This step loads the history of innovative drugs

This is the first time a Chinese pharmaceutical company has taken the lead in the commercialization of a specific innovative therapy.

The authoritative witness of The Lancet confirms that CARSGEN's global first randomized controlled trial (CT041-ST-01 trial) of CAR-T cell therapy in solid tumors has achieved success, demonstrating that Claudin18.2 CAR-T has significant advantages in prolonging progression-free survival (PFS) compared to current standard treatments, with a 63% reduction in the risk of disease progression or death, successfully achieving the primary endpoint. Overall survival (OS) also shows clear clinical benefits, with a 40% reduction in the risk of death for infused patients.

Based on the support of these research results, today, CARSGEN announced that the New Drug Application (NDA) for Claudin18.2 has been accepted by the NMPA, making it the world's first solid tumor CAR-T product to apply for market approval, marking a milestone in the history of innovative drugs.

CARSGEN began clinical research on Claudin18.2 CAR-T in 2017. The company has remained low-profile and has been underestimated by the market until the wave of revaluation of Chinese biotech assets brought it into the spotlight.

CARSGEN is the first in the world to solve the commercialization challenge of solid tumor CAR-T, which is also one of the signs of the rapid advancement of Chinese innovative drugs, evolving from following and parallel upgrading to leading. More significant breakthroughs are expected, and CARSGEN aims to advance solid tumor CAR-T to frontline treatment, exploring the potential for cures; the first universal CAR-T product is also expected to be launched within five years.

01 Giant Achievement

The CT041-ST-01 Phase II trial is the world's first randomized controlled clinical trial of CAR-T therapy for solid tumors, aimed at evaluating the efficacy and safety of Claudin18.2 CAR-T injection compared to the investigator's choice of treatment (TPC) in patients with advanced gastric cancer or gastroesophageal junction cancer (G/GEJC) who have failed prior treatments.

Globally, the CT041-ST-01 trial is the first confirmatory clinical trial to compare CAR-T cell therapy with current standard treatments head-to-head in solid tumors. Its success is a key step in leading global innovative drug research and development from China, achieving the remarkable feat of simultaneously topping three major academic platforms. The results of the CT041-ST-01 trial became the only Chinese study presented in the oral report session on gastric cancer at this year's ASCO conference. Notably, the full research paper was officially published in the prestigious medical journal The Lancet and was selected as the headline on the Nature website on the same day.

Shurui Jiao Lun Sai's treatment for gastric cancer randomized controlled study tops the headlines of The Lancet and Nature's official website.

Shurui Jiao Lun Sai enjoys market exclusivity, which will further promote the transition of CAR-T from niche drugs to large-scale production.

In 2024, the global sales of CAR-T cell therapy are expected to reach approximately $4.5 billion, initially gaining traction in the field of hematological malignancies. However, solid tumors are the main battlefield for CAR-T. According to WHO data, there were 19.758 million new cancer cases globally in 2021, of which approximately 1.305 million were new cases of hematological malignancies, accounting for less than 10%, while the remaining 90% were new cases of solid tumors.

In China, there are 300,000 to 500,000 new gastric cancer cases per year, with over 2 million existing patients, making the market size more than ten times that of hematological malignancies. Compared to overseas, a prominent feature of gastric cancer patients in China is the high proportion of advanced gastric cancer, with about 30% to 40% being inoperable advanced gastric cancer, classified as clinical stage IV, which has extremely poor treatment outcomes.

In the current treatment landscape for advanced gastric cancer, more and more patients have been exposed to anti-PD-1/PD-L1 and anti-angiogenesis treatments in first-line and second-line therapies, and after failing second-line treatment, they find themselves in a situation with no available drugs.

Most antibody or ADC drugs targeting Claudin18.2 positive G/GEJC are still in the experimental stage, and such treatments still involve chemotherapy components or require combination chemotherapy, necessitating repeated hospitalizations for patients, which may lead to cumulative toxicity from drug overlap and long-term periodic medication. In contrast, patients receiving Shurui Jiao Lun Sai treatment theoretically only need 1-3 hospitalizations, with common adverse events mainly concentrated in the early phase after CAR-T infusion, greatly alleviating the treatment burden and creating hope for patients to return to their daily lives.

In the clinical context of patients having "no available drugs," Shurui Jiao Lun Sai, with its breakthrough long-term survival benefits and broader positive criteria covering a larger proportion of the patient population, will effectively fill the gap for effective treatment after second-line failure in advanced gastric cancer, and is expected to become a new standard treatment for advanced gastric cancer.

The collective endorsement from top international journals and high recognition from the medical community provide strong confidence for the commercialization success of Shurui Jiao Lun Sai.

