ASCO 2025: Stratifying NSCLC Treatment by HER2-Alteration Subtype

At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, researchers from Caris Life Sciences and affiliated institutions presented a large-scale analysis examining the clinical and genomic characteristics of HER2 alterations in non-small cell lung cancer (NSCLC). In this study, investigators used next-generation DNA and RNA sequencing data from over 52,000 NSCLC tumor samples to assess outcomes in patients with distinct HER2 alteration subtypes—including HER2 mutations, amplification, and protein overexpression (immunohistochemistry [IHC] 2+).

Their findings revealed marked differences in overall survival (OS), co-mutation burden, and tumor microenvironment features across these HER2-altered subgroups, with HER2-mutant tumors showing significantly improved survival compared to amplified or IHC (2+) tumors. Notably, HER2 mutations within the kinase domain were associated with better outcomes on immunotherapy-based regimens, whereas HER2-amplified and IHC (2+) tumors exhibited higher frequencies of co-mutations linked to resistance, such as TP53, KEAP1, and SMARCA4.

In this interview with Pharmacy Times®, study authors Nikita Dahake, MD, and Hossein Borghaei, DO, MS—members of the Caris Life Sciences Precision Oncology Alliance—along with Yasmine Baca, MS, PhD candidate, MB(ASCP)CM, a senior molecular research analyst in Clinical and Translational Research at Caris, discuss the clinical implications of their ASCO data. The conversation explores how HER2 alterations inform treatment decisions in NSCLC, particularly regarding the selection of immunotherapy vs chemoimmunotherapy, the relevance of co-mutation profiling, and the potential for HER2-targeted agents such as trastuzumab deruxtecan (Enhertu; AstraZeneca and Daiichi Sankyo) to reshape sequencing strategies. For pharmacists and oncology care teams, this discussion highlights the growing role of biomarker-informed decision-making in tailoring treatment for patients with HER2-altered lung cancer.

Pharmacy Times: How do HER2 alterations influence treatment response in patients with NSCLC receiving immunotherapy or chemoimmunotherapy?

Nikita Dahake, MD, is a member of the Caris Life Sciences Precision Oncology Alliance in Philadelphia, Pennsylvania.

Nikita Dahake, MD and Hossein Borghaei, DO, MS: HER2 alterations in NSCLC (whether through mutation, amplification, or overexpression) are representative of biologically distinct subsets with varying responses to immunotherapy-based treatments.

In our study, patients with HER2 mutations demonstrated more favorable OS compared to those with HER2 amplification or HER2 expression by IHC (2+).In addition, compared to other actionable mutations such as EGFR, ALK, or ROS1, HER2 mutated tumors were associated with shorter survival, reinforcing the need for more tailored treatment approaches in this population. Thus, the true difference in treatment decision is within the second-line space where treatment with an antibody-drug conjugate targeting HER2 is associated with better clinical efficacy in HER2 mutant and HER2 IHC (3+) tumors.

Pharmacy Times: Based on the study findings, should HER2 alterations be considered when deciding between immunotherapy alone vs chemoimmunotherapy?

Hossein Borghaei, DO, MS, is a member of the Caris Life Sciences Precision Oncology Alliance in Philadelphia, Pennsylvania.

Dahake and Borghaei: Yes. Our findings support considering HER2 alteration subtypes when determining treatment strategy. HER2 alterations are becoming more recognized in determining treatment regimen, especially given the recent FDA approval for HER2 expression by IHC (3+) as second line treatment. Our findings suggest that HER2 mutation status should be incorporated into the decision-making algorithm, particularly when selecting between immunotherapy alone or in combination with chemotherapy. The presence of a HER2 mutation could confer improved survival outcomes with immunotherapy with or without chemotherapy compared to either HER2 amplified or HER2 overexpression by IHC (2+) in NSCLC in certain patient populations.

Pharmacy Times: Were there any HER2 mutation subtypes that appeared more or less responsive to immunotherapy regimens?

