Highlights of CStone's sugalimab in the treatment of stage III/IV NSCLC concurrently published in "The Lancet-Oncology"

Yimaike's recent hot reports ★CStone Pharmaceuticals and Hengrui Medicine reached a strategic cooperation of 1.
3 billion yuan to accelerate the development and commercialization of tumor immune skeleton products ★The combination of CAR-M and anti-PD-1 therapy to target solid tumorsYimai Meng broke the news in 2022 January 17th/eMedClub News/--The Lancet Oncology, the world’s top clinical oncology research journal, published an online publication of CStone’s sugelimab (Zetemy® ) results of a registration clinical study (GEMSTONE-301) in the treatment of stage III non-small cell lung cancer (NSCLC) and a randomized double-blind registration clinical study (GEMSTONE-302) in the first-line treatment of stage IV NSCLC
.

It is worth mentioning that a review article published in The Lancet-Oncology at the same time affirmed that sugelimab improved progression-free survival in patients with unresectable or metastatic NSCLC, and further proved that Immunotherapy can benefit patients with stage III/IV NSCLC
.

The results of the two clinical studies have once again appeared on the international academic stage, fully demonstrating the great academic value and clinical potential of sugelimab
.

Based on the results of the GEMSTONE-302 study, sugelimab has been approved in China in combination with chemotherapy for the first-line treatment of metastatic NSCLC
.

At the same time, based on the research results of GEMSTONE-301, the new drug marketing application for stage III NSCLC is under review by the China National Medical Products Administration and is expected to be approved this year
.

The pioneering experimental design covers the stage III/IV NSCLC population.
Lung cancer ranks first in the country and is the malignant tumor with the highest mortality rate.
NSCLC accounts for about 80%-85% of all lung cancer cases
.

70% to 80% of NSCLC patients are already in locally advanced stage (stage III) or distant metastasis (stage IV) at the time of initial diagnosis.
The number of new lung cancer cases is about 820,000, that is, about 656,000 to 697,000 new cases of NSCLC every year, of which about 459,200 to 557,600 are in stages III and IV
.

The standard chemotherapy regimen for NSCLC is a platinum-containing double-drug regimen, including gemcitabine combined with docetaxel, vinorelbine combined with platinum, and pemetrexed combined with cisplatin for the treatment of non-small cell non-squamous cell carcinoma
.

In addition, NSCLC can be divided into driver gene positive and driver gene negative.
For NSCLC patients with driver gene positive (EGFR, ALK, ROS1, RET, etc.
) Mainly for platinum doublet chemotherapy, anti-angiogenic drugs combined with chemotherapy
.

In recent years, with the development of immunotherapy represented by PD-(L)1 inhibitors, it has brought better combination treatment options for patients without driver gene mutations
.

At present, 12 PD-(L)1 mAbs have been marketed in China, including 8 PD-1 mAbs and 4 PD-L1 mAbs
.

As shown in the table above, 8 PD-(L)1 mAbs have been approved for the treatment of lung cancer in China
.

➤GEMSTONE-302 lung cancer patients covering stage IV squamous cell carcinoma and non-squamous cell carcinoma NSCLC patients have different treatment regimens due to differences in clinical manifestations, histological subtypes and biomarkers
.

The clinical trials of corresponding immunotherapy drugs also have different designs
.

Specifically for stage IV NSCLC patients, in addition to GEMSTONE-302 of sugalimab, the other PD-(L)1 clinical trial designs that have been approved for first-line treatment of stage IV NSCLC are all two types of PD-(L)1.
NSCLC was divided into two studies for patient enrollment
.

The GEMSTONE-302 study is the world's first randomized double-blind phase III clinical study of PD-L1 inhibitor combined with chemotherapy covering both stage IV squamous and non-squamous first-line metastatic NSCLC.
The innovative design requires two large phase III clinical trials The results that can only be obtained by research can be achieved in a phase III study, which greatly reduces the cost of resources and time, and brings both clinical and commercial success
.

Results of the analysis through 2021 at a median follow-up of 17.
8 months showed a median PFS of 9.
0 months for sugalimumab plus chemotherapy and a median PFS of 4.
9 months for placebo, with a hazard ratio (HR) of 0.
48
.

The combination of sugalimab with chemotherapy significantly enhanced the benefit of progression-free survival in patients with the primary efficacy endpoint
.

The results of the PFS subgroup analysis showed that both squamous and non-squamous NSCLC patients showed significant clinical benefit
.

