JAB-21822 (Glecirasib), a Novel KRAS G12C Inhibitor by Jacobi Pharma, Shows Promising Efficacy and Safety in Phase I/II Clinical Trials for Advanced Solid Tumors

To date, two KRAS G12C inhibitors have been launched globally: sotorasib from the U.S. company Amgen and adagrasib from the U.S. company Mirati Therapeutics. In China, no KRAS G12C inhibitor has yet been approved for market entry, but competition in this therapeutic area is intensifying. Notably, Jacobio Pharmaceuticals’ KRAS G12C inhibitor, glecirasib (JAB-21822), has demonstrated promising clinical results and is poised to become the first such agent approved in the Chinese market.

To accelerate the development of glecirasib, Jacobio has currently initiated multiple Phase I/II clinical trials in China, the United States, and several European countries for patients with advanced solid tumors, including pivotal clinical trials in non-small cell lung cancer and pancreatic cancer in China, as well as combination therapy studies with the SHP2 inhibitor JAB-3312 and cetuximab.

On September 25, at the 8th China Pharmaceutical Innovation and Investment Conference, Professor Shi Yuankai from the Cancer Hospital of the Chinese Academy of Medical Sciences announced the preliminary results of the Phase I/II clinical trial of Gleverese.Professor Shi Yuankai is a leading authority in medical oncology in China, particularly in the fields of lung cancer and lymphoma. With over 30 years of experience in cancer treatment, he has spearheaded hundreds of clinical trials for domestically developed new drugs and biosimilars. As the principal investigator for the lung cancer indication of glecirasib, he shared updates on the drug’s development progress at the “Global Premiere of Clinical Data” session of the 8th China Pharmaceutical Innovation and Investment Conference.

After the meeting,Ding Yuli, Senior Vice President of Clinical Development at Jacobio, further elaborated on the R&D progress in the KRAS G12C inhibitor landscape and outlined Jacobio’s future pipeline strategy.

“Since the launch of EGFR inhibitors, lung cancer treatment has gradually entered the era of targeted therapy. As the first oncogene ever discovered, KRAS underwent more than 40 years of research and development, with its first approved drug launched in the United States in 2021. China’s independently developed KRAS G12C inhibitors, such as gleorasib, are currently undergoing clinical trials,” introduced Professor Shi Yuankai.

During the Clinical Data Sharing Session,Professor Shi Yuankai stated that in the 800 mg once-daily oral dosing group of glecirasib, the objective response rate (ORR) was 42.5% and the median progression-free survival (mPFS) was 9.6 months among patients with advanced non-small cell lung cancer receiving second-line or later therapy.These data indicate that over 40% of patients experienced a tumor reduction of more than 30% after treatment, and half of the patients showed no further disease progression within 9.6 months of therapy. “Given the rapid progression of advanced lung cancer, a median progression-free survival (mPFS) exceeding 9.6 months delivers clinical benefit to patients.”

The following are excerpts from Professor Shi Yuankai’s report and key clinical data on Gleceirasib:

The Phase I study of glecirasib conducted comprehensive dose exploration, evaluating different dosing frequencies including once daily (QD), twice daily (BID), and three times daily (TID), and enrolled 56 patients with advanced solid tumors. Based on safety, efficacy, and pharmacokinetic (PK) results, the study team selected 400 mg QD and 800 mg QD for dose expansion, enrolling 30–40 patients with non-small cell lung cancer (NSCLC) in each cohort to compare efficacy and safety. As of the data cutoff date, the objective response rate (ORR) was 36.7% and the median progression-free survival (mPFS) was 5.6 months in the 400 mg QD group, while the ORR was 42.5% and mPFS was 9.6 months in the 800 mg QD group. Clinically meaningful efficacy was observed in patients receiving 400 mg QD; however, patients in the 800 mg QD group demonstrated superior long-term treatment benefits.

