Charu Aggarwal, MD, MPH

Panelists discuss the introduction of quantitative cell scoring (QCS) for TROP2 as a significant artificial intelligence (AI)-driven advancement in oncology, emphasizing its ability to provide precise, quantitative biomarker assessment that complements molecular data like EGFR status. The panelists also highlight the importance of pathologists embracing digital pathology tools to enhance diagnostic accuracy and treatment planning while recognizing the technology’s early but promising role in expanding patient identification for targeted therapies and its potential broader impact on precision oncology.

Panelists discuss the expanding potential of quantitative cell scoring (QCS) technology beyond TROP2, highlighting its ability to assess not only cell surface expression but also internalization critical for antibody-drug conjugate (ADC) efficacy. They also emphasize how artificial intelligence (AI)-driven pathology advancements promise to streamline lung cancer diagnostics, improve predictive accuracy, and reduce variability in biomarker testing, ultimately enabling more precise patient selection and better integration of complex biomarker data into clinical care.

Panelists discuss the strategic approach to implementing targeted therapies through advanced biomarker testing, emphasizing the importance of prioritizing next-generation sequencing (NGS) early in diagnostic workflows due to limited tissue availability, the growing role of liquid biopsies, and emerging technologies like multiplex immunohistochemistry (IHC) to maximize tissue use. The panelists also highlight the critical need for close collaboration and clear communication between oncologists and pathologists to streamline testing, reduce redundant procedures, and ensure timely, personalized treatment decisions.

Panelists discuss how biomarker testing in oncology is evolving beyond genomic sequencing to include complex protein and RNA analyses, highlighting challenges such as limited biopsy tissue, the need for recent samples, and the importance of clear, standardized reporting; they emphasize that effective collaboration between oncologists and pathologists, along with the use of specialized send-out labs, will be critical to streamline workflows and ensure timely, actionable results for personalized patient care.

Panelists discuss the significant changes needed to integrate quantitative continuous scoring (QCS) and TROP2 normalized membrane ratio (NMR) assays into routine clinical practice, emphasizing the current limited adoption of digital pathology, the likely use of artificial intelligence (AI)-based assays as send-out tests initially, and the importance of expanding digital infrastructure and collaboration to enable precise, automated biomarker evaluation that can guide personalized oncology treatment.

Panelists discuss several ongoing clinical trials, including AVANZAR and TROPION-Lung10, that are investigating the predictive utility of TROP2 normalized membrane ratio (NMR) in guiding treatment with datopotamab deruxtecan combinations in lung cancer while highlighting advances in artificial intelligence (AI)-driven pathology to refine biomarker assessments and emphasizing the need for prospective validation to establish NMR’s role in clinical practice.

Panelists discuss how data from the TROPION-PanTumor01, TROPION-PanTumor02, and TROPION-Lung02 studies reinforce the predictive value of the TROP2 normalized membrane ratio (NMR) biomarker across diverse patient populations and treatment regimens, highlighting its reproducibility and ability to specifically identify patients likely to benefit from datopotamab deruxtecan–based therapies rather than serving as a general prognostic marker.

Panelists discuss the TROPION-LUNG01 trial results, highlighting how datopotamab deruxtecan improved progression-free survival (PFS) in nonsquamous non–small cell lung cancer (NSCLC) and the role of the TROP2 normalized membrane ratio (NMR) as a predictive biomarker that helps identify patients most likely to benefit from the therapy.

Panelists discuss preclinical findings supporting TROP2 normalized membrane ratio (NMR) as a predictive biomarker for datopotamab deruxtecan, highlighting its ability to quantify functional membrane expression and internalization potential, refine patient selection beyond conventional immunohistochemistry (IHC), and drive broader adoption of artificial intelligence (AI)-powered digital pathology in precision oncology across multiple tumor types.

Panelists discuss the limitations of conventional immunohistochemistry (IHC) in assessing TROP2 expression for targeted therapies in non–small cell lung cancer and highlight how advanced tools such as quantitative continuous scoring (QCS) and normalized membrane ratio (NMR) offer more precise, objective, and functional evaluations of protein expression and internalization, paving the way for improved patient stratification and personalized treatment with antibody-drug conjugates (ADCs).

Panelists discuss the limitations of conventional immunohistochemistry (IHC) in assessing TROP2 expression for targeted therapies in non–small cell lung cancer and highlight how advanced tools such as quantitative continuous scoring (QCS) and normalized membrane ratio (NMR) offer more precise, objective, and functional evaluations of protein expression and internalization, paving the way for improved patient stratification and personalized treatment with antibody-drug conjugates (ADCs).

Panelists discuss the evolving role of advanced biomarker tools like quantitative continuous scoring (QCS) and normalized membrane ratio (NMR) in non–small cell lung cancer (NSCLC), highlighting their potential to overcome limitations of traditional TROP2 assessment, improve prediction of antibody-drug conjugate (ADC) efficacy, and enhance patient selection through more precise and functional tumor profiling.

Panelists discussed that despite advances in targeted therapies for EGFR-mutant lung cancer, challenges remain around defining meaningful clinical endpoints, improving access to molecular testing and treatments, expanding trial eligibility for high-risk patients, exploring curative approaches in select cases, and emphasizing personalized strategies with ongoing patient-centered care and education.

