Advances in EGFR+, HER2-Mutant, and CNS-Involved NSCLC Dominate Discussion After ESMO 2025

Following 5 days of data-driven discussion at the 2025 ESMO Congress, OncLive® asked some of our leading lung cancer experts to share the presentations they believe will most influence future directions in precision medicine and targeted therapy development in their field. Contributors included:

• Jonathan Wesley Riess, MD, MS, director of Thoracic Oncology and associate professor of medicine in the Division of Hematology and Oncology at the University of California (UC), Davis Comprehensive Cancer Center in Sacramento
• Pasi A. Jänne, MD, PhD, senior vice president for Translational Medicine, director of the Belfer Center for Applied Cancer Science, director of the Chen-Huang Center for EGFR Mutant Lung Cancers, a senior physician, and the David M. Livingston, MD, Chair at Dana-Farber Cancer Institute in Boston, Massachusetts; as well as a professor of medicine at Harvard Medical School
• Xiuning Le, MD, PhD, associate professor in the Department of Thoracic/Head and Neck Medical Oncology of the Division of Internal Medicine at the University of Texas MD Anderson Cancer Center in Houston

Notable trials included the phase 3 OptiTROP-Lung04 study (NCT05870319) and the phase 2 NorthStar trial (NCT03410043) in EGFR-mutant non–small cell lung cancer (NSCLC); the phase 1 Beamion LUNG-1 (NCT04886804) and phase 1/2 SOHO-01 (NCT05099172) trials in HER2-mutant disease; and a real-world study of leptomeningeal metastases in advanced lung cancer.

Whether you were unable to attend the meeting in Berlin, Germany or are seeking a concise overview of the most practice-informing presentations, watch the video above to hear insights directly from our experts, and read on for an expanded look at each highlighted study.

Does the phase 3 OptiTROP-Lung04 study signal a role for sacituzumab tirumotecan in EGFR-mutated NSCLC?

LBA5 - Sacituzumab tirumotecan (sac-TMT) vs platinum-based chemotherapy in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) following progression on EGFR-TKIs: results from the randomized, multi-center phase III OptiTROP-Lung04 study

Highly-anticipated data from OptiTROP-Lung04 support the TROP2-directed antibody-drug conjugate (ADC) sac-TMT as a viable new treatment option for patients with EGFR-mutated NSCLC who experienced disease progression on an EGFR TKI.1This agent is notable for incorporating a bifunctional linker that enhances the delivery of a belotecan-derivative topoisomerase I inhibitor payload to the tumor cells.2

Findings presented during the 2025 ESMO Congress demonstrated a significant improvement in progression-free survival (PFS) compared with chemotherapy. At a median follow-up of 18.9 months, the median PFS by blinded independent central review (BICR) was 8.3 months (95% CI, 6.7-9.9) with sac-TMT vs 4.3 months (95% CI, 4.2-5.5) with chemotherapy (HR, 0.49; 95% CI, 0.39-0.62; P < .0001). The 12-month PFS rates were 32.3% (95% CI, 25.5%-39.2%) and 7.9% (95% CI, 4.4%-12.8%), respectively, with consistent benefit observed across all prespecified subgroups.

Investigator-assessed PFS results were concordant, with a median of 8.4 months (95% CI, 7.1-9.7) in the sac-TMT arm vs 4.8 months (95% CI, 4.2-5.5) in the chemotherapy arm (HR, 0.51; 95% CI, 0.41-0.65; P < .0001). The corresponding 12-month PFS rates were 34.7% (95% CI, 27.7%-41.7%) and 10.7% (95% CI, 6.5%-16.0%), respectively.

Jänne noted that results from OptiTROP-Lung04 represent an important advancement for this molecularly-defined subgroup. “The study evaluating the TROP2-[directed] ADC [sacituzumab tirumotecan] vs chemotherapy is one of the first of its kind. There are not that many randomized trials comparing the two head-to-head. ADCs are an emerging area of therapeutics in lung cancer and many other cancers too, so understanding how they are a type of chemotherapy, but may differ in terms of their efficacy and safety compared with standard chemotherapy is an important piece of information for the field.”

Can local consolidative therapy enhance the benefit of osimertinib in EGFR-mutated NSCLC?

