21CC Oncology Intelligence (Issue 47): Reindeer Biologics/Innovent BCMA-targeted CAR-T therapy approved for marketing; THE LATEST PHASE 3 TRIAL OF ASTRAZENECA HAMALAYA HAS POSITIVE RESULTS

21CC (cancercare), we care about everything related to cancer! 21st Century New Health Research Institute's innovative information column - 21CC tumor information, combing the week's tumor information, comprehensively focusing on cancer prevention and treatment, early detection, early diagnosis and early treatment, and walking with Jun Health.

1. New drugs (new indications/technologies) were approved

• China's first! Reindeer Biologics/Innovent BCMA-targeted CAR-T therapy was approved for marketing

On June 30, the official website of China's National Food and Drug Administration (NMPA) announced that the B-cell maturation antigen (BCMA)-targeted CAR-T product Iquicel injection (formerly known as Iquilencel injection) jointly developed by Reindeer Biologics and Innovent Biologics has been approved for marketing for the treatment of adult patients with relapsed or refractory multiple myeloma (MM), which has progressed after at least 3 lines of therapy (at least one proteasome inhibitor and immunomodulator). It is worth mentioning that this is the first BCMA-targeted CAR-T therapy approved in China.

Iquicel injection (Reindeer Bio R&D code: CT103A; Innovent R&D code: IBI326) is an innovative CAR-T product candidate targeting BCMA. The candidate transfects autologous T cells with lentivirus as the gene vector, and the CAR includes fully human scFv, CD8a hinge and transmembrane, 4-1BB co-stimulation, and CD3ζ-activating domains. Previously, Iquicel injection has been included in the breakthrough therapy variety by NMPA and has been granted orphan drug designation by the FDA for the treatment of relapsed/refractory multiple myeloma. In February 2023, the FDA again granted the drug regenerative medicine advanced therapy designation and fast-track status for the treatment of relapsed/refractory multiple myeloma.

In China, the NMPA accepted the marketing application for Iquicel injection in June 2022 and included it in the priority review for the treatment of adult patients with relapsed or refractory multiple myeloma after receiving three or more lines of systemic therapy.

• Zai Lab's application for the marketing of reputinib was accepted by the Food and Drug Administration

On June 28, Zai Lab announced that the National Medical Products Administration (NMPA) has accepted a new drug application for repotinib for the treatment of adults with ROS1-positive locally advanced or metastatic non-small cell lung cancer.

Dr. Rafael Amado, President and Global Head of Oncology R&D at Zai Lab, said, "We are pleased that the NMPA has accepted our new drug application for reputinib, which further supports the potential for riplitinib as a potential best-in-class therapy for the treatment of ROS1-positive non-small cell lung cancer patients in China. Due to the limited durability of benefit from currently approved therapies, the development of drug resistance, and inevitable tumor progression, there is a huge unmet need in this subset of patients. We look forward to actively cooperating with the NMPA during the review process and working together to bring this important drug to patients in need as soon as possible."

In May this year, the Center for Drug Evaluation (CDE) of the State Food and Drug Administration included reputinib in the priority review for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer who are positive for ROS1.

• Qilu Pharmaceutical's first innovative drug, Iruak tablets, was approved for marketing

On June 28, according to the official website of the Food and Drug Administration, Qilu Pharmaceutical's Class 1 innovative drug Iluac tablets were approved for marketing for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with ALK mutation-positive ALK mutation who have progressed or are intolerant to crizotinib after receiving crizotinib in the past. Iruac is the first innovative drug approved for marketing by Qilu Pharmaceutical.

Iluak (R&D code WX-0593) is a novel ALK/ROS1 inhibitor independently developed by Qilu, which can inhibit the activity of ALK kinase with wild-type and ALK inhibitor-resistant mutations of different fusion types, and effectively inhibit the activity of ROS1 kinases of different fusion types. Studies have shown that WX-0593 has antitumor activity in ALK-positive or ROS1-positive NSCLC, with an acceptable safety profile, and very good pharmacokinetic parameters and safety in dosage regimens within 180 mg.

Previously, Qilu disclosed a single-arm, multicenter phase II clinical study to evaluate the efficacy and safety of Iruac in ALK mutation-positive advanced non-small cell lung cancer that had previously received crizotinib. A total of 146 patients with a median follow-up of 9.3 months were included in the trial; 90 patients had brain metastases, including 41 with measurable intracranial lesions, 20 patients had previous brain radiotherapy, and 56 patients had previously received chemotherapy.

The results showed that the ORR of the Iruak treatment group assessed by IRC was 67.8% and the DCR was 96.6%. The Iruak-treated group assessed by the investigators had an ORR of 61.6%, a DCR of 94.5%, a median DoR of 13.1 months, a median PFS/TTP of 14.4 months, and an overall survival rate of 81.9% at 18 months.

• CStone Pharmaceuticals Pujihua's new indication for first-line treatment of NSCLC was approved in China

On June 27, CStone announced that its first-of-its-kind precision therapy drug, the highly selective RET inhibitor Pujihua (Pratinib Capsules), has been approved by the National Medical Products Administration (NMPA) of China for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who are positive for RET gene fusion. It is understood that this is the third indication approved by Pujihua in Chinese mainland, and it is also the eleventh new drug application approved by CStone Pharmaceuticals in Greater China.

It is understood that the approval of Pujihua's extended indication in China is based on the ARROW study, which is a global phase I/II clinical study designed to evaluate the safety, tolerability and efficacy of Pudgehua in patients with RET fusion-positive NSCLC and other RET-fused advanced solid tumors.

• Hengrui Pharmaceutical's new indication of Dalcilil was approved

On June 27, Hengrui Pharmaceutical announced that Dalcilib isethionate tablets (trade name: Erlikon) were approved for new indications, combined with aromatase inhibitors as initial treatment, suitable for patients with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer. This is the second indication approved for Dalcili and is a first-line indication.

Dalcilib isethionate tablets are a class 1 new chemical drug independently developed by Hengrui Pharmaceutical, which is an oral, highly efficient and selective small molecule CDK4/6 inhibitor.

The world's first CDK4/6 inhibitor is pfipercillib (trade name: Ibrance) developed by Pfizer, which was approved by the US Food and Drug Administration (FDA) in February 2015 through accelerated review for the initial endocrine therapy with letrozole for the treatment of HR-positive and HER2-negative advanced breast cancer, and was approved in February 2016 for the combination of fulvestrant for the treatment of advanced or metastatic breast cancer that has progressed after HR-positive and HER2-negative endocrine therapy. Up to now, Palbociclib has been listed in the European Union, Japan and other countries and regions. Palbociclib was approved in China in July 2018 for the initial endocrine therapy of aromatase inhibitors for the treatment of HR-positive, HER2-negative locally advanced or metastatic breast cancer.

According to the EvaluatePharma database, the global sales of similar products of Dalcily isethionate tablets will be about $8.87 billion in 2022. According to the Insight database, the earliest approved piperacicil has a decline in market share after the listing of competing products, but still occupies 57.95% of the market, followed by libeccillib and abecilide.

• Fosun Kite CAR-T new indication was approved in China

On June 26, the official website of China's State Food and Drug Administration (NMPA) announced that the marketing application for a new indication of Aquilencel injection submitted by Fosun Kite has been officially approved. According to the priority review announcement of the Center for Drug Evaluation (CDE) of the State Food and Drug Administration of China, the approved indications of the product are: adult large B-cell lymphoma (r/r LBCL) that is ineffective in first-line immunochemotherapy or recurs within 12 months after first-line immunochemotherapy.

Aquilencel injection is a targeted CD19 autologous CAR-T cell therapy product that Fosun Kite introduced Yescarta (Axicabtagene Ciloleucel) technology from Kite Pharma, a subsidiary of Gilead Sciences, in 2017 and was authorized to produce locally in China. CAR-T immune cell therapy is genetically engineered to modify patients' own T cells to express chimeric antigen receptor molecules targeting tumor antigens, and activated T cells mediate the killing of tumor cells.

Second, R&D/clinical/market progress

• Amgen initiates Lumakras phase III clinical head-to-head K drug trial for NSCLC

On June 27, Amgen launched a Phase III clinical trial (CodeBreaK 202) to evaluate the efficacy and safety of sotorasib (trade name: Lumakras) plus chemotherapy versus pembrolizumab (K drug) plus chemotherapy in patients with stage IV or IIIB/C non-squamous non-small cell lung cancer (NSCLC).

The study is a multicenter, randomized, open-label clinical trial to include 750 patients with PD-L1-negative and KRAS p.G12C-positive non-squamous NSCLC. The primary endpoint of the study was progression-free survival (PFS). The study is expected to be initiated in September 2023 and completed in November 2030.

Sotorasib, a KRAC G12C inhibitor developed by Carmot Therapeutics and Amgen, was approved by the FDA in May 2021 for the second-line treatment of NSCLC patients with KRAS G12C mutations based on positive data from the Phase III CodeBreaK 200 study. Patients included in the CodeBreaK 200 study included patients with NSCLC whose disease progressed after receiving PD-1/PD-L1 drugs. Amgen's direct challenge to Sotorasib for K drugs is challenging for a product that has not yet really stabilized its foundation, but if it can be successfully matched, the gains will also be huge. K is currently approved for the treatment of PD-L1-positive and negative NSCLC.