02 Actual Efficacy Underestimated

Everyone learns statistics; this is the phenomenon that occurs whenever key clinical data is released, indicating that no one wants to miss the historical opportunity of innovative drug emergence. However, there may be a gap between scientific facts and public intuitive understanding, so today we will provide a lesson.

Patients with solid tumors are in poor physical condition and have a heavy disease burden at the end stage. Even with CAR-T, efficacy is limited; an increase in PFS by several months or doubling it actually plays a role in "turning the tide" and "supporting a collapsing building," representing a critical breakthrough compared to standard treatment.

The strong never complain about the environment; the actual efficacy of Shurui Jiao Lun Sai is underestimated, as it is in an unfavorable condition in clinical trial design, yet its survival benefits still far exceed those of standard treatment.

What impact does baseline design have? In clinical research, "baseline" refers to the state data of research subjects before receiving any intervention, serving as a benchmark for subsequent assessments. The CT041-ST-01 Phase II trial is a randomized controlled trial (RCT), with the core difference from previous single-arm trials being the selection of the baseline: single-arm trials use the tumor burden before infusion as the baseline, while RCTs use the tumor burden at enrollment as the baseline.

How does the baseline affect efficacy assessment? Suppose a patient has a tumor burden of 20 at enrollment, progresses to 40 during the CAR-T preparation period (about 3 weeks), and then decreases to 30 at the first efficacy assessment after infusion, indicating a 25% tumor reduction. However, the RCT uses 20 (tumor burden at enrollment) as the baseline, which is deemed disease progression, leading to an underestimation of actual efficacy. In contrast, the single-arm trial uses 40 (tumor burden before infusion) as the baseline, which is deemed tumor remission, clearly reflecting efficacy. The baseline design of the RCT significantly hampers ORR, PFS, and OS.

This raises another question: why not set the first efficacy assessment time longer to allow patients to achieve greater remission? The median PFS in the control group (standard treatment) is only 1-2 months, and the trial group is also set for the first assessment at 6-8 weeks. Extending the assessment time would distort the control group data.

In summary, the RCT trial of Claudin18.2 CAR-T cannot be directly compared to single-arm trials or ADC class drugs due to differences in baseline design or treatment lines.

The "underestimation effect" observed in RCT trials shows that subjects had an increase in tumor size at the first efficacy assessment compared to baseline, but subsequent follow-ups indicated continued tumor reduction. About 50% of patients who received a second or third infusion could further observe tumor shrinkage or improvement in trends. Patients who were assessed as PD (disease progression) at the first efficacy evaluation would also lose the opportunity for re-infusion, further affecting their PFS and OS. Additionally, patients have significant concerns about potentially being randomly assigned to the control group in RCT trials, thus unable to receive CAR-T treatment, leading to delays in enrollment willingness and relatively poorer disease status and tolerance at the actual trial entry.

What impact do baseline characteristics have?

The CT041-ST-01 trial includes the most difficult and challenging patient population in clinical practice. In previous clinical trials for advanced gastric cancer, the proportion of signet-ring cell carcinoma was about 15%-30%, the proportion of Lauren classification diffuse/mixed type was about 20%-50%, and the proportion of peritoneal metastasis was about 19%-26%. This trial population shows worse baseline characteristics, specifically manifested as: a high proportion of signet-ring cell carcinoma (about 40-50%), a prominent proportion of Lauren diffuse/mixed type (about 70%), a high number of metastatic organs, especially a very high proportion of peritoneal metastasis (about 60-70%), all of which are significant adverse prognostic factors affecting patient survival.

Against this background of disease characteristics, Surufatinib not only shows statistically and clinically significant efficacy improvement compared to the control group but also has a clear advantage over historical data of the control group drugs previously used in the entire population without Claudin18.2 selection What impact does the "filter" have?

Currently, CAR-T therapy for hematological malignancies is conducted using single-arm studies. Vinay Prasad, the new director of the FDA CBER, questions the clinical trial design of CAR-T therapies for hematological malignancies, pointing out that excluding patients with manufacturing failures or disease progression in single-arm trials leads to inflated response rates. If all patients were included, the results could be significantly different.

It's like an exam where some candidates do not submit their papers, but only the scores of those who submitted are counted, resulting in biased outcomes. Excluding patients who did not receive CAR-T infusion in clinical analysis is akin to applying a "filter" to the results, exaggerating the efficacy.

The CT041-ST-01 trial is a randomized controlled trial that honestly has no filters; clinical analysis includes all populations. Due to 16 patients in the trial group not receiving infusion because of rapid disease progression, the overall efficacy is affected. In the real world, early collection and preparation of CAR-T could reduce the proportion of these patients.

What impact does crossover treatment have?