LBA72 - NorthStar: A phase II randomized study of osimertinib (OSI) with or without local consolidative therapy (LCT) for metastatic EGFR-mutant non-small cell lung cancer (NSCLC)

Riess highlighted the NorthStar trial, which explored whether adding local consolidative therapy (LCT) to osimertinib (Tagrisso) could improve outcomes in patients with metastatic EGFR-mutant NSCLC.3 Previous research suggested that combining LCT with EGFR TKIs could eradicate resistant clones and delay systemic progression, but prior to NorthStar, no prospective, randomized evidence was available to elucidate the role of strategy.

“At UC Davis Comprehensive Cancer Center, we have a large population of patients with EGFR-mutant lung cancer,” Riess explained. “In terms of integrating radiation with a TKI and [generating more robust data], this is an important study.”

During the 2025 ESMO Congress, findings from NorthStar demonstrated a statistically significant PFS improvement with the addition of LCT. The median PFS was 25.3 months (95% CI, 19.4-45.0) with osimertinib plus LCT (n = 56) vs 17.5 months (95% CI, 14.5-24.3) with osimertinib alone (n = 63), corresponding to a 34% reduction in the risk of progression or death (HR, 0.66; 95% CI, 0.50-0.87; 1-sided log-rank P = .025).

Among patients who underwent LCT, 58.9% received radiation, 32.1% underwent surgery, and 9% received both modalities. No unexpected toxicity was observed, and notably, the addition of LCT did not increase the incidence of pneumonitis beyond that expected with thoracic radiation. The most frequent treatment-related adverse effects (occurring in ≥ 20% of patients) in the combination arm included skin disorders (64.4%), paronychia (57.6%), fatigue (55.3%), diarrhea (46.4%), dry skin (33.9%), dyspnea (30.3%), cough (28.6%), and musculoskeletal pain (27.1%), with grade 3 toxicity being rare.

Do ERBB2 TKIs have practice-hanging potential for HER2-mutant NSCLC?

LBA74 - Zongertinib as first-line treatment in patients with advanced HER2-mutant NSCLC: Beamion LUNG 1

LBA75 - Sevabertinib (BAY 2927088) in advanced HER2-mutant non-small cell lung cancer (NSCLC): Results from the SOHO-01 study

Two oral ERBB2 TKIs garnered significant attention at the 2025 ESMO Congress: zongertinib (Hernexeos) and sevabertinib (BAY 2927088).

The phase 1 Beamion LUNG-1 trial evaluated zongertinib as first-line therapy in patients with treatment-naive, advanced HER2-mutant NSCLC.4 Notably, data featured at the meeting focused on cohort 2, which enrolled patients who were treatment naive and had a tyrosine kinase domain (TKD) mutation. The objective response rate (ORR) in this cohort was 77% (95% CI, 66%-85%; P < .0001), including a complete response rate of 8% and partial response rate of 69%. The disease control rate (DCR) reached 96% (95% CI, 89%-99%), with a median time to response of 1.4 months (range, 1.1-6.9). At data cutoff, 47% of patients remained on treatment.

Treatment-related adverse effects (TRAEs) occurred in 91% of patients, with 18% of patients reporting grade 3 AEs. No grade 4 or 5 TRAEs occurred. Dose reductions and discontinuations due to AEs were reported in 15% and 9% of patients, respectively, and 2 cases of grade 2 interstitial lung disease (ILD)/pneumonitis were observed.

Notably, in August 2025, the FDA granted accelerated approval to zongertinib for patients with previously treated metastatic or unresectable nonsquamous NSCLC harboring HER2 TKD activating mutations, as detected by an FDA-approved test.5

The Beamion LUNG 1 results were presented alongside data from the phase 1/2 SOHO-01 trial evaluating sevabertinib, an irreversible small molecule HER2 inhibitor in HER2-mutant advanced NSCLC.6 Across cohorts D, E, and F, sevabertinib monotherapy induced robust and durable responses in both previously treated and treatment-naive patients. In cohort D (n = 81; previously treated), the ORR by BICR was 64% (95% CI, 53%-75%) and the DCR was 81% (95% CI, 71%-89%). Moreover, efficacy was consistent across subgroups regardless of age, sex, race, prior therapies, or baseline brain metastases.

Drug-related AEs occurred in 69% of patients in cohort D, 100% of those in cohort E, and 97% of those in cohort F, with grade 3 AEs reported in 36%, 31%, and 21% of patients, respectively. Grade 3 diarrhea was observed in 23%, 11%, and 5% of patients in the respective cohorts, and no cases of ILD or pneumonitis were reported.

