Trastuzumab Deruxtecan Combination Strongly Enhances Responses and Overcomes Sotorasib Resistance in KRAS G12C
Introduction:
Recent advances in the treatment of KRAS -mutant non-small cell lung cancer (NSCLC) have led to the development of KRAS G12C inhibitors, such as sotorasib and adagrasib. However, resistance and disease progression remain significant challenges. In this study, we investigated the therapeutic potential of combining trastuzumab deruxtecan (T-DXd), an anti-HER2 antibody-drug conjugate, with sotorasib in KRAS G12C -mutant NSCLC, while also evaluating HER2 expression in NSCLC samples.
Methods:
The HER2 expression dependence of xenograft responses to sotorasib, T-DXd, and their combination was evaluated in therapy-naïve and sotorasib-treated tumors by immunohistochemistry (IHC). Also, we analyzed 191 clinical (pre- or on-treatment) and rapid autopsy (post-treatment) samples from 31 patients with driver-positive and driver-negative advanced stage NSCLC, assessing HER2 expression using interpretation guidelines developed for breast cancer (BC) and gastroesophageal adenocarcinoma (GEA).
Results:
In the majority of preclinical models, including sotorasib-resistant tumors, the sotorasib-T-DXd combination induced stronger and more durable responses compared to monotherapies. The strong effect of the combination therapy was likely attributable to sotorasib-induced adaptive HER2 upregulation; stronger HER2 expression in sotorasib-treated tumors was linked with stronger responses. Although HER2 expression was higher in samples from patients with KRAS G12C -mutant NSCLC compared to NSCLC with other driver mutations or no drivers, the difference was not statistically significant. HER2 IHC score discrepancy was also observed between BC and GEA interpretation guidelines.
Conclusions:
Our results support the potential clinical utility of the sotorasib-T-DXd combination, including tumors with intrinsic and acquired resistance to sotorasib monotherapy. Since the strengths of the responses depend on HER2 expression levels, successful clinical implementation necessitates optimizing patient selection. Our results highlight the complexities of accurate HER2 interpretation in NSCLC and highlight the need for standardized testing methods.
Insights
Combining trastuzumab deruxtecan (T-DXd) with sotorasib shows promise for KRAS-mutant non-small cell lung cancer (NSCLC), even in resistant cases. Patient selection based on HER2 expression is key for effective treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- KRAS-mutant non-small cell lung cancer (NSCLC) has limited treatment options, with resistance to KRAS G12C inhibitors like sotorasib being a challenge.
- Trastuzumab deruxtecan (T-DXd) is an anti-HER2 antibody-drug conjugate with potential in various cancers.
Purpose of the Study:
- To investigate the efficacy of combining T-DXd with sotorasib in KRAS-mutant NSCLC.
- To evaluate the role of HER2 expression in response to this combination therapy.
- To assess HER2 expression in NSCLC patient samples.
Main Methods:
- Preclinical xenograft models were used to assess responses to sotorasib, T-DXd, and their combination.
- Immunohistochemistry (IHC) was employed to evaluate HER2 expression in tumors.
- 191 clinical and autopsy samples from NSCLC patients were analyzed for HER2 expression using breast cancer and gastroesophageal adenocarcinoma guidelines.
Main Results:
- The combination of sotorasib and T-DXd demonstrated stronger and more durable responses than monotherapies in preclinical models, including sotorasib-resistant tumors.
- Sotorasib treatment led to adaptive HER2 upregulation, correlating with enhanced responses to the combination therapy.
- While HER2 expression was slightly higher in KRAS-mutant NSCLC, the difference was not statistically significant, and HER2 IHC scoring showed discrepancies between interpretation guidelines.
Conclusions:
- The combination of sotorasib and T-DXd holds potential for treating KRAS-mutant NSCLC, including cases resistant to sotorasib monotherapy.
- Optimizing patient selection based on HER2 expression levels is crucial for clinical success.
- Standardized HER2 testing methods are needed for accurate interpretation in NSCLC.
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