In addition, the HR was 0.
56 in patients with PD-L1 expression <1%, and the benefit was more pronounced in patients with PD-L1 expression ≥1%
.

Compared with the published data of several other PD-(L)1 mAbs, the GEMSTONE-302 study not only covers a wider population, but its therapeutic effect can also comprehensively compete with other PD-(L)1
.

Especially in patients with squamous cell carcinoma, the efficacy of sugelimab combined with chemotherapy was more significant, and the risk of disease progression or death was reduced by 66%
.

➤Expanding concurrent chemoradiotherapy to sequential chemoradiotherapy GEMSTONE-301 for stage III NSCLC patients returns to the stage III NSCLC patient population, and stage IIIA patients undergo surgery after neoadjuvant chemotherapy, and there is a high chance that radical surgery can be achieved
.

However, patients with stage IIIA-N2, IIIB and IIIC are inoperable lung cancer.
According to NCCN guidelines, the preferred treatment for locally advanced lung cancer patients who cannot undergo radical surgery is concurrent chemoradiotherapy
.

If the constitution is not good, sequential radiotherapy and chemotherapy can be used, so that the toxic and side effects are relatively small, and the patient can tolerate it
.

According to public data, less than 30% of Chinese patients are suitable for concurrent chemoradiotherapy, and the rest are sequential chemoradiotherapy patients
.

The only approved consolidation therapy for stage III NSCLC is durvalumab only for patients with concurrent chemoradiotherapy
.

For domestic patients, 70% of NSCLC patients with sequential chemoradiotherapy currently have no PD-(L)1 antibody available
.

This is the most significant value of the GEMSTONE-301 study, sugalimab brings PD-(L)1 antibody therapy to patients with stage III NSCLC who have undergone sequential chemoradiotherapy
.

The results of the GEMSTONE-301 study showed that compared with the placebo group, sugelimab significantly improved the progression-free survival of patients, the difference was statistically significant and clinically significant, the median PFS was 9.
0 months vs 5.
8 months, HR is 0.
64
.

The median PFS in the concurrent chemoradiotherapy group was 10.
5 months vs 6.
4 months, and the HR was 0.
66 (95%CI: 0.
44, 0.
99); the median PFS in the sequential chemoradiotherapy group was 8.
1 months vs 4.
1 months, and the HR was 0.
59 (95% CI: 0.
44, 0.
99).
CI: 0.
39, 0.
91), both concurrent and sequential chemoradiotherapy patient subgroups showed clinical benefit
.

Once approved, this will be the "enclosure" of sugelimab.
According to the clinical registration application currently available on CDE, it is estimated that this exclusive time will be as long as 3 years
.

At the same time, sugelimab is expected to become the first PD-(L)1 mAb in the world to cover the entire population of stage III and IV NSCLC at the same time
.

The multi-indication clinical progress is gratifying and the prospect is promising.
In addition to the impressive data obtained in stage III and IV NSCLC, sugelimab has been registered in a phase II clinical trial for lymphoma (GEMSTONE-201), as well as gastric and gastric cancer.
Phase III registration clinical trials for esophageal cancer have shown good prospects
.

➤ Natural killer/T-cell lymphoma Natural killer/T-cell lymphoma (ENKTL) is a subtype of mature T- and NK-cell lymphomas
.

A multicenter pathological analysis of 10,002 lymphoma patients in China in 2012 showed that ENKTL accounted for about 6% of all lymphomas and 28% of mature T-cell and NK-cell lymphomas
.

R/R ENKTL is highly malignant and aggressive
.

Clinically, there has been a lack of effective therapeutic drugs, resulting in a low cure rate and poor prognosis of the disease
.

On January 13, CStone Pharmaceuticals announced that the registrational clinical study (GEMSTONE-201) of sugalimumab in the treatment of relapsed or refractory extranodal natural killer cell/T-cell lymphoma (R/R ENKTL) achieved the primary endpoint.

.

This is the third pivotal clinical study of sugelimab following the Phase III and IV NSCLC registration studies
.

Earlier, sugalimab was granted Orphan Drug Designation (ODD) by the US FDA for the treatment of T-cell lymphoma and Breakthrough Therapy Designation (BTD) for the treatment of adults with R/R ENKTL, and It was included in the "Breakthrough Therapy Drug" by the China National Medical Products Administration Evaluation Center, and the proposed indication is relapsed or refractory extranodal natural killer cell/T-cell lymphoma
.

