Helena A. Yu, MD

In this final episode, Dr. Puri and Dr. Yu close the program with the most important unanswered questions after TOP. The overall survival (OS) data remain immature at roughly 30% maturity, and TOP did not compare osimertinib/chemotherapy head-to-head with amivantamab/lazertinib, so it cannot tell clinicians which intensification regimen is better for the TP53 subgroup.

In this episode, Dr. Yu and Dr. Puri offer practical guidance for community oncologists treating newly diagnosed EGFR-mutant metastatic non–small cell lung cancer (NSCLC), where access to rapid TP53 reporting and multidisciplinary supportive care may be limited.

In this episode, Dr. Puri and Dr. Yu address sequencing after first-line intensification. Whether patients start with osimertinib plus chemotherapy or amivantamab/lazertinib, the second-line landscape includes COMPEL, MARIPOSA-2, MET-directed therapies, and antibody–drug conjugates (ADCs) such as datopotamab deruxtecan.

In this episode, Dr. Yu and Dr. Puri address the safety profile of combination regimens and how to counsel patients. In TOP, grade 3 or higher treatment-related adverse events (TRAEs) occurred in 62% of the combination arm versus 14.9% with monotherapy, driven by neutropenia, anemia, and thrombocytopenia.

In this episode, Dr. Puri and Dr. Yu walk through the prespecified subgroup analyses from TOP, where progression-free survival (PFS) benefit was consistent across all subgroups.

In this episode, Dr. Yu and Dr. Puri compare the TOP results against FLAURA2 and MARIPOSA. TOP delivered a roughly 18-month median progression-free survival (PFS) improvement (hazard ratio [HR], 0.44) and an early overall survival (OS) signal (HR, 0.57) at 30% maturity.

In this episode, Dr. Puri and Dr. Yu discuss how TP53 status informs first-line intensification in clinic. Both have moved to an opt-out approach: combination therapy is the default, and monotherapy is reserved for patients whose performance status, comorbidities, or preferences make combination unsuitable. Dr. Yu notes she had been intensifying selectively based on progression-free survival (PFS) data from FLAURA2 and MARIPOSA, but the overall survival (OS) readouts shifted her to upfront combination for nearly all patients. Dr. Puri agrees, noting the discussion in her clinic now starts with combination and works backward. They address the borderline patient — exon 19 deletion, low burden, no central nervous system (CNS) disease, but TP53 co-mutation — and conclude that risk factors are additive and even a single high-risk feature like TP53 generally tips the decision toward intensification. Roughly 60% of EGFR-mutant cases harbor TP53 alterations, so this is not a niche subgroup. On TP53 mutation type, Dr. Yu treats it as binary in practice while acknowledging truncating mutations confer worse prognosis than missense mutations. Dr. Puri notes that at Moffitt, paired tissue and liquid next-generation sequencing (NGS) often deliver TP53 results in time for first-line decisions, but she emphasizes that even without it, the opt-out strategy holds. In the next episode, “Interpreting TOP Alongside FLAURA2 and MARIPOSA,” Dr. Yu and Dr. Puri compare the strength of evidence across the three intensification trials.

In this episode, Dr. Yu and Dr. Puri share their initial reactions to the phase 3 TOP study, the first prospective trial to specifically test treatment intensification in EGFR-mutant non–small cell lung cancer (NSCLC) patients selected by concurrent TP53 mutation. Dr. Yu reviews the headline data: median progression-free survival (PFS) of 34.0 versus 15.6 months (hazard ratio [HR], 0.44), overall response rate (ORR) of 83% versus 72%, median duration of response (DoR) of 32.7 versus 15.3 months, and an interim overall survival (OS) hazard ratio of 0.57 at roughly 30% maturity. Dr. Puri notes that the positivity of the result was not surprising given prior signals from FLAURA2 and MARIPOSA, but the magnitude of benefit was striking. She underscores that TP53 had previously been examined only post-hoc or as a secondary endpoint, never as the primary selection criterion. Dr. Yu frames the contribution of TOP as confirming that TP53 is not only prognostic but also predictive of benefit from intensification, with TP53-altered patients potentially deriving as much or more benefit than lower-risk groups. Both agree that TOP definitively answers the question of whether the TP53 co-mutated subgroup needs intensification, while acknowledging that OS data remain immature. In the next episode, “Operationalizing First-Line Intensification: TP53 and the Borderline Patient,” Dr. Yu and Dr. Puri discuss how they translate TP53 status into upfront treatment decisions.

This presentation examines the effectiveness and clinical role of reusing chemotherapy after disease progression in patients with EGFR-mutated advanced non-small cell lung cancer.

Heather Wakelee, MD, and Helena Yu, MD, discuss emerging biomarkers and key evidence gaps in EGFR-mutant NSCLC.

