Updates from ASCO 2025 in Advanced Non‒Small Cell Lung Cancer

Session Overview and Highlights

Antibody-Drug Conjugates in Advanced NSCLC

The TROPION-Lung02 study evaluating datopotamab deruxtecan plus pembrolizumab generated mixed reactions among faculty. While objective response rates were encouraging (»55%-56%), treatment discontinuation rates approaching one-third of patients raised significant tolerability concerns. Faculty noted that overlapping toxicities between immunotherapy and ADCs, particularly pneumonitis and interstitial lung disease, complicate clinical management and attribution of adverse events.

The introduction of AI-driven biomarkers through the QCS platform represents a promising development for patient selection beyond simple TROP2 expression by immunohistochemistry. However, faculty emphasized that stronger survival data and improved tolerability profiles are prerequisites for ADCs to earn roles in first-line treatment.

HER2-Targeted Therapies: An Expanding Landscape

Faculty expressed considerable enthusiasm for emerging oral HER2-targeted TKIs, particularly zongertinib and sevabertinib. Zongertinib demonstrated a 71% objective response rate in HER2 tyrosine kinase domain-mutated patients who were HER2 therapy-naive, with a manageable safety profile and notably no cases of interstitial lung disease. Faculty favored positioning oral TKIs before HER2 ADCs like trastuzumab deruxtecan to avoid overlapping pulmonary toxicities.

Sevabertinib showed similar response rates (60%) in both treatment-naive and pretreated patients without prior HER2-directed therapy, surprising faculty who typically expect different response rates across treatment lines. The consistency suggests robust HER2 dependency in this patient population, though concerns about cumulative diarrhea with sequential TKI use were noted.

Central nervous system efficacy remains a critical consideration, as patients with HER2-mutant NSCLC frequently develop brain metastases. Faculty emphasized the need for agents with proven intracranial activity to prevent disease progression in this challenging anatomic site.

Perioperative EGFR-Targeted Therapy

The NeoADAURA trial (NCT04351555) results showing significant improvement in major pathologic response (MPR) rates with perioperative osimertinib generated cautious optimism. Both osimertinib plus chemotherapy (26% MPR) and osimertinib monotherapy (25% MPR) significantly outperformed chemotherapy alone. However, faculty emphasized that pathologic response is a surrogate end point, and mature event-free survival and overall survival data are essential before changing practice patterns.

Faculty debated whether osimertinib should be used both before and after surgery, raising concerns about resistance development and cumulative toxicity. Real-world experiences with osimertinib making lung tissue “sticky” and potentially complicating surgical procedures were discussed, though the clinical significance remains uncertain.

KRAS G12C Inhibition in First-Line Treatment

The KRYSTAL-7 study (NCT04613596) of first-line adagrasib plus pembrolizumab demonstrated promising efficacy signals, particularly in patients with PD-L1 expression greater than or equal to 50%. However, the 68% rate of grade 3-4 adverse events and high pill burden raised significant feasibility concerns for real-world implementation. Faculty questioned whether the observed benefit was primarily driven by pembrolizumab rather than the KRAS inhibitor, particularly given similar outcomes to historical pembrolizumab monotherapy data.

The competitive landscape with other KRAS G12C inhibitors, including divarasib, was acknowledged, with faculty preferring to await phase 3 data before considering practice changes.

Novel Biomarker Approaches

A tissue-agnostic, genome-wide methylation-based circulating tumor DNA assay showed ability to detect treatment failure a median of 5 months before clinical progression. Faculty were most enthusiastic about using such assays for treatment de-escalation rather than escalation, given the challenges of interpreting positive results without radiographic progression.

Serial ctDNA monitoring is already being implemented by some faculty for scan interpretation and patient counseling, though they emphasized the need for prospective trial validation before widespread adoption.

Discussion Themes and Expert Insights

Faculty consistently emphasized the importance of quality-of-life considerations in treatment selection, particularly given the chronic nature of advanced NSCLC management. The pill burden associated with oral targeted therapies, infusion complexity of bispecific antibodies like amivantamab, and overlapping toxicity profiles of combination regimens were recurring themes.

Treatment sequencing emerged as a central challenge, with faculty acknowledging that optimal approaches remain unclear in many scenarios. The availability of multiple active agents creates both opportunities and complexity, requiring individualized decision-making based on patient factors, prior treatments, and toxicity profiles.

Financial barriers and access issues were highlighted as ongoing concerns, particularly for newer agents and complex combination regimens that may strain health care system resources.

Unmet Needs and Recommendations

Standardized approaches to biomarker testing and treatment sequencing are critically needed as the therapeutic landscape becomes increasingly complex. Faculty emphasized the importance of incorporating novel biomarkers into prospective clinical trials rather than relying solely on retrospective analyses.