Based on the robust results from Phase I/II clinical studies, in September 2022, the Center for Drug Evaluation (CDE) approved a registrational clinical trial of glecirasib for non-small cell lung cancer (NSCLC), which is a single-arm trial granted conditional approval. Additionally, in November 2022, glecirasib received Breakthrough Therapy Designation from the CDE for the NSCLC indication.

Currently, patient enrollment has been completed for the single-arm, registrational Phase IIb clinical trial of glecirasib in non-small cell lung cancer (NSCLC). The inclusion criteria were patients with advanced NSCLC harboring KRAS G12C mutations who had experienced failure of standard therapy after ≥2 prior lines of treatment. The primary endpoint was the objective response rate (ORR) assessed by an independent review center according to RECIST 1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and duration of response (DOR). Additionally, safety and pharmacokinetics were evaluated, and exploratory biomarker studies were conducted.

In addition to the clinical trials of glecirasib for non-small cell lung cancer, studies on colorectal cancer and pancreatic cancer are also underway.

Colorectal cancer is the second most common malignancy in China, with approximately 550,000 new cases diagnosed annually. Among these patients, about 3% harbor the KRAS G12C gene mutation.Preliminary clinical data from the late-stage colorectal cancer study of Glecirasib indicate that the drug demonstrates a favorable safety profile and good tolerability, both as monotherapy and in combination regimens.Currently, a Phase III clinical trial of glecirasib in combination with cetuximab is being planned.

Meanwhile, Glecirasib has also been approved to conduct registration-enabling clinical trials for the indication of pancreatic cancer. Pancreatic cancer is known as the “king of cancers” due to its high malignancy; current treatment options yield poor outcomes, with a five-year overall survival rate of only 5%.In August 2023, the pancreatic cancer indication for Glecloserib received “Breakthrough Therapy Designation” from the Center for Drug Evaluation of the National Medical Products Administration, and its registrational clinical trial is currently underway.Furthermore, Glecloset is the first KRAS G12C inhibitor globally approved to conduct pivotal clinical trials for pancreatic cancer, and we are currently designing the protocol for a global multicenter clinical study.

Finally, I would like to express my sincere gratitude once again to all investigators and participants in the glecirasib clinical trial, especially the participants and their families. Thank you all!

Approximately 70,000 new patients with KRAS G12C-mutant tumors are diagnosed annually in China, including about 40,000 cases of lung cancer. For non-small cell lung cancer (NSCLC) with KRAS G12C mutations, Gleclorasib has completed patient enrollment in its pivotal clinical trials and has received “Breakthrough Therapy” designation from the Center for Drug Evaluation of the National Medical Products Administration.It is understood that Glelesel will submit a new drug application for market approval in the first half of 2024.

In addition to glecirasib, Jacobio is also actively expanding its other oncology therapeutic pipelines. To provide a more comprehensive understanding of Jacobio’s future strategic plans for its product pipeline, Dr. Yuli Ding, Senior Vice President of Clinical Development at Jacobio, offered detailed insights.

Q: As a KRAS G12C inhibitor, what is the innovativeness of Gleorasib?

Ding Yuli:Over the past 40 years, KRAS has remained a notoriously undruggable oncogene, primarily due to the smooth surface of the KRAS protein, which makes it difficult to identify binding sites for inhibitors. Furthermore, KRAS exhibits extremely high affinity for its substrates, GDP and GTP, with dissociation constants (KD) in the picomolar range, posing significant challenges for the development of small-molecule inhibitors capable of competitively binding to KRAS.

Thus, Jacobio and other companies developing KRAS G12C inhibitors are overcoming the challenge of "undruggability" through covalent binding. Jacobio is primarily leveraging its allosteric site platform technology to develop KRAS G12C inhibitors.

Q: Jacobio completed its Phase II clinical trials in a relatively short period and achieved impressive results in terms of safety and efficacy. Are there any relevant experiences or insights you can share?

Ding Yuli:Regarding the development efficiency of KRAS G12C inhibitors, it is well known that competition in this field is intense. There are more than 10 domestic companies with comparable products in preclinical and clinical stages. We were the fifth company to obtain an Investigational New Drug (IND) approval, receiving clearance from the Center for Drug Evaluation (CDE) in May 2021.

