Optimism has taken root after recent findings from clinical studies indicated that patients with Epidermal Growth Factor Receptor (EGFR)-mutated Non-Small Cell Lung Cancer (NSCLC) experience improved survival outcomes when treated with various combination-based therapeutic strategies.1,2 Unfortunately, these benefits are largely accompanied by a higher incidence of treatment-related adverse events and, as a result, regimen selection has become increasingly complex and requires careful consideration of efficacy–toxicity tradeoffs.3 In an interview with Dr. Zosia Piotrowska, MD, MHS, a lung and thoracic cancer specialist at Mass General Brigham Cancer Institute and associate professor of medicine at Harvard Medical School, recent medical and scientific advances, current challenges, and new therapeutic approaches in NSCLC care were discussed.3
In 2025, clinical evidence supported combination regimens as a central development in the management of EGFR-mutated NSCLC, particularly following the Overall Survival (OS) gains reported in the FLAURA2 and MARIPOSA trials.3 These results shifted clinical practice toward combination approaches as the preferred first-line therapy for many patients; however, unresolved issues persist. Among them is how to optimally weigh therapeutic efficacy against the heightened toxicity profiles observed with combination strategies relative to oral osimertinib monotherapy.3 Another issue concerns patient selection: it is unclear whether specific individuals derive greater benefit from one regimen versus another, and whether individual tumor biological characteristics could eventually shape more precise matching of patients to therapies.3 Additionally, there are currently no robust biomarkers available for NSCLC, which further hinders personalized treatment decision-making.3
The lack of NSCLC-specific biomarkers is especially relevant given that combination regimens operate through distinct mechanisms of action.3 Ideally, future biomarker development would enable the identification of tumors that are especially responsive to specific approaches, such as amivantamab-based combinations.3 The absence of reliable biomarkers significantly complicates treatment selection in the second-line setting; More and more, the most effective therapies are being administered in the frontline, which creates a therapeutic gap for patients requiring later-line treatment.3 For example, individuals who receive first-line osimertinib monotherapy may still be eligible for amivantamab combined with chemotherapy upon progression.3 In contrast, when regimens like those used in FLAURA2 or MARIPOSA are deployed first, the most appropriate second-line approach becomes far less clear.3
Fortunately, multiple clinical trials are currently underway in the frontline setting, including investigations of antibody-drug conjugates (ADCs) such as datopotamab, izalontamab brengitecan, sacituzumab tirumotecan, and other agents.3 Like other emerging therapies, a persistent key concern will be how these treatments compare in terms of efficacy and safety.3 In the second-line context, several of these ADCs are currently being evaluated against chemotherapy, and some studies have already reported encouraging findings.3 Of note, certain datasets (such as those from the sacituzumab tirumotecan OptiTROP-lung program) originated from trials conducted in China, highlighting the need for broader global evidence.3 Additional comparative testing in the second-line setting will be essential to determine which agents are most appropriate for routine clinical practice.3
Regarding additional unmet needs, considerable attention has focused on measures such as clearance of circulating tumor DNA (ctDNA), which could prove valuable in determining which patients require intensified treatment and/or for personalizing regimen selection during the course of the disease.3 Another unmet need involves the development of combination strategies with improved tolerability.3 While therapeutic efficacy has improved, these gains have largely been accompanied by poorer safety profiles; There is hope that progress in supportive care approaches, like the COCOON regimen evaluated in certain studies, and the introduction of new agents, may eventually restore balance between effectiveness and tolerability.3 Additionally, more effective oral treatment options are needed; Many patients prefer all-oral regimens, particularly those that are well tolerated, and recent trends have shifted away from that model.3 Ideally, future development would return to this approach, similar to the trajectory observed in other molecularly defined lung cancers, where successive generations of targeted inhibitors have achieved greater potency and clinical benefit.3
Efforts from this year have already drawn attention; the NorthStar trial, from MD Anderson Cancer Center, demonstrated how adding local consolidation therapy to first-line osimertinib may enhance outcomes for patients with EGFR-mutated NSCLC.3 Still, which patients are most likely to benefit, which disease sites should be targeted, and the optimal timing and type of local therapy are all persistent questions in this approach. Overall, combining systemic treatment with targeted local interventions is an exciting avenue that could complement modern regimens.
Sources
- Wang, Yating, et al. “Survival Trends among Patients with Metastatic Non–Small Cell Lung Cancer before and after the Approval of Immunotherapy in the United States: A Surveillance, Epidemiology, and End Results Database–Based Study.” Cancer, 10 July 2024, https://doi.org/10.1002/cncr.35476.
- Huang, Hong, et al. “Adjuvant Immunotherapy Improves Survival in Completely Resected Stage IB–III NSCLC: A Systematic Review and Meta-Analysis.” Frontiers in Oncology, vol. 15, 8 Apr. 2025, pmc.ncbi.nlm.nih.gov/articles/PMC12011596/, https://doi.org/10.3389/fonc.2025.1493221. Accessed 9 Feb. 2025.
- Osterweil, Neil. “As Practice-Changing Data Hit EGFR-Mutated NSCLC Care, What’s Next?” Oncology News Central, ONC, 21 Jan. 2026, www.oncologynewscentral.com/nsclc/as-practice-changing-data-hit-egfr-mutated-nsclc-care-whats-next. Accessed 6 Feb. 2026.
