preface
The approval of the new indication with just the right amount makes it the best arrangement.
On September 30, 2024, Akeso announced that the China Food and Drug Administration (NMPA) approved cadonilimab in combination with fluorouracil and platinum-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.
Cadonilimab is the world's first PD-1/CTLA-4 bispecific antibody, which has been approved for the post-line treatment of cervical cancer in June 2022, and this time "first-line gastric cancer in the whole population" is the second indication.
A few days ago, the United States Food and Drug Administration (FDA) convened a meeting of the Oncology Drug Advisory Committee (ODAC) to reevaluate the use of PD-1 inhibitors in the treatment of gastric cancer. The results of the meeting were approved by a high vote of 10 in favor, 2 against and 1 abstention (10-2), and it was concluded that the risks of PD-1 inhibitors as first-line treatment outweigh the benefits in patients with advanced HER2-negative microsatellite stable gastric and gastroesophageal junction (GEJ) adenocarcinoma with PD-L1 expression less than 1.
Although the FDA has not officially "announced" the tightening of the indication, there is a de facto gap in immunotherapy for the first-line treatment of PD-L1-negative gastric cancer patients. China is a big country for gastric cancer, and among the gastric cancer patients in China, more than half of the patients with PD-L1 CPS<5 and nearly 40% of patients are PD-L1 negative.
As the first immunobispecific antibody drug in the field of gastric cancer, cadonilimab has become the best supplement.
Upgrade! Enter the era of gastric cancer immunity 2.0
Immunotherapy has established itself as a cornerstone in the first-line treatment of gastric cancer.
Compared with traditional treatments such as radiotherapy and chemotherapy, tumor immunotherapy has the advantages of strong specificity and few adverse reactions. For tumor cells that form immune escape, intervening in the body's immune system to reactivate it by external means can restore and improve the body's anti-tumor immune response, and achieve the therapeutic purpose of controlling or even specifically removing the tumor.
In the era of immunotherapy for gastric cancer, the anti-tumor function of chemotherapy has increased the role of activating immunity on the basis of simple tumor killing. For gastric cancer with PD-L1 CPS>5, first-line treatment with PD-1 monoclonal antibody combined with chemotherapy has achieved an overall survival benefit of more than 19 months, and the median overall survival (mOS) of less than 12 months in the era of chemotherapy alone has increased by more than 50%.
However, in patients with low or negative PD-L1 expression, PD-1 monoclonal antibodies are inadequate. After all, as a single-target inhibitor, the abundance of target expression cannot have a small impact on efficacy. In the RATIONALE-305 study, patients with PD-L1 CPS<1 who received PD-1 monoclonal antibody plus chemotherapy even increased the risk of mortality compared with chemotherapy alone, with an HR value of 1.01.
Iterative escalation of immunotherapy is imperative. Dual immune checkpoint inhibition is a viable idea.
PD-1 and CTLA-4 are both mature immune checkpoints that have been developed, and the synergistic effect of the two has been verified in the past few years, but the increased toxicity of PD-1 monoclonal antibody combined with CTLA-4 monoclonal antibody makes its application very limited, and it is currently only included in the level 2 recommendation of dMMR/MSI-H gastric cancer treatment by CSCO guidelines, and cannot be used in combination with chemotherapy.
Cadonilimab as a PD-1/CTLA-4 bispecific antibody successfully broke the deadlock.
It is designed to introduce mutations in the Fc fragment portion of the antibody to eliminate its binding to the Fcγ receptor (FcγRs) and C1q, avoiding Fc-mediated effector functions, including antibody-dependent cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). These properties all help to reduce the toxic effects of the drug.
In addition, compared with PD-1 monoclonal antibody alone, cadonilimab showed higher binding affinity in the environment of high-density PD-1 and CTLA-4 co-expression, which can bind more firmly to the target, increase the drug retention time in the tumor area, and make the treatment more precise. When PD-1 and CTLA-4 are co-expressed in the tumor microenvironment, it also helps to attire toxicity and increase efficiency.
These transformations have brought about qualitative changes in clinical practice, allowing gastric cancer immunotherapy to officially enter the 2.0 era.
Redefine the benefits of the whole population, and the guidelines are recommended in advance
At the 2024 AACR Congress, the interim analysis results of the COMPASSION-15 study, a large-scale phase III clinical trial of cadonilimab for the first-line treatment of gastric cancer, were announced in the form of oral presentations, marking the official arrival of the "dual-engine era" of gastric cancer immunity.
In terms of study design, 22.95% (140/610) of patients were included in PD-L1 CPS<1 and 49.84% (304/610) of patients with PD-L1 CPS<5 in the COMPASSION-15 study, which was more than 10% higher than all the phase III clinical studies of PD-1 monoclonal antibody for gastric cancer indications that have been approved, which is highly consistent with the population distribution of gastric cancer patients in mainland China and provides solid evidence.
For patients with low PD-L1 expression, the results showed that at a median follow-up of 18.69 months, cadonilimab plus chemotherapy achieved an mOS of 14.8 months, which was better than the control group with chemotherapy alone (11.1 months), with an HR value of 0.70, which was the best in both absolute mOS and HR benefit. In the PD-L1 CPS<1 population, the HR value of cadonilimab combined with chemotherapy was also reduced to 0.77, which was a considerable benefit, filling the gap in the treatment of gastric cancer with low PD-L1 expression.
For patients with PD-L1≥5, mOS had not been reached at follow-up (control group: 10.6 months, HR 0.56). In the population, cadonilimab plus chemotherapy also achieved mOS at 15 months (control: 10.8 months, HR 0.62). All subgroup analyses of the COMPASSION-15 study showed efficacy advantages over the Phase III clinical data of PD-1 monoclonal antibodies. Redefined "benefits for the whole population".
The quality of the data and rigorous trial design allowed cadonilimab to be included in the guideline recommendations before it was approved.
In the 2024 CSCO Guidelines for the Diagnosis and Treatment of Gastric Cancer and the 2024 CSCO Guidelines for the Clinical Use of Immune Checkpoint Inhibitors, cadonilimab in combination with chemotherapy has been recommended for the first-line treatment of advanced gastric cancer (HER2-negative) (regardless of PD-L1 expression status).
Since it has not yet been approved, it has only been included in the level III recommendation, but the level of evidence is already category IA among the recommended treatment regimens for all PD-L1 low expression populations, and the gold content has been recognized by authoritative guidelines in China.
Heaven and earth are all working together
In this era when the competition in the immunotherapy market is almost saturated, it is possible to obtain the blessing of the FDA's expert advisory committee before approval, squeezing out a gap in the market, and the approval of cadonilimab is as long as possible.
In gastric cancer, a high-incidence cancer in China, the use of class IA evidence provides a solid evidence-based for more than half of the patients with low PD-L1 expression in China, and the use of cadonilimab is unique.
With the blessing of the right time and place, this drug, which is full of "people" in the development process, has shaped huge market expectations and patient needs.
Reviewer: Squid
Typography: Squid
Execution: Squid
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