The development of better supportive care strategies for ADC-related toxicities, particularly interstitial lung disease and cytopenias, is essential for broader implementation. Proactive management approaches were emphasized, including prophylactic measures for diarrhea with TKIs. .

Central nervous system activity must be a priority in drug development, given the high propensity for brain metastases in oncogene-driven NSCLC subtypes. Faculty called for dedicated CNS end points in clinical trials rather than post-hoc analyses.

Conclusion

The 2025 ASCO meeting highlighted the rapid evolution of NSCLC treatment, with multiple promising agents across different targets and mechanisms. While the expanding therapeutic arsenal provides new hope for patients, it also creates complexity in treatment selection and sequencing.

Faculty agreed that the field is at an inflection point where personalized approaches based on molecular profiling, biomarker-driven patient selection, and careful consideration of toxicity profiles will be essential. The coming years will likely see further refinement of treatment algorithms as survival data mature and resistance mechanisms are better understood.

Despite the challenges, faculty expressed optimism about the trajectory of NSCLC care, acknowledging that having “too many good options” represents a welcome problem in a disease that has historically had limited therapeutic choices.

References

1. Califano R, Passaro A, Tan JL, et al. Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutant advanced NSCLC after disease progression on osimertinib: Outcomes by osimertinib resistance mechanisms in MARIPOSA-2. Abstract 8639. Presented at: ASCO Annual Meeting 2025; May 30–June 3, 2025; Chicago, IL. Accessed June 26, 2025. https://meetings.asco.org/abstracts-presentations/251502
2. Chaft J, Weder W, He J, et al. Neoadjuvant (neoadj) osimertinib (osi) ± chemotherapy (CT) vs CT alone in resectable (R) epidermal growth factor receptor-mutated (EGFRm) NSCLC: NeoADAURA. Abstract 8001. Presented at: ASCO Annual Meeting 2025; May 30–June 3, 2025; Chicago, IL. Accessed June 26, 2025. https://meetings.asco.org/abstracts-presentations/243667
3. Heymach JV, Ruiter G, Ahn MJ, et al. Zongertinib in patients with pretreated HER2-mutant advanced NSCLC: Beamion LUNG-1. Abstract CT050. Presented at AACR Annual Meeting 2025; April 25‒30, 2025; Chicago, IL. Accessed June 26, 2025. https://www.abstractsonline.com/pp8/#!/20273/presentation/10423
4. Hoang T, Yang Y, Lau S, et al. Identification of immunotherapy early treatment failure in non-small cell lung cancer (NSCLC) using a novel cell-free DNA (cfDNA) tissue-agnostic genome-wide methylome enrichment assay. Abstract 8550. Presented at: ASCO Annual Meeting 2025; May 30–June 3, 2025; Chicago, IL. Accessed June 26, 2025. https://meetings.asco.org/abstracts-presentations/251770
5. Jänne P, Theelen W, Garassino M, et al. First-line adagrasib (ADA) with pembrolizumab (PEMBRO) in patients (pts) with advanced/metastatic KRASG12C-mutated non-small cell lung cancer (NSCLC) from the phase 2 portion of the KRYSTAL-7 study. Abstract 8500. Presented at: ASCO Annual Meeting 2025; May 30–June 3, 2025; Chicago, IL. Accessed June 26, 2025. https://meetings.asco.org/abstracts-presentations/247319
6. Levy B, Paz-Ares L, Lin CC, et al. TROPION-Lung02: Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) as first-line (1L) therapy for advanced non-small cell lung cancer (aNSCLC). Abstract 8501. Presented at: ASCO Annual Meeting 2025; May 30–June 3, 2025; Chicago, IL. Accessed June 26, 2025. https://meetings.asco.org/abstracts-presentations/247953
7. Loong H, Li L, Wu L, et al. SOHO-01: Safety and efficacy of BAY 2927088 in patients with advanced HER2-mutant non-small cell lung cancer (NSCLC) who were pretreated but naive to HER2-targeted therapy or had not received any treatment for advanced disease. Abstract 8504. Presented at: ASCO Annual Meeting 2025; May 30–June 3, 2025; Chicago, IL. Accessed June 26, 2025. https://meetings.asco.org/abstracts-presentations/247321
8. Mok T, Yu H, Lim SM, et al. Patritumab deruxtecan (HER3-DXd) in resistant EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) after a third-generation EGFR TKI: The phase 3 HERTHENA-Lung02 study. Abstract 8506. Presented at: ASCO Annual Meeting 2025; May 30–June 3, 2025; Chicago, IL. Accessed June 26, 2025. https://meetings.asco.org/abstracts-presentations/246421
9. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 5.2025. Accessed June 26, 2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf