Jacobio Pharma’s oncology combination of glecirasib and sitneprotafib has shown promise during an early-stage trial as a first-line treatment for non-small cell lung cancer (NSCLC).
In the Phase I/IIa trial (NCT05288205), the combination, of glecirasib, a Kirsten rat sarcoma G12C (KRAS G12C) inhibitor and sitneprotafib, an Src homology-2 protein tyrosine phosphatase (SHP-2) inhibitor, triggered an objective response rate (ORR) of 71% in 102 previously untreated NSCLC patients.
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Alongside its ORR impact, glecirasib-sitneprofatib also touted a 12.2-month median progression-free survival (PFS) rate in the first-line NSCLC setting.
The combination triggered Grade 3 and 4 treatment-emergent adverse events (TEAEs) in 46% of patients. The most common TEAEs of any grade were anaemia and hypertriglyceridaemia, which impacted 61% and 60% of the 171 patients enrolled, respectively.
Despite this, only three patients discontinued treatment with glecirasib and sitneprofatib due to TEAEs.
According to the Beijing, China, headquartered company, this shows the combination has potential to be a fully oral, chemotherapy-free solution for the KRAS G12C-mutant NSCLC population. It is currently estimated that 10-13% of patients with NSCLC present with a KRAS G12C mutation.
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By GlobalDataIn 2024, Jacobio initiated a Phase III trial on glecirasib-sitneprofatib for the treatment of frontline, KRAS G12C-mutated NSCLC in China following approval from China’s Centre for Drug Evaluation (CDE).
If the combination proves efficacious in this study, it could become the first incorporating an SHP-2 inhibitor to gain regulatory approval, further opening a potential new target avenue for solid tumours.
The combination would also push glecirasib to the first line setting, following its approval as a monotherapy for second-line NSCLC throughout China in May 2025. In a registrational study, the drug demonstrated an ORR of 49.6%.
Drugging the ‘undruggable’
While KRAS has long been acknowledged as one of the most commonly mutated oncogenes across solid tumour indications, it has traditionally been a challenging target.
This is due to its structure, which presents few regions in which a drug can successfully bind to it, leading some to consider it an ‘undruggable’ protein.
Despite the hurdles associated with KRAS-targeting drug development, two therapies have gained approval from the US Food and Drug Administration (FDA) thus far in NSCLC. This includes Amgen’s Lumykras (sotorasib) and Bristol Myers Squibb (BMS)-owned Mirati Therapeutics’ Krazati (adagrasib), which got the regulatory greenlight in 2021 and 2022, respectively.
GlobalData’s patient-based forecast predicts that Krazati will reach $281m in NSCLC sales in 2031. Across all its approved indications, which includes colorectal cancer, the drug is expected to bring in global sales of $779m in the same year.
Meanwhile, analysts predict that Lumykras’ global sales will peak at $585m in 2031, with $242m of that in NSCLC.
The sales growth of Krazati and Lumykras will come amid the ballooning worth of the NSCLC market, which analysts forecast will be worth $63.4bn across the seven major markets (7MM: the US, France, Germany, Italy, Spain, the UK and Canada) by 2032.
GlobalData is the parent company of Clinical Trials Arena.
