Sandip P. Patel, MD

Dr. Doroshow steps back and asks Dr. Patel for the single most important insight or data point likely to change his clinical practice in the near term. Dr. Patel returns to a foundational message: precision therapy is impossible without a precision diagnosis. He stresses the importance of identifying not only canonical EGFR mutations (exon 19 deletions and L858R) but also distinguishing them from EGFR exon 20 insertions, where some agents are useful and others are not. Understanding the patient's full molecular landscape determines whether FLAURA2, MARIPOSA, or osimertinib monotherapy is most appropriate, and these upfront decisions have downstream consequences in later lines of treatment. None of those conversations can begin without comprehensive upfront molecular testing.

Dr. Doroshow transitions to MET-directed resistance and invites Dr. Patel to lead. He describes MET amplification or overexpression as a resistance pathway in roughly 15% of EGFR-mutated metastatic non-small cell lung cancer (NSCLC) patients. Amivantamab-based regimens, which target both EGFR and MET, may reduce MET-driven resistance though not eliminate it. Testing must distinguish DNA-level events (MET amplification, by copy number) from protein-level overexpression (by immunohistochemistry [IHC]). Telisotuzumab vedotin (Teliso-V), a MET-directed antibody-drug conjugate (ADC) with a monomethyl auristatin E (MMAE) payload, is an option for 3+ MET protein overexpression in more than 25% of cells. For genomic MET amplification, small molecule combinations — savolitinib (a CNS-penetrant third-generation MET inhibitor with peripheral edema and hepatotoxicity), capmatinib, or tepotinib paired with osimertinib or lazertinib — are standard.

Dr. Doroshow asks how Dr. Patel weighs COMPEL (osimertinib continuation with chemotherapy; progression-free survival [PFS] 8.4 vs. 4.4 months) against MARIPOSA-2 (amivantamab plus chemotherapy; PFS 6.3 vs. 4.2 months) for patients progressing on frontline osimertinib, and whether a prolonged chemotherapy-free interval changes willingness to rechallenge with platinum.

Dr. Doroshow opens with a question on the role of antibody-drug conjugates (ADCs) in EGFR-mutated lung disease, asking what it would take for Dr. Patel to consider a first- or second-line datopotamab deruxtecan (Dato-DXd) plus osimertinib approach. Dr. Patel describes Dato-DXd as a TROP2-directed ADC with FDA approval in refractory EGFR-mutated non-small cell lung cancer (NSCLC). He uses it second line after FLAURA2 or MARIPOSA, and typically third line after osimertinib monotherapy followed by MARIPOSA-2 (chemotherapy plus amivantamab). He is interested in moving Dato-DXd earlier with osimertinib based on preliminary efficacy and CNS-protective signals, but flags ADC chemotherapy-like toxicities — stomatitis, low-rate interstitial lung disease, dry eye, cytopenias, and alopecia.

Dr. Patel asks how the next step differs based on whether the patient received osimertinib monotherapy, FLAURA2, or MARIPOSA, and how progression pattern, CNS involvement, and re-biopsy guide decisions, including which patients should get stereotactic body radiation therapy (SBRT) and which need a histologic diagnosis to rule out small cell transformation.

Dr. Patel asks how anticipated next-line options factor into upfront treatment choice, framing it as a chessboard where early moves determine what is available later. Dr. Doroshow says she tries to think one step at a time because she cannot see three moves ahead, given how many ways therapies can be mixed and matched.

Dr. Patel asks how supportive care demands, quality of life, and financial and time toxicities shape shared decision-making in frontline EGFR-mutated non-small cell lung cancer (NSCLC), and whether subcutaneous amivantamab has changed his colleague's risk-benefit assessment. Dr. Doroshow argues quality of life, time, and financial toxicity cannot be separated from efficacy, because efficacy is determined in a trial vacuum while effectiveness depends on whether patients can actually receive and tolerate the medicine.