“It’s a good thing for patients and physicians to have more than one treatment option as oral medication, both zongertinib and sevabertinib,” Le emphasized. “We reported out the new updated results [for SOHO-1] in the same session [as Beamion LUNG-1]. Hopefully by next year, both of these medications will be available for patients.”

How is the management of leptomeningeal metastases evolving in advanced NSCLC?

659O - Molecular diagnosis and management of leptomeningeal metastases with evolving therapeutic paradigm in advanced lung cancer

Another notable presentation was a global, multicenter retrospective analysis of evolving therapeutic strategies for patients with leptomeningeal disease (LMD) and advanced NSCLC.7 The study included 2052 patients with NSCLC and LMD from institutions across Asia, the United States, and Europe.

“[This trial] looked at a large cohort of patients with NSCLC and leptomeningeal carcinomatosis, which is involvement of the central nervous system [CNS] coating of the brain with lung cancer. It’s the largest [data] series evaluating that,” Riess added.

Results showed that the prevalence of LMD has increased since 2014, largely due to prolonged survival among patients with advanced NSCLC across molecular subtypes. The median time to LMD diagnosis was 14.2 months (95% CI, 13.2-15.2). Importantly, leptomeningeal overall survival (LMOS) improved significantly over time, particularly among patients receiving targeted therapies or checkpoint inhibitors.

For patients with actionable genomic alterations (AGA), the median LMOS with targeted therapy was 17.4 months (95% CI, 15.9-18.9) in the contemporary cohort (2014-2024; n = 1093) compared with 10.8 months (95% CI, 8.3-13.3) in the historical cohort (2007-2013; n = 81; P = .02). In contrast, patients who did not receive targeted therapy had a median LMOS of 4.1 months (95% CI, 2.8-5.4) in the contemporary cohort and 4.0 months (95% CI, 0.9-7.1) historically (P = .6).

Among non-AGA patients, checkpoint inhibitor therapy extended LMOS to 15.6 months (95% CI, 11.3-19.8) vs 7.2 months (95% CI, 3.8-10.0) in the historical cohort (P = .01). For patients who did not receive checkpoint inhibition, LMOS was 3.4 months (95% CI, 1.2-5.6) in the contemporary cohort and 2.3 months (95% CI, 1.5-3.2) historically (P = .4).

The investigators also observed that CNS-penetrant TKIs can delay, though not entirely prevent, the development of LMD. Continued use of third-generation EGFR TKIs after LMD diagnosis may confer an LMOS benefit in EGFR-mutated NSCLC, warranting further prospective validation.

References

1. Zhang L, Fang W, Wu L, et al. Sacituzumab tirumotecan (sac-TMT) vs platinum-based chemotherapy in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) following progression on EGFR-TKIs: results from the randomized, multi-center phase 3 OptiTROP-Lung04 study. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA5.
2. Zhao S, Cheng Y, Wang Q, et al. Sacituzumab tirumotecan in advanced non-small-cell lung cancer with or without EGFR mutations: phase 1/2 and phase 2 trials. Nat Med. 2025 Jun;31(6):1976-1986. doi:10.1038/s41591-025-03638-2.
3. Elamin YY, Gandhi SJ, Antonoff MB, et al. NorthStar: a phase II randomized study of osimertinib (osi) with or without local consolidative therapy (LCT) for metastatic EGFR-mutant non-small cell lung cancer (NSCLC). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA72.
4. Popat S, Yamamoto N, Girard N, et al. Zongertinib as first-line treatment in patients with advanced HER2-mutant NSCLC: Beamion LUNG-1. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA74.
5. FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations. FDA. August 8, 2025. Accessed October 29, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-non-squamous-nsclc-her2-tkd-activating-mutations
6. Le X, Kim TM, Dong X, et al. Sevabertinib (BAY 2927088) in advanced HER2-mutant non-small cell lung cancer (NSCLC): results from the SOHO-01 study. Presented at: 2025 ESMO Congress; October 17-20, 2025; Berlin, Germany. Abstract LBA75.
7. Wu Y, Zheng M, Tu H, et al. Molecular diagnosis and management of leptomeningeal metastases with evolving therapeutic paradigm in advanced lung cancer. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 6590.