In September 2022, Jacobio initiated its registrational clinical study, completing dose escalation and expansion within one year. By September 2023, we had completed patient enrollment for the pivotal registrational study. This means that Jacobio accomplished the entire clinical development process—from first patient dosing to the completion of patient enrollment in the registrational study—in just two years, demonstrating remarkable efficiency.

Jacobio has a clear clinical trial design strategy. In early-phase trials, we conducted thorough dose exploration by evaluating different dosages and administration frequencies to identify the optimal dose. Furthermore, during the initial dose-escalation phase, we simultaneously expanded enrollment to include patients with KRAS G12C-mutant tumors, thereby achieving the dual objectives of dose finding and efficacy evaluation while maximizing R&D efficiency.

Furthermore, we adopted a seamless clinical research strategy, integrating innovative designs in current oncology clinical trials. The Ethics Committee employed a hybrid review model combining expedited and full-committee reviews to ensure scientific rigor while efficiently advancing the study.

Q: What challenges remain for KRAS-targeted therapies? In your view, what trends will shape the future of KRAS-targeted drugs?

Ding Yuli:In fact, beyond inhibitors targeting the KRAS G12C mutation, numerous other KRAS mutational sites exist. The industry eagerly anticipates the emergence of novel drugs and therapies that can benefit a broader population of cancer patients.

KRAS G12C inhibitors target only 3%–4% of lung cancer patients. The prevalence in colorectal cancer is approximately 3%, in pancreatic cancer it is 1%, and in other solid tumors such as cholangiocarcinoma, liver cancer, and gastric cancer, the incidence rate is also around 1%. Therefore, the overall patient population eligible for this therapy is relatively limited. In fact, other KRAS mutations, such as G12D and G12V, account for the majority of patients with pancreatic and colorectal cancers, yet there are still no approved therapies available for these individuals. In clinical practice, we frequently receive inquiries from patients with KRAS mutations asking whether they can enroll in Jacobio’s clinical trials. However, upon review, many are found to have non-G12C subtypes and are thus ineligible for enrollment. This is deeply regrettable, and we keenly feel the urgent need for treatment options among these patients.

Jacobio has been conducting R&D focused on the KRAS G12C pathway, but this is merely a starting point. We will continue to develop other KRAS targets in the future.^multiInhibitor: a KRAS inhibitor effective against various KRAS-mutant tumors, including those with KRAS G12D/V/R, G13D, and Q61H mutations^multiThis inhibitor is scheduled for IND submission in the first half of next year, with clinical trials to commence in the second half. The target population will be five times larger than that of KRAS G12C-mutant patients, or even greater.

In addition, we have a single-target inhibitor against KRAS G12D, and the monoclonal antibody LIF targeting the RAS pathway is also under development.

Q: SHIP2 inhibitors are also a key pipeline focus for Jacobio. Could you share any updates on their progress?

Ding Yuli:Jacobio’s SHP2 inhibitor is the second globally to enter clinical trials. After five years of research, it has accumulated clinical data from nearly 500 patients worldwide. Early efficacy signals have been observed in various combination therapies, including those with PD-1 inhibitors and KRAS G12C inhibitors, making the clinical application profile of this target increasingly clear for Jacobio. At the ESMO Congress this October, we will present early data on the combination therapy of our SHP2 inhibitor and glecirasib in an oral presentation. Notably, the volume of data and sample size we are disclosing are the largest among all SHP2 inhibitors globally to date. The data primarily focus on patients with first-line KRAS G12C-mutant lung cancer, demonstrating a substantial improvement in efficacy compared to current standard-of-care treatments. A Phase III study evaluating the combination of glecirasib and the SHP2 inhibitor is currently being planned.

Meanwhile, Jacobio will consider combining its SHP2 inhibitor with its self-developed KRAS^multiCombination with inhibitors to fully leverage SHP2 as a sensitizer for targeted therapy.