NSCLC Experts Highlight Clinical Trials to Watch in 2025

The non–small cell lung cancer (NSCLC) treatment paradigm is rapidly evolving, with multiple clinical trials poised to reshape standards of care for several patient subgroups. OncLive® asked leading lung cancer experts to share the research and readouts they’re most highly anticipating over the next few months. We heard from:

• Erminia Massarelli, MD, PhD, MS, a clinical faculty physician at The University of Texas (UT) at Tyler Health Science Center under the UT Tyler School of Medicine
• Misako Nagasaka, MD, PhD, an associate professor of medicine in the Division of Hematology and Oncology at the University of California, Irvine School of Medicine
• Corey J. Langer, MD, a professor of medicine (hematology-oncology) in the Department of Medicine at the Hospital of the University of Pennsylvania; as well as a thoracic medical oncologist in the Division of Hematology Oncology at the Perelman Center for Advanced Medicine in Philadelphia
• Karen L. Reckamp, MD, a professor of medicine, director of Medical Oncology, associate director of Clinical Research, and medical oncology director of the Lung Institute at Cedars-Sinai Medical Center in Los Angeles, California

Read more about these pivotal trials and why these experts are keeping a close eye on the pending findings.

DESTINY-Lung04

The phase 3 DESTINY-Lung04 trial (NCT05048797) is a first-line study evaluating fam-trastuzumab deruxtecan-nxki (Enhertu)—an antibody-drug conjugate (ADC)—against the widely used phase 3 KEYNOTE-189 trial (NCT02578680) regimen of carboplatin, pemetrexed, and pembrolizumab (Keytruda) in patients with HER2-mutated NSCLC, Nagasaka said.1 The findings from this trial are especially anticipated because HER2 alterations are a target of growing interest, Nagasaka added. Positive results could mark the first time an ADC becomes a preferred first-line therapy in this population, potentially changing practice standards, Nagasaka noted.

Beamion LUNG-2

The phase 3 Beamion LUNG-2 study (NCT06151574) is testing the HER2-targeted TKI zongertinib (BI 1810631) compared with the KEYNOTE-189 regimen in patients with HER2-mutated NSCLC.2 This trial will determine whether moving HER2 TKIs earlier in the treatment paradigm offers efficacy advantages, Nagasaka stated.

SOHO Studies

Similar to Beamion LUNG-2, the phase 1/2 SOHO-01 (NCT05099172) and phase 3 SOHO-02 (NCT06452277) trials are also exploring a HER2-targeted TKI—sevabertinib (BAY 2927088)—in patients with HER2-mutated NSCLC. SOHO-01 evaluated the agent in patients with pretreated, advanced HER2-mutant NSCLC who were naive to HER2-targeted therapy, or those not exposed to any therapy for advanced disease.3 The agent was associated with a manageable safety profile. Additionally, the objective response rates in patients with progressive disease and those naive to treatment for advanced disease, respectively, were 59.3% (95% CI, 47.8%-70.1%) and 59.0% (95% CI, 42.1%-74.4%). The ongoing, randomized SOHO-02 trial is investigating the efficacy and safety of first-line sevabertinib vs the KEYNOTE-189 regimen in patients with locally advanced or metastatic NSCLC harboring HER2 activating mutations.4

FLAURA2

The phase 3 FLAURA2 trial (NCT04035486) evaluated the combination of osimertinib (Tagrisso) and platinum-based chemotherapy vs osimertinib alone in patients with first-line EGFR-mutated advanced NSCLC.5 Prior data from this study supported the February 2024 FDA approval of osimertinib plus platinum-based chemotherapy for patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.6

A July 2025 news release announced an overall survival (OS) advantage with the combination over osimertinib alone, although exact hazard ratios and statistical details remain undisclosed and will be shared at a future medical meeting.7 Historically, findings from the phase 3 FLAURA trial (NCT02296125) established osimertinib as the first-linestandard of care (SOC) for patients with EGFR-mutated advanced NSCLC,8 and data with the FLAURA2 regimen indicate a further survival improvement. Langer stated that he is eager to see whether this OS benefit is comparable with or exceeds that seen in studies of amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze) in this population.

HARMONi-2

The phase 3 HARMONi-2 study (NCT05499390) is investigating ivonescimab (SMT112)—a PD-1 x VEGF bispecific antibody—vs pembrolizumab in patients with locally advanced or metastatic, PD-L1–positive NSCLC without sensitizing EGFR or ALK mutations.9 Although progression-free survival data from this trial have been presented and favored the ivonescimab arm across patient subgroups, including those with a PD-L1 tumor proportion score (TPS) of 1% to 49% (HR, 0.54; 95% CI, 0.37-0.78) and a PD-L1 TPS of at least 50% (HR 0.48; 95% CI, 0.29-0.79), the OS results are still pending. The outcomes from this trial might inform sequencing strategies in this population, according to Reckamp.

