Chinese Thoracic Oncology Group

AstraZeneca's Tagrisso-chemo regimen also sets a new bar for a Johnson & Johnson combination. AstraZeneca’s Tagrisso is the standard of care in newly diagnosed, EGFR-mutated non-small cell lung cancer (NSCLC). The company hopes to offer a new combination with chemotherapy, but the lack of patient survival showing may be a problem for that effort. Compared with Tagrisso monotherapy, the drug’s combination with chemotherapy cut the risk of disease progression or death by 38% in first-line, EGFR-mutant NSCLC, according to data presented at the 2023 World Conference on Lung Cancer (WCLC) in Singapore. The results “demonstrated a remarkable improvement in progression-free survival” for the combo approach and support the regimen “as a new and promising first-line treatment option,” Pasi A. Jänne, M.D., Ph.D., from the Dana-Farber Cancer Institute, who leads the current phase 3 FLAURA2 trial, said in a statement. But before the official data release, AstraZeneca had already tempered enthusiasm for the combo. “We believe Tagrisso monotherapy will remain standard of care in first line, but see the opportunity for FLAURA2 to become a valuable regimen for patients with higher tumor burden,” AZ’s oncology R&D chief Susan Galbraith, Ph.D., said during the company’s second-quarter earnings call in July. The combo's progression-free survival data were compelling. By investigators’ analysis, the combo extended the median time before disease worsening or death by 8.8 months to 25.5 months versus solo Tagrisso. By an independent review, the median PFS was improved by 9.5 months to 29.4 months. Both patients with exon 19 deletion and exon 21 mutations, and those with or without smoking history, experienced similar PFS benefits. However, when it comes to the gold-standard patient survival data, the signal was less clear. At the interim analysis, the combo reduced the risk of death by 10% over Tagrisso alone. What's more, patients in the monotherapy group appeared more likely to be alive than those in the combo arm as the trial grows longer. The interpretation of overall survival isn’t conclusive at this point as only 27% of deaths had taken place for a final evaluation. But during a WCLC presentation, Yi-Long Wu, M.D., a top lung cancer expert from China’s Guangdong Provincial People's Hospital, said he was not optimistic that FLAURA2 will eventually show an overall survival benefit. He noted that previous Tagrisso studies produced clear life-extension signals early. The extra toxicity associated with the chemotherapy might have cost the combo a clear overall survival win. Side effects led to a 48% discontinuation rate for any component of treatment in the combo arm, versus 6% for the Tagrisso monotherapy group. The rates of anemia, nausea and neutropenia were markedly higher for the combination. With this combo approach, AZ appears to believe that doctors might think only patients with a high tumor burden can benefit from the efficacy-safety trade-off because they need a stronger regimen to quickly put the cancer under control. Feedback from doctors suggested that “Tagrisso’s value proposition extends beyond efficacy, and is significantly driven by safety/tolerability and dosing convenience,” analysts at Leerink Partners wrote in a note in August. While Tagrisso comes in tablets, the chemotherapy is given via intravenous infusion. A survey conducted by Wu showed that even if Tagrisso and chemo had shown a progression improvement of 10 months, about 80% of 655 members in the Chinese Thoracic Oncology Group would still prefer monotherapy over the combo. More than 70% of patients and their family members said no to chemo combo in that same question.   AZ’s FLURA2 regimen also sets a new bar for rival Johnson & Johnson, which is pairing Yuhan-partnered EGFR inhibitor lazertinib with its own EGFRxMET bispecific antibody Rybrevant. The phase 3 MARIPOSA trial pitting that J&J combo against Tagrisso in first-line NSCLC is expected to read out soon. Ultimately, the J&J cocktail will face a similar question of whether greater antitumor activity can justify potentially greater toxicity, the Leerink analysts figured. After speaking with doctors, the Leerink team put the PFS benefit bar for the Rybrevant-lazertinib combo at seven months. That kind of improvement, plus a positive overall survival trend, could make a compelling case for the J&J therapy, the team said. Now, the Tagrisso-chemo combo has set the bar for Tagrisso monotherapy at around nine months.  “Still, the lack of a clear survival trend in FLAURA2 leaves the door open for further improvement,” William Blair analyst Matt Phipps, Ph.D., wrote in a Monday note. “Therefore, a PFS delta of over 10 months with clear separation of overall survival curves is likely needed to garner enthusiasm for the MARIPOSA regimen.” Editor's Note: The story has been updated with additional information from Yi-Long Wu's presentation and Matt Phipps' note.

