Osimertinib opens the door for patients with EGFR-mutated advanced non-small cell lung cancer and a poor performance status: comment on the OPEN/TORG2040 trial

We are profoundly grateful for the insightful and constructive comments provided by Drs. Pham and Arulananda (1), as well as Dr. Guinel and colleagues (2), regarding our OPEN/TORG2040 trial. Their rigorous analysis underscores the clinical imperative to establish robust, prospective evidence for the “frail” population in thoracic oncology—a cohort frequently marginalized in pivotal clinical research.

Patients with poor performance status (PS) are commonly excluded from landmark international trials due to clinical instability and perceived vulnerability to adverse events (AEs). Consequently, a significant disparity remains between clinical trial populations and real-world practice. While the primary goals of systemic therapy for advanced non-small cell lung cancer (NSCLC) include disease control, improving quality of life (QoL) is equally as critical as prolonging survival for patients with poor PS. Our trial demonstrated an objective response rate (ORR) of 63.3%, which was mirrored by an identical PS improvement rate (63.3%). These findings, together with rapid symptomatic amelioration, confirm that osimertinib provides immediate and meaningful clinical benefits by mitigating cancer-related symptoms.

As the commentators aptly noted, a distinctive feature of the OPEN trial was the high prevalence of brain metastases. Epidermal growth factor receptor (EGFR)-mutated NSCLC is characterized by a high frequency of central nervous system (CNS) involvement (3), and controlling these metastases is essential for maintaining daily function and enabling treatment continuity (4). The combination of poor PS, CNS involvement, and advanced age constitutes a challenging prognostic constellation (5-8). These factors inherently account the shorter progression-free survival and overall survival observed in our cohort compared to the FLAURA trial, which predominantly enrolled patients with good PS (PS 0–1) (9). Nevertheless, for this high-risk population with limited therapeutic options, our findings provide important prospective validation of osimertinib efficacy.

The management of AEs in vulnerable patients requires meticulous attention. Grade 3 or higher AEs occurred in 53.3% of participants, highlighting the need for intensive monitoring. Interstitial lung disease (ILD) remains the most critical concern. While the global FLAURA trial reported an ILD incidence of 3.7% (12% in the Japanese subgroup) (9,10), our trial observed an incidence of 20% (6/30). Notably, most occurred within 100 days and were reversible; however, one fatal late-onset case (day 455) emphasizes that vigilance must be maintained throughout the entire treatment duration. Poor PS itself may be an independent risk factor for ILD (11), particularly within the Japanese population. Furthermore, the high incidence of anemia (60%) likely reflects the interplay of advanced age (median 75 years) and cancer cachexia, necessitating comprehensive supportive care and nutritional optimization to sustain treatment continuity, despite our inclusion criteria required a hemoglobin level ≥9.0 g/dL.

We agree with the commentators regarding the heterogeneity of the poor PS population. The OPEN trial specifically targeted a “cancer-driven” poor PS to evaluate the potential for functional recovery through potent anti-tumor activity. While our results provide a valuable benchmark, the management of patients with significant underlying comorbidities or uncommon EGFR mutations must remain highly individualized, guided by multidisciplinary clinical judgment.

In conclusion, osimertinib can significantly improve cancer-related symptoms and QoL in patients with EGFR-mutated NSCLC and poor PS, provided they are managed with rigorous toxicity monitoring. We hope the OPEN trial encourages future collaborative efforts to refine therapeutic strategies for this underserved patient population.

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