• THE LATEST PHASE 3 TRIAL OF ASTRAZENECA HAMALAYA HAS POSITIVE RESULTS

On June 30, AstraZeneca announced the latest data from its HIMALAYA Phase 3 trial. The analysis showed that at year 4, his immunocombination therapy Imjudo (tremelimumab) combined with Imfinzi (durvalumab) showed durable and clinically meaningful overall survival (OS) improvement when used in the first-line treatment of patients with unresectable liver cancer.

Liver cancer is the third leading cause of cancer death worldwide and the sixth most common cancer. In the United States, Europe and Japan, about 80,000 people a year, and in China, 260,000 people have advanced, unresectable hepatocellular carcinoma, and the 5-year survival rate of advanced patients is only 7%.

Imfinzi is an anti-PD-L1 monoclonal antibody that relieves tumor cells from inhibiting the immune response by blocking PD-L1's binding to PD-1 and CD80 proteins. It has been approved in several countries and regions for the treatment of extensive-stage small cell lung cancer, and has been approved by the FDA for the treatment of non-small cell lung cancer and advanced bladder cancer. Imjudo is an anti-CTLA-4 monoclonal antibody that blocks the activity of CTLA-4, thereby promoting T cell activation and stimulating the immune system's immune response to cancer.

The combination therapy of Imfinzi and Imjudo with an innovative dosing and dosing regimen is called the STRIDE regimen (Single Tremelimumab Regular Interval Durvalumab) and involves the first dose of only one dose of Imjudo (300 mg) plus anti-Imfinzi (1500 mg) and subsequent administration of Imfinzi every four weeks. Based on the results of the Phase 3 clinical study HIMALAYA, the combination regimen was approved in the United States last October for the treatment of adult patients with unresectable hepatocellular carcinoma, the most common type of liver cancer.

• CStone Pharmaceuticals announced the data of the Phase III clinical study of the ® first-line treatment of esophageal squamous cell carcinoma

On June 30, CStone announced that data from the Phase III clinical study (GEMSTONE-304) of Zegemeth (sugemelimab ® injection) in combination with chemotherapy for the treatment of locally advanced, recurrent or metastatic esophageal squamous cell carcinoma that cannot be resected inoperably has been presented orally at ESMO GI 2023.

The GEMSTONE-304 study is a randomized, double-blind, multicenter, placebo-controlled, phase III registrational clinical trial designed to evaluate the efficacy and safety of the first-line treatment of unresectable ® locally advanced, recurrent or metastatic esophageal squamous cell carcinoma in combination with FP chemotherapy (fluorouracil + cisplatin). The primary endpoints of the trial were PFS and OS assessed by BICR, and secondary endpoints included investigator-assessed PFS, BICR, and investigator-assessed objective response rate (ORR) and duration of response (DoR).

The data published at this conference is based on the PFS final analysis and OS interim analysis due on October 7, 2022. The results show that the GEMSTONE-304 study has reached the preset double endpoint. Compared with placebo plus chemotherapy, the combination of chemotherapy ® significantly improved PFS and OS as assessed by BICR, and the difference was statistically significant and clinically significant.

• Jacobio announces clinical data on the treatment of colorectal cancer by Glarece

On June 29, Jacobio Pharmaceuticals (1167. HK), a clinical-stage company developing the world's first innovative drug for difficult-to-drug targets, today unveiled its proprietary KRAS G12C inhibitor Glerecet (JAB-21822) monotherapy and combination with cetuximab for the treatment of KRAS at the 2nd JCA-AACR Precision Cancer Medicine International Conference Clinical data of advanced colorectal cancer with G12C mutation.

In single-agent clinical trials, the objective response rate was 33.3% (11/33) and the disease control rate was 90.9% (30/33). The median progression-free survival (mPFS) was 6.9 months. In clinical trials in combination with cetuximab, the objective response rate was 62.8% (27/43) and the disease control rate was 93% (40/43). As of 23 May 2023, median progression-free survival data are not yet available. From the safety data, treatment-related adverse events (TARE) with monotherapy and combination drugs were mainly grade 1-2.

Colorectal cancer is the second most common tumor in China, with about 550,000 new cases per year, of which about 3% of colorectal cancer patients have KRAS G12C mutation. Patients with the KRAS G12C mutant gene are insensitive to existing standard chemotherapy and targeted therapies, have rapid disease progression, short survival, and have a high unmet clinical treatment need. Glarese promises to bring more treatment options to patients.