The CT041-ST-01 trial allows patients in the control group to cross over to receive CAR-T treatment after disease progression, reflecting a patient-centered approach to care. However, the control group's receipt of CAR-T treatment will inevitably extend overall survival (OS), thus diluting the significance of the trial group's benefits.

Faced with the challenge of 16 patients in the trial group not receiving infusion and 20 patients in the control group subsequently receiving CAR-T treatment, the trial group still showed a 31% and 40% reduction in mortality risk in the intention-to-treat (ITT) and modified intention-to-treat (mITT) populations, respectively. After adjusting for crossover treatment effects using the RPSFT model, the trial group demonstrated more pronounced survival benefits, with a median OS approximately doubled compared to the control group, and mortality risk reduced by 53% and 63% in the ITT and mITT populations, respectively.

Combining all 108 patients who actually received CAR-T treatment (including 88 from the trial group and 20 from the control group who crossed over) for analysis, the median OS reached 9.17 months, while the median OS for control group patients who did not receive CAR-T infusion was only 3.98 months, further indicating that Shurui Jiao Lun Sai provides clear survival benefits in real clinical use.

03 Challenges in Early-Line Cure of Solid Tumors

Lastly, there is a bonus.

Professor Shen Lin and Professor Qi Changsong, the principal investigators of the CT041-ST-01 trial at Peking University Cancer Hospital, presented updated data with an additional 5 months of follow-up in an oral report at ASCO. In both the ITT and mITT populations, the median OS of the trial group was further extended, surpassing the control group by 2.7 months and 4.0 months, respectively, demonstrating the durability of Shurui Jiao Lun Sai's benefits on patient OS and its immense value for long-term survival.

Shurui Jiao Lun Sai holds the potential to surpass other drug types and is expected to cure solid tumors in early or early-line treatment. Early and effective treatment methods are crucial for extending the survival and maximizing benefits for cancer patients. Currently, Shurui Jiao Lun Sai treatment for patients with advanced gastric cancer at the end stage (third line and above, about 25% are fourth line, with severe conditions) still shows significant survival benefits, with efficacy far exceeding existing standard treatments. If CAR-T therapy can be applied in the early stages of the disease or early treatment phases, when patients' immune and organ function states are better, it may achieve greater and more lasting benefits.

According to previously published data, among 5 patients with gastric/esophagogastric junction adenocarcinoma receiving first-line sequential treatment with Shurui Jiao Lun Sai, only 1 patient receiving standard first-line treatment achieved objective remission, 3 patients did not respond to standard first-line treatment, and 1 patient could not tolerate standard first-line treatment. However, after sequential administration of Shurui Jiao Lun Sai, all 4 patients with target lesions showed further reduction in tumor burden, achieving objective remission. The median progression-free survival (mPFS) calculated from the start of Shurui Jiao Lun Sai infusion was 15.2 months, and the median overall survival (mOS) was 16.4 months, with 2 patients undergoing conversion surgery after infusion of Shurui Jiao Lun Sai, with overall survival exceeding 36.0 months and 39.0 months, respectively, and both are still alive.

With the advancement of treatment stages, Shurui Jiao Lun Sai is expected to reshape the disease process through earlier intervention, providing patients with a longer survival benefit window and even exploring potential cure possibilities. Shurui Jiao Lun Sai is currently conducting a Phase Ib clinical trial in China for adjuvant treatment of pancreatic cancer, exploring sequential CAR-T treatment after first-line treatment for advanced gastric cancer, as well as CAR-T consolidation treatment after postoperative adjuvant chemotherapy, aiming to see more advanced patients gain surgical opportunities and early patients extend recurrence-free time or even achieve cure.

In fact, CARsgen Pharmaceuticals has been exploring the possibility of CAR-T curing solid tumors. Previously reported cases of 2 patients with advanced liver cancer treated with local therapy combined with CAR-T cell infusion have achieved 9 years of disease-free survival. The CAR-T technology, which involves genetically engineering T cells to redirect them to recognize and eliminate tumors, brings hope to cold tumors that do not respond well to PD-1/PD-L1 antibody treatment, and may more likely target and eliminate residual tumor cells after surgery to achieve a cure (PD-(L1) antibodies have not succeeded in adjuvant treatment for gastric/liver cancer, leaving chemotherapy as the only adjuvant treatment for gastric cancer and no standard treatment for liver cancer).

Innovation never sleeps; pharmaceutical innovation has no rest stops or endpoints, only the next station. The successful experience accumulated by CARsgen Pharmaceuticals in solid tumors CAR-T is nurturing the next generation of products. For solid tumors, CARsgen Pharmaceuticals is also developing a universal CAR-T candidate product KJ-C2114.

Curing cancer while ensuring accessibility is the goal that CARsgen strives for.

Chinese innovative drugs are increasingly becoming leaders in more fields, bringing greater benefits to patients with their unique efficiencies.

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