Panelists discussed that consolidation osimertinib after chemoradiation significantly improves progression-free survival in unresectable stage III EGFR-mutant NSCLC, neoadjuvant osimertinib plus chemotherapy shows promise in early-stage disease, and new antibody-drug conjugates offer effective, better-tolerated options after progression on osimertinib and chemotherapy.

Panelists discussed that although a HER3-targeted ADC showed limited benefit and lost FDA approval, emerging therapies like new ADCs, bispecific antibodies, and personalized sequencing based on molecular testing are expanding treatment options for EGFR-mutant NSCLC resistant to TKIs.

Panelists discuss that when patients progress after frontline osimertinib without histologic transformation or secondary drivers, treatment options include switching to chemotherapy combined with targeted agents like anti-MET antibodies, considering toxicity and patient tolerance, while molecular testing guides sequencing decisions—especially in cases with MET amplification—and that after newer combination regimens, biopsy and personalized approaches remain essential for optimizing therapy and managing side effects.

Panelists discuss that after progression on frontline therapy, treatment decisions hinge on prior regimens, progression patterns, and detailed molecular profiling—including tissue biopsy to detect transformations and resistance mechanisms like MET or HER2 alterations—with sequencing strategies tailored accordingly and clinical trial enrollment encouraged for patients without clear targets.

Panelists discuss that managing systemic progression in EGFR-mutant lung cancer requires thorough molecular profiling via tissue and liquid biopsies to identify resistance mechanisms like histologic transformation and MET amplification, with comprehensive testing guiding next-line targeted therapies or clinical trial enrollment to optimize patient outcomes.

Panelists discuss that resistance to frontline osimertinib is diverse, involving on-target mutations like C797S, MET amplification, and small cell transformation, highlighting the need for tissue biopsies alongside liquid biopsies to guide treatment, and note that newer combination therapies such as Mariposa may reduce certain resistance mutations and alter tumor evolution, offering hope for improved outcomes.

Panelists discuss that the Cocoon trial’s four-part prophylactic regimen—including oral antibiotics, clindamycin topical treatment, nail toxicity prevention, and ceramide-based lotions—significantly reduces skin toxicities like scalp rashes in EGFR inhibitor therapies, emphasizing the importance of patient and provider education to ensure adherence and improve treatment tolerability.

Panelists discuss that the skipper regimen—a prophylactic dexamethasone schedule started days before infusion—has significantly reduced infusion-related reactions from about 66% to 22%, improving patient comfort and clinic workflow while emphasizing ongoing education and early management to ensure safety.

Panelists discuss that chemotherapy plus osimertinib requires managing early hematologic toxicities and EGFR-related rash and diarrhea with close monitoring, while the bispecific antibody regimen involves proactive prevention of infusion reactions, anticoagulation for VTE risk, and intensive rash management to support treatment adherence and patient quality of life.

Panelists discuss the evolving safety profiles of first-line EGFR-mutated lung cancer treatments, highlighting that chemotherapy combinations cause expected hematologic toxicities and fatigue, while bispecific antibody regimens bring unique challenges such as infusion reactions, more severe rashes and diarrhea, peripheral edema, and a notably increased risk of venous thromboembolism that warrants prophylactic anticoagulation and careful patient monitoring.

Panelists discuss the critical role of regular brain MRI monitoring in EGFR-mutant lung cancer, balancing timely detection of intracranial progression with the risks of early radiation; they emphasize individualized treatment sequencing guided by progression patterns and resistance profiling through biopsies and liquid biopsies to optimize patient outcomes.

Panelists discuss the evolving management of CNS metastases in EGFR-mutant lung cancer, highlighting how third-generation TKIs and combination regimens from the FLORA and Mariposa trials delay CNS progression and reduce new brain metastases, supporting a shift away from upfront radiation in asymptomatic patients.

Panelists discuss how the availability of three frontline options for EGFR-mutant NSCLC has complicated treatment selection, prompting highly individualized, hour-long consultations that balance disease biology, patient values, and the trade-offs between monotherapy and combination regimens.

Panelists discuss the Mariposa trial’s landmark overall survival benefit with amivantamab plus lazertinib over osimertinib monotherapy in EGFR-mutant NSCLC, marking a paradigm shift toward durable survival and reinforcing the value of optimized patient selection and adherence to combination regimens.

Panelists discuss how the FLAURA2 trial has reshaped EGFR-mutant NSCLC treatment by demonstrating meaningful progression-free survival gains with osimertinib plus chemotherapy, while emphasizing the importance of protocol adherence, long-term outcome potential, and the ongoing pursuit of curative strategies.

Panelists discuss evolving first-line strategies for EGFR-mutant NSCLC, highlighting the expanding role of combination regimens, CNS efficacy, and the need for personalized treatment selection and toxicity management, especially in younger, well-informed patients.

Charu Aggarwal, MD, MPH, and Geoffrey Liu, MSc, MD, on novel approaches being investigated in ROS1-positive non–small cell lung cancer.