The SHERLOCK clinical trial was developed to evaluate the KRAS G12C-specific targeted therapy sotorasib as a first-line treatment for non-squamous non-small cell lung cancer (NSCLC) harbouring the KRAS G12C mutation. While sotorasib has already demonstrated meaningful activity in patients previously treated with chemotherapy, resistance inevitably develops through multiple molecular escape pathways.
Why Combine Sotorasib with Chemotherapy and Bevacizumab?
SHERLOCK tested a combination approach, pairing sotorasib with chemotherapy and bevacizumab. The rationale was to:
Broaden the ability to kill tumour cells through multiple mechanisms
Overcome drug resistance
Improve tumour drug delivery by normalising tumour blood vessels
This multi-pronged strategy aimed to achieve deeper, more durable responses in KRAS G12C-mutated advanced NSCLC.
Key Findings Presented at the 2025 World Conference on Lung Cancer
The SHERLOCK trial results were presented by Professor Chee Khoon Lee at the 2025 World Conference on Lung Cancer (WCLC).
With a median follow-up of 19 months, 47 of 52 participants enrolled across 13 hospitals were evaluable for efficacy, with the following outcomes:
Confirmed OTRR: 64%
Duration of response: 7.5 months
Intracranial response: 30%
Liquid biopsy analyses examined co-mutations in STK11, KEAP1, and TP53—genes often associated with immunologically cold tumours where responses may be reduced. Despite this, high response rates and clinical benefit were seen across all PD-L1 levels and molecular subgroups, including those with these co-mutations.
The safety profile and side effects were consistent with other studies in this treatment setting.
How does SHERLOCK fit with other KRAS G12C NSCLC research?
Compared with other emerging strategies—such as adagrasib-based combinations and KRAS inhibitors paired with immunotherapy—SHERLOCK provides valuable evidence supporting the feasibility of pairing a KRAS inhibitor with both chemotherapy and an anti-angiogenic agent. Together, these studies are shaping a more refined understanding of how to tackle drug resistance and optimise sequencing for KRAS-mutant NSCLC.
For Australian patients, these findings highlight the value of access to innovative clinical trials that bring new therapies closer to the point of care. The strong performance of the SHERLOCK clinical trial demonstrates the importance of collaborative, multi-site studies that accelerate access to targeted treatments within the Australian health system.
Several additional KRAS G12C NSCLC clinical trials remain open to recruitment, continuing to expand treatment options for people with this common oncogenic driver.
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