• Grand Pharma's Global Innovative RDC domestic phase I clinical trial completed the first patient enrollment administration

On June 27, Grand Pharma announced that its global innovative radionuclide conjugate (RDC) TLX250-CDx (89Zr-TLX250) Phase I clinical trial for the diagnosis of renal clear cell carcinoma (ccRCC) in China has completed the first patient enrollment administration, which is another important R&D progress of GP in the field of nuclear anti-tumor diagnosis and treatment.

The TLX250-CDx domestic phase I clinical trial is a single-arm, open-label phase I clinical study to enroll 10 patients with uncertain renal mass or suspected recurrence of renal clear cell carcinoma, aiming to evaluate the safety, tolerability, radiation dosimetry and pharmacokinetic characteristics of the product for non-invasive detection of renal clear cell carcinoma by positron emission tomography/computed tomography (PET/CT) imaging.

TLX250-CDx is a globally innovative RDC drug for ccRCC diagnostics, targeting carbonic anhydrase IX (CA9), which is overexpressed in ccRCC and many other cancers. TLX250-CDx has been granted breakthrough therapy by the US FDA for its potential breakthrough in the noninvasive diagnosis of ccRCC, the most common and aggressive form of kidney cancer, and in patient follow-up treatment and management decisions.

3. Cancer investment and financing and enterprise dynamics

• Innovent and Remegen reached a clinical research collaboration on new drugs in combination with Cindilimab combined with ADC

On June 26, Innovent Biopharmaceutical Group and Remegen Biopharmaceutical Co., Ltd. announced a clinical research and drug supply cooperation agreement to carry out clinical research cooperation on the combination drug of Cindilimab injection (PD-1 inhibitor, trade name: Daboshu) and a novel antibody conjugate (ADC) RC88 targeting mesothelin (MSLN) and RC108, a novel antibody conjugate drug (ADC) ® targeting interstitial epithelial conversion factor (c-MET).

Under the agreement, Innovent will provide the trial use of Cindilimab injection, and Remegen will conduct a Phase I/IIa study in China to evaluate the safety, tolerability and preliminary efficacy of Cindilimab injection combined with RC88 or RC108 in Chinese oncology patients.

Daboshu ® (Cindilimab injection) is an innovative drug PD-1 inhibitor with international quality jointly developed by Innovent and Eli Lilly, which has been approved for seven indications, of which the first six have been included in the national medical insurance catalog, becoming the only PD-1 inhibitor that includes the first-line treatment of five high-incidence solid tumors (non-squamous non-small cell lung cancer, squamous non-small cell lung cancer, liver cancer, gastric cancer, esophageal cancer) into the national medical insurance catalog. At the same time, it is also the first and only immunotherapy drug in the field of gastric cancer to be included in the national medical insurance catalog.

RC88 is an ADC drug targeting MSLN independently developed by Remegen, which was approved for phase I clinical trial in China in November 2018, and the trial is currently underway, and preliminary results show that RC88 monotherapy has anti-tumor activity and controllable safety against MSLN-expressed solid tumors.

RC108 is an ADC drug independently developed by Remegen Biologics targeting c-MET, which was approved in November 2020 to carry out a phase I clinical trial for c-Met-positive advanced solid tumors in China, and the trial is currently progressing smoothly, and preliminary results show that RC108 monotherapy has anti-tumor activity and controllable safety against c-MET-expressed solid tumors.

Fourth, the week's view

• Aspartame fell into a "carcinogenic" storm

On June 29, the International Agency for Research on Cancer (IARC), an intergovernmental agency of the World Health Organization, issued a statement saying that the potential carcinogenic effects of aspartame had been evaluated in a "hazard identification" study. Next, the Joint Expert Committee on Food Additives (JECFA) of the Food and Agriculture Organization of the United Nations and the World Health Organization will carry out further testing and risk assessment. Finally, the two bodies will release their conclusions simultaneously on July 14.

Aspartame is the most common synthetic sweetener, such as diet cola and sprite, which are used to replace sucrose. Back in May this year, the WHO published a new guide on non-sugar sweeteners, recommending that most people should avoid non-sugar sweeteners such as acesulfame K, aspartame, saccharin, sucralose, stevia, etc.

On June 29, the International Beverage Association Committee (ICBA) responded in a post on its website, saying that public health authorities should be wary of this view because it contradicts decades of high-quality scientific evidence, and conclusions drawn with reference to low-quality scientific studies may mislead consumers in anticipation of a broader and more comprehensive food safety review of aspartame.

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