfolio following Pfizer’s $14 billion acquisition of Medivation in August 2016. This trajectory exemplifies the classic “big fish eat small fish, small fish eat shrimp” consolidation pattern in the pharmaceutical industry.
So, what is the clinical efficacy of this drug? In December 2017, Pfizer announced the results of the Phase III EMBRACA study evaluating talazoparib for the treatment of locally advanced and/or metastatic breast cancer in patients with germline BRCA1/2 mutations (gBRCA+). The results demonstrated that, compared with standard chemotherapy regimens, talazoparib significantly prolonged median progression-free survival (8.6 months vs. 5.6 months) and reduced the risk of disease progression by 46%. Furthermore, the objective response rate in the talazoparib group was more than twice that of the chemotherapy group (62.6% vs. 27.2%). Regarding safety, the incidence of serious adverse events was 31.8% in the talazoparib group and 29.4% in the chemotherapy group. The proportion of patients who discontinued treatment due to serious adverse events was 7.75% in the talazoparib group versus 9.5% in the chemotherapy group. Overall, the clinical efficacy of talazoparib is quite satisfactory, and its prospects for market approval and commercial sales are optimistic.
01
NeuVax
NeuVax is a therapeutic cancer vaccine (for a detailed explanation of cancer vaccines, see: “New Drug Watch: Interpretation of Cancer Vaccines”). It is a synthetic peptide composed of the HER2/neu p366-379 peptide fragment encoded by the proto-oncogene, an immune linker, and recombinant human GM-CSF produced in yeast. Its mechanism of action is as follows: NeuVax binds to specific HLA molecules on antigen-presenting cells and HER2-expressing tumor cells, thereby activating CD8-positive cytotoxic T lymphocytes to attack residual cancer cells expressing HER2/neu. The drug was initially developed by Galena Biopharma, which was acquired by Sellas in August 2017, transferring ownership of NeuVax to the latter. In April this year, Sellas released interim results from a Phase II clinical trial involving nearly 200 breast cancer patients, demonstrating that NeuVax combined with Roche’s Herceptin yielded favorable therapeutic outcomes in treating breast cancers with low to moderate HER2 expression. Specifically, the five-year recurrence rate for node-positive breast cancer decreased from 26% to 6%, with no significant adverse reactions reported. Following the announcement, Sellas’ stock price surged by 150% in a single day, reflecting strong market optimism regarding the drug. However, the FDA will require more positive data from Phase III trials before granting approval. Once approved, this drug would represent a milestone event in the history of cancer treatment.
Source: New Health World
Author: Feng Yun