Dahake and Borghaei: In our study, we observed that the majority of HER2 mutations were within the kinase domain, which may influence responsiveness to HER2-directed therapies. The trend toward improved survival in HER2-mutated NSCLC suggests there may be variability in response based on mutation location or type. As a next step for our manuscript, we plan to stratify patients by HER2-mutation subtype to further explore differential responses to immunotherapy regimens. This could yield further insight into personalized treatment strategies.

Pharmacy Times: Did any specific co-mutations (eg, STK11, KEAP1, TP53) appear to confer resistance or sensitivity to immunotherapy?

Yasmine Baca, MS, PhD candidate, MB(ASCP)CM, is a senior molecular research analyst in Clinical and Translational Research at Caris in Phoenix, Arizona.

Yasmine Baca, MS, PhD candidate, MB(ASCP)CM: Yes. Our analysis showed that HER2 amplified and HER2 overexpressed by IHC (2+) tumors harbored significantly higher frequencies of co-mutations associated with reduced immunotherapy efficacy such as TP53, KEAP1, and SMARCA4 when compared to HER2-mutated tumors. While these associations are suggestive of co-mutation profiles being a contributor to resistance mechanisms within HER2-altered subgroups, further investigation is warranted to validate these markers as predictive tools.

Pharmacy Times: Were PD-L1 expressions or tumor mutational burden (TMB) found to correlate with treatment outcomes in this population?

Baca: Interestingly, we found no significant differences in PD-L1 expression across HER2 alteration types. TMB-high, however, was more frequently observed in HER2-amplified tumors compared to HER2 mutant tumors (47% vs 21%), although HER2 mutant tumors were associated with better survival. This suggests that TMB alone may not be a sufficient predictor of immunotherapy benefit in HER2-altered NSCLC. These findings highlight the need to consider a broader range of genomic and immunologic factors when evaluating potential benefits.

Pharmacy Times: Do your data support using any co-mutations as predictive markers to guide therapy selection?

Dahake and Borghaei: Our data support the hypothesis that co-mutation profiling may enhance treatment stratification in HER2-altered NSCLC. Specifically, the presence of mutations, such as TP53, KEAP1, and SMARCA4, could help identify patients that are less likely to benefit from immunotherapy alone. Integrating co-mutation analysis with HER2 status could help guide more precise individualized therapeutic decisions.

Pharmacy Times: How might these findings influence the role of HER2-targeted therapies such as trastuzumab deruxtecan in treatment sequencing?

Detailed cross section view of non-small cell lung cancer cells. Image Credit: © Pichapob - stock.adobe.com

Dahake and Borghaei: Our study demonstrated survival advantage in HER2-mutated NSCLC and supports prioritizing HER2-directed therapies in treatment sequencing.As trastuzumab deruxtecan and other HER2-targeted agents continue to show efficacy in HER2 altered lung cancer, our findings reinforce the importance of early and comprehensive genomic profiling to identify HER2 alterations and guide the integration of targeted therapies, potentially before or in conjunction with immunotherapy in select patients.

Pharmacy Times: Were there any safety concerns specific to HER2-altered patients receiving immunotherapy-based regimens?

Dahake and Borghaei: Our study focused on genomic and survival data rather than adverse event profiles, so we did not analyze safety data directly. Given the increasing use of combination regimens, we recognize that further real-world safety assessments in HER2-altered subgroups are critical. This is especially important for patients with overlapping co-mutations that may influence both efficacy and toxicity profiles.

Pharmacy Times: How should pharmacists involved in biomarker-driven oncology care interpret and apply your findings in treatment planning or education?

Dahake and Borghaei: Our findings emphasize the importance of distinguishing between HER2-alteration types (eg, mutation, amplification and overexpression), as they correlate with differing survival outcomes and potential therapeutic implications. Pharmacists play a crucial role in biomarker informed care by advocating for early, comprehensive genomic testing and assisting in the interpretation of molecular data to guide therapy sequencing. These insights can support more personalized treatment planning and patient education across care teams.