TRITON

The phase 3 TRITON trial (NCT06008093) is comparing pembrolizumab plus standard chemoimmunotherapy vs a 4-drug regimen that adds dual checkpoint blockade with durvalumab (Imfinzi) and tremelimumab (Imjudo) to chemotherapy in patients with nonsquamous metastatic NSCLC with STK11, KEAP1, or KRAS mutations or co-mutations.10 This combination is hypothesized to improve outcomes, particularly in patients with PD-L1–low tumors and/or co-mutations in STK11 or KEAP1, Langer explained.

INSIGNIA

The phase 3 INSIGNIA trial (NCT03793179) is a cooperative group study comparing single-agent pembrolizumab vs pembrolizumab plus chemoimmunotherapy in patients with nonsquamous NSCLC with PD-L1 expression of 1% to 49%.11 A second randomization will assess whether continuing pembrolizumab beyond progression with chemotherapy improves outcomes, Langer reported. The trial will clarify whether all PD-L1–positive patients truly need chemotherapy up-front or whether some can avoid it, he continued.

Overarching Trends in NSCLC Research

The experts underscored that NSCLC management is entering an era of unprecedented complexity. Researchers are pushing targeted therapies, ADCs, and immunotherapy combinations into the first-line setting. Treatment sequencing strategies will become a central challenge in the future. The field is also grappling with information overload, as results from these trials could rapidly shift practice patterns and prompt oncologists to rethink longstanding treatment algorithms.

References

1. A study to investigate the efficacy and safety of trastuzumab deruxtecan as the first treatment option for unresectable, locally advanced/​metastatic non-small cell lung cancer with HER2 mutations. ClinicalTrials.gov. Updated July 8, 2025. Accessed August 6, 2025. https://clinicaltrials.gov/study/NCT05048797
2. Beamion LUNG-2: a study to test whether zongertinib (BI 1810631) helps people with advanced non-small cell lung cancer with HER2 mutations compared with standard treatment. ClinicalTrials.gov. Updated August 6, 2025. Accessed August 6, 2025. https://clinicaltrials.gov/study/NCT06151574?term=NCT06151574&rank=1
3. Loong HH, Li L, Wu L, et al. SOHO-01: safety and efficacy of BAY 2927088 in patients with advanced HER2-mutant non-small cell lung cancer (NSCLC) who were pretreated but naïve to HER2-targeted therapy or had not received any treatment for advanced disease. J Clin Oncol. 2025;43(suppl 16):8504. doi:10.1200/JCO.2025.43.16_suppl.8504
4. Le X, Goto K, Lu S, et al. SOHO-02: phase III trial of BAY 2927088 in patients with locally advanced or metastatic NSCLC with HER2-activating mutations. J Clin Oncol. 2025;43(suppl 16):TPS8648. doi:10.1200/JCO.2025.43.16_suppl.TPS8648
5. Tagrisso (osimertinib) plus chemotherapy demonstrated statistically significant and clinically meaningful improvement in overall survival in EGFR-mutated advanced lung cancer. News release. AstraZeneca. July 21, 2025. Accessed August 6, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/tagrisso-plus-chemotherapy-demonstrated-statistically-significant-and-clinically-meaningful-improvement-in-overall-survival-in-egfr-mutated-advanced-lung-cancer.html
6. FDA approves osimertinib with chemotherapy for EGFR-mutated non-small cell lung cancer. FDA. February 16, 2024. Accessed August 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer
7. Tagrisso (osimertinib) plus chemotherapy demonstrated statistically significant and clinically meaningful improvement in overall survival in EGFR-mutated advanced lung cancer. News release. AstraZeneca. July 21, 2025. Accessed August 7, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/tagrisso-plus-chemotherapy-demonstrated-statistically-significant-and-clinically-meaningful-improvement-in-overall-survival-in-egfr-mutated-advanced-lung-cancer.html
8. FDA approves osimertinib for first-line treatment of metastatic NSCLC with most common EGFR mutations. FDA. April 18, 2018. Accessed August 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-first-line-treatment-metastatic-nsclc-most-common-egfr-mutations
9. Xiong A, Wang L, Chen J, et al. Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): a randomised, double-blind, phase 3 study in China. Lancet. 2025;405(10481):839-849. doi:10.1016/S0140-6736(24)02722-3
10. A study to investigate the efficacy of durvalumab plus tremelimumab in combination with chemotherapy compared with pembrolizumab in combination with chemotherapy in metastatic NSCLC patients with non-squamous histology who have mutations and/​or co-mutations in STK11, KEAP1, or KRAS (TRITON). ClinicalTrials.gov. Updated July 20, 2025. Accessed August 6, 2025. https://www.clinicaltrials.gov/study/NCT06008093
11. Testing the timing of pembrolizumab alone or with chemotherapy as first line treatment and maintenance in non-small cell lung cancer. ClinicalTrials.gov. Updated August 6, 2025. Accessed August 6, 2025. https://www.clinicaltrials.gov/study/NCT03793179