Heather Wakelee, MD, and Helena Yu, MD, discuss how to plan long-term treatment sequencing from the time of diagnosis.

Heather Wakelee, MD, and Helena Yu, MD, discuss how ADCs are being incorporated into sequencing strategies after osimertinib.

Heather Wakelee, MD, and Helena Yu, MD, discuss how TP53 and other co-mutations influence prognosis and sequencing decisions.

Heather Wakelee, MD, and Helena Yu, MD, discuss when chemotherapy rechallenge may be appropriate in EGFR-mutant NSCLC.

Heather Wakelee, MD, and Helena Yu, MD, examine how FLAURA2 and emerging post-progression data inform sequencing decisions.

Heather Wakelee, MD, and Helena Yu, MD, discuss how they approach patient selection for osimertinib monotherapy vs combination therapy in 2026.

Experts discuss the persistent challenges in EGFR-mutated non–small cell lung cancer , including central nervous system (CNS) progression and treatment sequencing, emphasizing the urgent need for more transformative strategies beyond current combination regimens, greater inclusion of complex patient populations in trials, and the critical role of comprehensive biomarker testing and shared decision-making in delivering personalized, future-forward care.

Experts discuss the expanding treatment landscape for EGFR-mutated non–small cell lung cancer (NSCLC), highlighting emerging strategies beyond tyrosine kinase inhibitors (TKIs)—including novel immunotherapy combinations and antibody-drug conjugates (ADCs)—with particular interest in bispecific antibodies and TROP2-directed ADCs that may offer new options for patients progressing on targeted therapy, despite ongoing challenges in translating immune-based approaches into consistent survival gains.

Experts discussed how, despite several new third-generation EGFR tyrosine kinase inhibitors (TKIs) in development, the real progress in treating EGFR-mutant lung cancer is likely to come from combination therapies rather than new monotherapies, emphasizing the need for treatments that deliver meaningful improvements over current standards rather than just incremental changes.

Resistance management in EGFR-mutant lung cancer relies on both liquid and tissue biopsies to guide therapy, with careful interpretation of molecular findings and multidisciplinary collaboration essential to balancing precision medicine advances against patient safety and evidence-based care.

Experts shared that while amivantamab combined with chemotherapy in MARIPOSA- 2 can cause challenging toxicities, careful dose adjustments, premedication, and vigilant monitoring help manage adverse effects and support continued treatment.

Experts highlight evolving evidence that continuing EGFR tyrosine kinase inhibitors (TKIs) with chemotherapy after progression may improve outcomes, but emphasize that treatment sequencing decisions must be personalized based on emerging data, patient factors, and drug availability.

Experts discuss the promise of subcutaneous (SubQ) amivantamab in improving logistical efficiency and reducing infusion-related reactions in the MARIPOSA regimen, while emphasizing that chronic toxicities persist regardless of administration route, underscoring the ongoing need for proactive monitoring, supportive care, and close clinical oversight.

Experts discuss the cumulative toxicities of pemetrexed in the FLAURA2 regimen, emphasizing the need for personalized, flexible approaches to maintenance therapy duration that balance ongoing efficacy with tolerability, guided by patient-specific factors and real-world clinical experience.

Experts discuss the critical role of toxicity management in deciding whether to use amivantamab/lazertinib up-front or in later lines, highlighting the need for intensive supportive care, coordinated care teams, and structured patient education to navigate the regimen’s unique and often burdensome adverse effect profile.

Experts discuss the comparative merits of FLAURA2 and MARIPOSA frontline regimens for EGFR-mutant non–small cell lung cancer, noting similar survival benefits but highlighting key differences in toxicity profiles, supportive care demands, and real-world practicality that make individualized patient counseling essential to treatment selection.

Experts discuss the vital role of shared decision-making in lung cancer treatment, emphasizing personalized, ongoing conversations that align therapy choices with patients’ values, quality-of-life considerations, and life circumstances to support informed and compassionate care.

Experts discuss a key finding from FLAURA2 showing that many patients never reach second-line therapy, reinforcing the importance of delivering the most effective treatment—such as combination therapy—up-front, particularly when patients are fit, as real-world barriers and rapid progression may limit later opportunities for intervention.

Experts discuss the slow but growing real-world adoption of combination therapy for EGFR-mutant non–small cell lung cancer (NSCLC) despite strong FLAURA2 survival data, citing factors such as clinical inertia, comfort with monotherapy, and regional practice variations, while anticipating broader uptake as confidence, education, and infrastructure catch up with the evolving standard of care.

Experts discuss the gap between current clinical guidelines and emerging trial data in EGFR-mutant lung cancer, highlighting calls to elevate combination therapies in treatment recommendations following robust survival benefits, while underscoring the continued importance of individualized care and patient-centered flexibility in frontline decision-making.