At present, no PD-1 or PD-L1 antibody has been approved for the treatment of R/R ENKTL, so the NDA of sugalimab for R/R ENKTL is very much anticipated
.

➤Gastric cancer According to the National Cancer Center, gastric cancer is the second most deadly malignant tumor after lung cancer
.

The incidence of gastric adenocarcinoma accounts for more than 90% of gastric malignant tumors.
About 40%-60% of gastric adenocarcinoma patients have developed advanced disease when they are diagnosed, and the treatment methods are limited
.

 CStone Pharmaceuticals uses sugalimab combined with the XELOX regimen (oxaliplatin + capecitabine) as the first-line treatment for patients with advanced gastric adenocarcinoma or gastroesophageal junction adenocarcinoma
.

Research data presented at the 2020 CSCO Annual Meeting showed that the objective response rate as assessed by the investigator was 62.
1%, the disease control rate was 82.
8%, the median progression-free survival was 8.
3 months, and the median overall survival was 17.
0 months.

.

The good safety and tolerability of sugalimab combined with XELOX regimen provides data support for the ongoing phase III clinical trial, which is expected to benefit more gastric cancer patients in the future
.

➤Esophageal squamous cell carcinoma The new cases and deaths of esophageal cancer in China account for more than 50% of the world, and more than 90% of the patients are squamous cell carcinoma; at present, the first-line treatment of advanced esophageal squamous cell carcinoma mostly adopts platinum-based chemotherapy regimen , but with limited efficacy and no immunotherapy drugs are approved
.

CStone has developed sugalimab in combination with cisplatin and fluorouracil (CF) chemotherapy as a first-line treatment for esophageal squamous cell carcinoma
.

As of July 1, 2019, the results of the 1b clinical trial of the regimen showed good anti-tumor activity, the ORR reached 77.
8%, and the remission was sustainable
.

It can be seen that sugelimab has also shown great potential in the treatment of esophageal squamous cell carcinoma, and is expected to bring new treatment options for patients with esophageal squamous cell carcinoma
.

Multi-product strategy to form a lung cancer treatment array The development of immunotherapy drugs in China is getting faster and faster.
From the first approval of two imported PD-1 inhibitors in 2018, to the end of 2021, just three years later, there are 12 domestic drugs.
PD-(L)1 inhibitors are approved, covering 44 indications
.

It can be said that this is the best era of PD-(L)1 inhibitors, and it is also the era of the most powerful "involution".
How can we stand out? Effectively addressing the urgent needs of cancer patients has become a question that each "player" needs to answer
.

CStone has built a strong product pipeline around sugelimab in lung cancer
.

The first commercialized drug in 2021, Pujihua®, is a targeted drug for RET fusion-positive mutation-driven lung cancer.
It was approved for marketing in March and is the first domestically approved selective RET inhibitor for RET Second-line therapy in patients with fusion-positive NSCLC
.

There are more than 80,000 new RET-mutant cancer patients (including lung adenocarcinoma) in China every year.
CStone is currently actively expanding the first-line treatment of RET fusion-positive NSCLC and thyroid cancer
.

In June 2021, CStone and Pfizer announced the joint development of lorlatinib in Greater China for patients with ROS1-positive advanced NSCLC
.

There are about 10,000 to 20,000 new ROS1-positive patients in China every year
.

In November 2021, CStone Pharmaceuticals and Hengrui Medicine reached a strategic cooperation and exclusive license agreement in Greater China for CTLA-4 mAb CS1002
.

Although the oncology market is extremely complex, understanding the market around one disease area and using different varieties to cover a wider patient population will surely bring tangible benefits to companies and patients, and CStone has achieved this in the field of lung cancer
.

Excellent products help value return.
With its excellent characteristics, sugalimab has completed full coverage of advanced NSCLC patients for the first time, including patients with stage III concurrent chemoradiotherapy and sequential chemoradiotherapy, and stage IV squamous cell carcinoma and non-squamous cell carcinoma patients
.

This time, the two innovative research data of GEMSTONE-301 and 302 were published in the same period of The Lancet, which is a high recognition of CStone's clinical research and development level and the quality of clinical research, and also a manifestation of the excellent clinical value of sugelimab
.

In 2021, CStone's commercialization capabilities will begin to highlight.
With the opening of the market for various approved products, CStone is believed to deliver a dazzling report card in 2022
.

Under the circumstance that the US and Chinese concept stocks are "sorrowful" and the innovative drug sector of Hong Kong stocks generally plummets, CStone Pharmaceuticals will also return to a reasonable market value level
.