SHANGHAI, Jan. 29, 2023 /PRNewswire/ -- Alpha Biopharma, a developer of innovative drugs, announces that the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) has accepted its New Drug Application (NDA) for Zorifertinib, a next-generation EGFR-TKI specially designed to treat advanced EGFR-mutated non-small cell lung cancer (NSCLC) patients with central nervous system (CNS) metastases. Zorifertinib is the first EGFR-TKI to be tested in a prospective, controlled registration clinical study for this difficult-to-treat patient population, and if approved, it will bring a much-needed new treatment option for these patients. Data released by the International Agency for Research on Cancer (IARC) of the World Health Organization (SHO) showed that there were 9.96 million cancer deaths worldwide in 2020, and 1.8 million deaths were from lung cancers, making it the most common cause of cancer deaths. Due to the low CNS penetration rate of most current lung cancer drugs, lung cancers metastasized to the CNS were poorly controlled and have become one of the leading causes of NSCLC patient deaths. Zorifertinib is a next-generation EGFR-TKI targeting sensitive EGFR mutations (exon 19 deletion and exon 21 L858R) designed for complete blood-brain barrier (BBB) permeability. In addition, Zorifertinib is not a substrate for the efflux transporters P-gp and BCRP, which allows it to achieve and maintain effective drug exposure in the brain tissues and the cerebrospinal fluid. The EVEREST study was a multinational, multicenter, randomized, open-label, controlled phase II/III clinical trial designed to evaluate the efficacy and safety of Zorifertinib as a first-line treatment for advanced EGFR-mutated NSCLC patients with CNS metastases. The study was carried out in 55 study sites located in the Chinese mainland, Taiwan, South Korea, and Singapore, with a total enrollment of 492 patients. The last patient last visit (LPLV) of the EVEREST study was completed in the third quarter of 2022. Results from the EVEREST study demonstrated that Zorifertinib effectively reduced the risk of disease progression and patient deaths in the target patient population and showed significant efficacy in treating metastatic lesions in the CNS. In addition, Zorifertinib's safety profile is comparable to other approved EGFR-TKI's. The primary resistance mutation at the time of disease progression is the EGFR T790M mutation. Professor Yilong Wu, President of the Chinese Thoracic Oncology Group (CTONG) and the leading principal investigator (PI) of the EVEREST study, said, "Clinical results from this high-quality, controlled study demonstrated that Zorifertinib provided consistent and statistically significant benefits to EGFR-mutated NSCLC patients with different levels of CNS metastasis. It could provide a much-needed new treatment option for these difficult-to-treat patients. The development of Zorifertinib represents a great example of a patient-centric, targeted precision approach to address unmet medical needs. Eric Zhang, CEO of Alpha Biopharma, said, "after many years of dedicated research and development, we are very pleased to witness that all pre-clinical and clinical data have demonstrated that Zorifertinib can achieve and maintain high CNS exposures, that it is safe, and it is advantageous in controlling CNS and overall disease progression in this difficult-to-treat population. We look forward to working closely with the regulatory agencies around the world to bring this innovative treatment option to patients in dire need. About Zorifertinib Zorifertinib is a potent, oral, reversible inhibitor of mutated EGFR (Exon19Del and Exon21L858R). EGFR is widely expressed in human epidermal and stromal cells and is highly expressed in various human malignancies, such as NSCLC. EGFR gene mutation will cause excessive epidermal growth factor receptors on the cell membrane surface, accelerate the abnormal growth and division of cells, and eventually lead to tumorigenesis. CNS metastases are common in EGFR-mutated NSCLC patients and are accompanied by a poor prognosis of earlier disease progression, shorter survival, and lower quality of life. The BBB significantly increases the difficulty of drug penetration into the CNS, which allows the CNS to be a refuge for lung cancer cells. Zorifertinib is a next-generation EGFR-TKI with full blood-brain barrier penetration targeting advanced NSCLC patients with CNS metastases and EGFR-sensitizing mutations. Zorifertinib is currently under NDA submission and has global patent protection. About Alpha Biopharma Alpha Biopharma is a late-stage biopharmaceutical company focusing on developing new therapies for cancers and other unmet medical needs. The Company has submitted its first NDA submission for its small molecule drug Zorifertinib to treat advanced NSCLC patients with CNS metastases and EGFR sensitizing mutations. In addition, in partnership with leading cell therapy company Wugen, Alpha Biopharma is developing memory NK-cells to treat multiple blood and solid tumors and CAR-T cells to treat T-cell lymphomas. It has initiated an IIT clinical study testing memory NK cells in relapse and recurring AML patients. Alpha Biopharma has assembled an experienced management team with solid capabilities in pre-clinical development, pharmacology, medical sciences, clinical operations, and business development to advance its innovative treatment solutions to the market and improve life quality for cancer patients and commercialization. SOURCE ALPHA BIOPHARMA

