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Jacobio Pharma to Seek Approval in China for Glecirasib in KRAS-Mutant NSCLC After Phase II Readout


NEW YORK – After reporting promising data from a pivotal Phase II trial on the activity of glecirasib in KRAS G12C-mutant advanced non-small cell lung cancer, Jacobio Pharma is planning to submit an application seeking approval for the KRAS G12C inhibitor in China.

The Phase II data, presented in April during a plenary presentation webcast by the American Society of Clinical Oncology, was from a trial that included 119 Chinese patients with previously treated locally advanced or metastatic KRAS G12C-mutated NSCLC. A spokesperson for Beijing-headquartered Jacobio said in an email that the company has submitted the data from this study in a new drug application (NDA) seeking approval for glecirasib in the second-line setting in China.

This submission would make glecirasib the second KRAS G12C inhibitor that is presently under review at the Center for Drug Evaluation within the National Medical Products Administration (NMPA) in China, where there are currently no commercially available KRAS-targeted therapies. In November 2023, Innovent Biologics submitted an NDA to NMPA for its KRAS G12C inhibitor IBI351, licensed from GenFleet Therapeutics, as a second-line treatment for advanced NSCLC patients harboring a KRAS G12C mutation. NMPA has not yet issued a decision on that application.

In Asia, KRAS mutations are less common than in the US, Stephen Liu, director of thoracic oncology at the Georgetown Lombardi Comprehensive Cancer Center, said during the ASCO webcast. About 14 percent of NSCLC patients in Asia will harbor any KRAS mutation, while in the US, the incidence is about 30 percent, Liu noted in his discussion of the glecirasib data. Around 4 percent of NSCLC patients in Asia harbor a KRAS G12C mutation, the most common KRAS variant in lung cancer, he said.

In the Phase II trial, 47.9 percent of 119 patients responded to glecirasib, and four patients, or 3.4 percent, achieved a complete response, Yuankai Shi, associate dean at the Cancer Hospital of the Chinese Academy of Medical Sciences, said while presenting the data during the ASCO webcast. The disease control rate, including both responders and patients with stable disease, was 86.3 percent.

The treatment led to deep and durable responses in many patients. About one-third of patients saw their tumors shrink on glecirasib by more than 50 percent. The median duration of response was not reached at a median follow-up of 10.4 months. After the initial response, 73.6 percent of those patients were still responding to treatment at six months and 56.6 percent were still responding at one year.

The median progression-free survival was 8.2 months, with six-month and 12-month progression-free survival rates of 56.6 percent and 40 percent, respectively. Median overall survival was 13.6 months, with 83 percent of patients alive at six months and 55 percent alive at one year.

"This study demonstrated promising efficacy in previously treated KRAS G12C-mutated non-small cell lung cancer patients," Shi said, adding that glecirasib also had a favorable gastrointestinal toxicity profile.

While these efficacy results for glecirasib are slightly better than the performance of other US Food and Drug Administration-approved KRAS G12C inhibitors in NSCLC, such as Amgen's Lumakras (sotorasib) and Bristol Myers Squibb's Krazati (adagrasib), experts cautioned that the study was a single-arm trial with a small population.

"This drug is similar to the current FDA-approved KRAS inhibitors, which both bind in a covalent fashion to the 'off' configuration of KRAS," Julia Rotow, clinical director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, said during the webcast.

Comparing the efficacy of glecirasib, Lumakras, and Krazati across Phase II trials shows a potential "modest improvement" over the approved agents, said Rotow, who was not involved with the glecirasib study. For example, in the Phase II trials of Lumakras and Krazati, median progression-free survival was 6.8 months and 6.5 months, respectively, compared to 8.2 months with glecirasib. Median overall survival in the Phase II glecirasib trial was about a month longer (13.6 months) than what was seen with Lumakras and Krazati (12.5 months and 12.6 months, respectively).