Dr. Sandip Patel (University of California San Diego, Moores Cancer Center) welcomes Dr. Deborah Doroshow (Mount Sinai) for a practical discussion on treatment selection and sequencing in advanced EGFR-mutated non-small cell lung cancer (NSCLC). Dr. Patel frames the conversation around how clinical features, molecular findings, CNS involvement, and real-world treatment burden shape both frontline and post-progression decisions, and how emerging data on resistance, re-biopsy, and antibody-drug conjugate (ADC) approaches are entering practice.

Sandip Patel, MD, discusses key unmet needs and open questions surrounding EGFR-mutant NSCLC that has transformed to SCLC.

Eric K. Singhi, MD, and Sandip P. Patel, MD, discuss future areas of research and unmet needs in non–small cell lung cancer.

Eric K. Singhi, MD, and Sandip P. Patel, MD, discuss key data from the 2025 World Conference on Lung Cancer.

Eric K. Singhi, MD, and Sandip P. Patel, MD, discuss the use of immunotherapy after prior immunotherapy for early-stage NSCLC.

Eric K. Singhi, MD, and Sandip P. Patel, MD, discuss 5-year data for cemiplimab plus chemotherapy in advanced NSCLC.

Eric K. Singhi, MD, and Sandip P. Patel, MD, discuss the management of immune-related adverse effects in advanced NSCLC.

Eric K. Singhi, MD, and Sandip P. Patel, MD, discuss the impact of the FDA approval of cemiplimab plus chemotherapy in advanced NSCLC.

Eric K. Singhi, MD, and Sandip P. Patel, MD, discuss treatment and sequencing considerations in advanced non–small cell lung cancer.

Sandip P. Patel, MD, discusses remaining gaps in biomarker testing and their implications for targeted therapies in early-stage NSCLC.

Sandip P. Patel, MD, discusses toxicities associated with the use of immunotherapy-based combination regimens in patients with advanced NSCLC.

Panelists discuss how future developments in EGFR-mutated non–small cell lung cancer (NSCLC) will focus on biomarker-driven patient selection, rational sequencing strategies, and emerging therapies including cellular therapy and treatments for atypical EGFR mutations.

Panelists discuss how ADC-based therapies like dato-DXd offer superior efficacy compared with traditional chemotherapy options like docetaxel, while requiring careful monitoring for unique toxicities including ILD, stomatitis, and ocular effects.

Panelists discuss how TROP2-targeted ADC dato-DXd represents another promising option with evolving digital pathology biomarker approaches, though practical implementation and patient selection strategies remain challenging.

Panelists discuss how HER3-directed ADC patritumab deruxtecan shows promise as a later-line therapy with approximately 30% response rates and intracranial activity, though biomarker selection remains elusive and mechanism of CNS penetration unclear.

Panelists discuss how second-line treatment selection depends heavily on frontline therapy choice, emphasizing the importance of repeat biopsies to identify resistance mechanisms and considering continuation of TKI with added chemotherapy for patients with controlled CNS disease.

Panelists discuss how balancing safety and efficacy in frontline regimens involves managing distinct toxicity profiles, with FLAURA2 requiring standard chemotherapy monitoring vs MARIPOSA necessitating complex supportive care for EGFR-related skin toxicity and venous thromboembolism prophylaxis.

Panelists discuss how oligometastatic disease treatment requires careful definition of metastatic burden, with liver metastases potentially indicating more aggressive biology and warranting consideration of intensified frontline therapy.

Panelists discuss how CNS metastases in EGFR-mutated NSCLC require multidisciplinary management with close radiation oncology collaboration, frequent monitoring, and preference for FLAURA2 regimen due to superior intracranial efficacy data.

Panelists discuss how the MARIPOSA regimen (amivantamab plus lazertinib) shows promising overall survival benefits in first-line treatment, though with increased toxicity concerns including rash, edema, and VTE risk requiring careful patient selection.

Panelists discuss how FLAURA2 regimen (osimertinib plus chemotherapy) is being incorporated into frontline EGFR-mutated NSCLC treatment, with considerations for escalating to combination therapy based on disease burden, CNS metastases, and patient tolerance factors.

Sandip P. Patel, MD, discusses the potential role of antibody-drug conjugates in early-stage non–small cell lung cancer.