SHANGHAI, Aug. 24, 2022 /PRNewswire/ -- Alpha Biopharma, a developer of innovative drugs, announces the completion of last patient last visit (LPLV) in its international, multicenter EVEREST phase II/III clinical study of Zorifertinib, a next-generation EGFR-TKI, in first line patients with advanced EGFRm+ non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastases. Topline data from this MRCT study are expected around the end of 2022, at which time Alpha Biopharma could submit a New Drug Application (NDA) to the National Medical Products Administration (NMPA). As the international leading principal investigator (PI) of EVEREST study, Professor Yilong Wu, President of the Chinese Thoracic Oncology Group (CTONG), said: "EVEREST study is an international, multicenter, phase II/III randomized clinical study. It is also the only large-scale prospective international multicenter clinical study worldwide for first line EGFRm+ NSCLC patients with CNS metastases to date. It was carried out in 55 study sites located in Chinese mainland, Taiwan, South Korea, and Singapore, with a total enrollment of 492 patients. The clinical and preclinical data of Zorifertinib have shown its high blood-brain barrier (BBB) penetration, anti-tumor activity in metastatic CNS lesions, overall efficacy in both CNS and extra-cranial diseases, and similar safety profile as other EGFR-TKI drugs. If approved, it is expected to provide a valuable choice for treatment of EGFRm+ NSCLC patients with CNS metastases. As the name EVEREST suggests, the study sponsor and investigators are dedicated to solving important unmet clinical needs." Professor Jie Wang, Director of Oncology Department of Cancer Hospital Chinese Academy of Medical Sciences, and co-leading PI of EVEREST study, said: "Lung cancer with CNS metastases has always been a challenging problem and leading cause of death for these patients. Zorifertinib is a next-generation, high-potent EGFR-TKI drug targeting sensitive mutations of exon 19 deletion or L858R in EGFR gene with good exposure in CNS lesions. It is not a substrate of efflux transporter P-gp and BCRP, thus not only capable of fully passing through BBB, but also maintaining high drug exposure in the brain tissue and cerebrospinal fluid. It was intentionally designed to optimize its physicochemical and biochemical properties meet the requirements of CNS penetration, which has been proven to be the case in this and prior clinical studies. We look forward to the finale data readout and if positive, a direly needed treatment for these patients." Dr. Ruilin Song, Executive President of China Pharmaceutical Innovation and Research Development Association, said: "In the past three years, the COVID-19 pandemic in some regions of China has brought great challenges to innovative biotech companies. Many clinical study sites faced challenges in terms of regional lockdown, logistics, and clinical operations. However, the clinical development team at Alpha Biopharma and investigators worked together to overcome difficulties to achieve the key milestones of the EVEREST study. They diligently communicated with study sites to come up with solutions, paid full attention to the safety of the subjects and the quality of the trial data while ensuring the uninterrupted treatment of the subjects. In recognizing this pivotal milestone of EVEREST study completion, we would like to express sincere respect for the efforts of all relevant personnel involved in the study and wish Zorifertinib a smooth NDA submission. We are a step closer to bringing new hope to patients with CNS metastases of EGFRm+ NSCLC." About Zorifertinib Zorifertinib is a potent, oral, reversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR-TKI) activating mutation (L858R and Exon19Del). EGFR is widely expressed in human epidermal cells and stromal cells and is highly expressed in a variety of human malignancies, such as NSCLC. EGFR gene mutation will cause excessive epidermal growth factor receptors on the cell membrane surface, accelerate the abnormal growth and division of cells, and eventually lead to tumorigenesis. CNS metastases is common in EGFRm+ NSCLC patients and accompanied with poor prognosis of earlier disease progression, shorter survival, and lower quality of life. The BBB significantly increases the difficulty of drug penetration into CNS, which allows the CNS to be a refuge for lung cancer cells. Zorifertinib is a new-generation EGFR-TKI specifically designed to fully penetrate the BBB to target brain metastases. Zorifertinib is in late-stage clinical studies and has global intellectual property protection. About Alpha Biopharma Alpha Biopharma is a late-stage biopharmaceutical company focused on developing potential new therapies for cancer's unmet medical need. Founded in 2017, the Company has advanced its EGFRm+ targeted small molecule drug Zorifertinib to its Phase II/III trial (EVEREST) to treat NSCLC patients with brain metastases. In addition, Alpha Biopharma has initiated an IIT clinical study of an NK cell therapy targeting AML and is developing CAR-T cell therapy that it licensed from Wugen Inc. for the Greater China region. Alpha BioPharma's experienced team, leading clinicians, and collaborators integrate their oncology expertise to find innovative solutions to transform the lives of cancer patients. SOURCE ALPHA BIOPHARMA