However, comparing between trials isn't ideal, and Rotow noted that the slight improvements in progression-free and overall survival seen with glecirasib may be within the range of cross-trial variation. She pointed out that efficacy results typically decline slightly between Phase II and Phase III trials, because Phase III trials typically enroll a larger population.

"When we look at [KRAS G12C inhibitor] responses of about 40 percent, the natural question is how we can get to where we are with ALK or RET [targeted therapies], where we see an 83 percent response rate," Liu said. "These drugs have progression-free survival measured in years, not months. We're just not there yet; there's a lot of challenges with KRAS inhibition."

On the plus side, glecirasib demonstrated a better safety profile than other KRAS inhibitors, Shi said. Only one patient experienced grade 3 nausea, and a few patients experienced grade 1 or 2 gastrointestinal events.

There were no grade 5 treatment-related adverse events reported in the trial, and the incidence of gastrointestinal events, like nausea and vomiting, was lower than what was reported for other KRAS inhibitors, he added. Five percent of patients in the trial discontinued glecirasib treatment due to an adverse event.

This improved GI tolerability could support more combination approaches, Rotow said. The most common adverse events in the glecirasib trial were blood and liver toxicities, including anemia and increases in certain liver enzymes in the blood.

The data from this Phase II trial, however, still left Rotow with questions about glecirasib's tolerability after patients receive an immune checkpoint inhibitor in the first-line setting. Previous research has suggested that some patients experience severe liver toxicity if they receive Lumakras within 30 days of an immune checkpoint inhibitor, but not all KRAS inhibitors seem to have this issue, Rotow said. The safety data in the glecirasib trial was not broken down by prior treatment type, however, so it is difficult to determine if the KRAS inhibitor has a similar effect after immunotherapy, she said.

To put the glecirasib data into context, Rotow also looked at other strategies for targeting KRAS in clinical development, such as other KRAS (OFF) inhibitors in development at Genentech and Novartis and KRAS (ON) inhibitors being advanced by Revolution Medicines. The next-generation KRAS (OFF) inhibitors have reported some early clinical data with response rates above 50 percent, which Rotow hopes that these drugs are "moving our patients' response rates into a more clinically efficacious range."

"Emerging RAS-targeted therapies continue to offer hope for improved outcomes for patients with KRAS-mutated NSCLC," she added.

While moving glecirasib and another KRAS inhibitor into the first-line setting may improve response rates, the experts cautioned that skipping first-line immunotherapy in order to give a KRAS-targeted therapy may not provide the most benefit to patients.

"In the second line, [using glecirasib] is no problem compared to traditional docetaxel chemotherapy because the overall response rate and progression-free survival are both longer compared to docetaxel," Shi said, adding that further clinical trials are needed to better understand the activity of glecirasib as a single agent and in combination with other agents in the first-line setting. Jacobio is currently only studying glecirasib in the second-line or later setting. The firm also has an ongoing trial of glecirasib in this same setting in the US.

Rotow agreed, adding that if KRAS inhibitors continue to improve patients' outcomes, there may be a time when oncologists will reach for a KRAS-targeted agent over immunotherapy as a frontline option. She also said the KRAS-immunotherapy combinations being tested in the first-line setting, such as in an ongoing trial evaluating Krazati with Merck's checkpoint inhibitor Keytruda (pembrolizumab), may show that the KRAS inhibitor enhances the benefit of immunotherapy in some patients. "I don't think we're there just yet," she concluded.

Liu said for other targeted therapies, such as EGFR, ALK, and RET inhibitors, it makes sense to prescribe the targeted agent over immunotherapy in the first-line setting, "because immunotherapy doesn't work for these [oncogenic drivers]."

"That's not true for KRAS. KRAS-mutant lung cancer can respond and often does respond well to immunotherapy, and in some cases, better than KRAS wild-type [lung cancer]," he continued. "Our standard [in the first line] is immunotherapy because it offers a greater potential for durable benefit and long-term survival."