Targeted Therapies Move the Needle in NSCLC

Findings from the phase 3 NeoADAURA study (NCT04351555) evaluating neoadjuvant osimertinib (Tagrisso) in early-stage EGFR-mutated non–small cell lung cancer (NSCLC) suggest a potential shift in the treatment paradigm for patients, according to Benjamin P. Levy, MD, FASCO. Moreover, other therapies—such as taletrectinib (Ibtrozi) for patients with ROS1-positive NSCLC and zenocutuzumab-zbco (Bizengri) for patients whose disease harbors NRG1 fusions—have emerged with new targeted approaches, he said.

“Neoadjuvant chemotherapy plus immunotherapy is the standard of care [SOC] for patients with early-stage NSCLC,” Levy said in an interview with OncologyLive. “[However], we are now seeing interesting data in the neoadjuvant setting for patients with EGFR-mutated disease.” Levy is the clinical director of medical oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital and an associate professor of oncology at Johns Hopkins School of Medicine in Baltimore, Maryland.

Neoadaura Data Shake Up Resectable EGFR-Mutated NSCLC

NeoADAURA was a global study to determine whether neoadjuvant osimertinib with or without chemotherapy could improve pathological, surgical, and long-term outcomes in patients with resectable EGFR-mutated stage II to IIIB NSCLC.1 Patients were randomly assigned 1:1:1 to receive osimertinib plus chemotherapy (n = 121), osimertinib monotherapy (n = 117), or placebo plus chemotherapy (n = 120).

The primary end point was major pathologic response (MPR) per blinded central pathology review. Findings from NeoADAURA presented during the 2025 American Society of Clinical Oncology Annual Meeting, revealed that the MPR rates in the combination, osimertinib monotherapy, and placebo arms were 26% (95% CI, 18%-34%), 25% (95% CI, 17%-34%), and 2% (95% CI, 0%-6%), respectively. Using the placebo arm as the reference, the ORs were 19.8 (95.002% CI, 4.6-85.3; P < .0001) and 19.3 (99.9% CI, 1.7-217.4; P < .0001) in favor of the combination and osimertinib monotherapy arms, respectively.

Interim event-free survival (EFS) data from NeoADAURA showed that treatment with the combination (HR, 0.50; 99.8% CI, 0.17-1.41; P = .0382) and osimertinib monotherapy (HR, 0.73; 95% CI, 0.40-1.35) offered an EFS benefit vs the placebo arm. The 12-month EFS rates in the combination, osimertinib monotherapy, and placebo arms were 93%, 95%, and 83%, respectively. “The NeoADAURA data that were presented during ASCO could potentially be transformative in terms of how we approach patients with early-stage EGFR-mutated [disease],” Levy commented. “It’s incredible to think about how far we’ve moved the needle in early-stage [disease]. We used to think that all the science was leveraged in the advanced stage setting, but we’ve finally started to apply those same [principles] to early-stage disease.”

New Options Emerge in NSCLC With Gene Fusions

Beyond the EGFR-mutated space, significant updates have also emerged for patients with ROS1-positive NSCLC and those with advanced disease harboring an NRG1 fusion. Taletrectinib and zenocutuzumab, respectively, have gained FDA approval in the past year for patients with disease harboring these gene fusions. In June 2025, the FDA approved taletrectinib for the treatment of patients with locally advanced or metastatic ROS1-positive NSCLC.2 The regulatory decision was supported by pooled data from the phase 2 TRUST-I (NCT04395677) and TRUST-II (NCT04919811) studies. Updated data from TRUST-I and TRUST-II published in the Journal of Clinical Oncology in June 2025 revealed that tyrosine kinase inhibitor (TKI)–naive patients who received taletrectinib (n = 160) achieved a confirmed overall response rate (ORR) of 88.8% (95% CI, 82.8%-93.2%) per independent review committee assessment, including 8 patients who achieved a complete response (CR).3

Among patients previously treated with a ROS1 TKI (n = 113), the confirmed ORR was 55.8% (95% CI, 46.1%-65.1%), with 5 patients achieving CR. The median duration of response (DOR) in the TKI-naive and TKI-pretreated cohorts was 44.2 months (95% CI, 30.4-not reached) and 16.6 months (95% CI, 10.6-27.3), respectively. The respective disease control rates were 95.0% (2-sided 95% CI, 90.4%-97.8%) and 87.6% (2-sided 95% CI, 80.1%-93.1%).

In December 2024, zenocutuzumab received accelerated approval from the FDA for the treatment of patients with advanced, unresectable, or metastatic NSCLC with an NRG1 fusion who experienced disease progression on or after previous systemic therapy.4

The approval was supported by data from the phase 1/2 eNRGy study (NCT02912949). Updated findings from eNRGy published in the New England Journal of Medicine in February 2025 showed that patients with NRG1 fusionpositive NSCLC who received the HER2/HER3 bispecific antibody (n = 94) experienced an ORR of 31% (95% CI, 22%-41%) per blinded independent central review (BICR).5 The BICR-assessed median DOR was 13.4 months (range, 1.9+ to 29.5+) in these patients.

“The list is getting longer and longer [in terms of] all of the targeted therapies that can be leveraged for [patients with] gene fusions,” Levy said. “We now have these newer drugs, [such as] zenocutuzumab and taletrectinib, in addition to repotrectinib [Augtyro]. It’s exciting for all these agents to now be in our therapeutic armamentarium.”

ADCs Further Cement Their Place in the NSCLC Treatment Paradigm

Levy also noted that the recent FDA approvals of additional antibody-drug conjugates (ADCs) for the treatment of patients with NSCLC have had a significant effect on the clinical landscape of the disease. “There’s been a lot of movement here; 6 months ago, we only had 1 ADC that was FDA approved,” he commented. In May 2025, the FDA granted accelerated approval to the c-Met–directed ADC telisotuzumab vedotin-tllv (Emrelis) for the treatment of patients with locally advanced or metastatic, nonsquamous NSCLC with strong (immunohistochemistry 3+) c-Met protein overexpression in at least 50% of tumor cells (as determined by an FDA-approved test) who had received a prior systemic therapy.6 Data from the phase 2 LUMINOSITY study (NCT03539536) supported the accelerated approval.

At the time of the approval, findings from LUMINOSITY demonstrated that patients with EGFR wild-type NSCLC achieved a confirmed ORR by BICR per RECIST 1.1 criteria of 35% (95% CI, 24%-46%). The median DOR was 7.2 months (95% CI, 4.2-12). Additionally, findings from an analysis of LUMINOSITY presented during the ASCO meeting revealed that low baseline circulating tumor DNA (ctDNA) levels could be a biomarker for response to telisotuzumab vedotin.7 Patients with low baseline ctDNA (mean variant allele frequency [VAF] < 2.05%; n = 41) had a median progression-free survival (PFS) and median overall survival (OS) of 9.9 months (95% CI, 5.5-12.7) and 16.5 months (95% CI, 14.3-20.2), respectively. Comparatively, patients with high baseline ctDNA levels (mean VAF ≥ 2.05%; n = 42) experienced a median PFS of 5.4 months (95% CI, 3.0-6.9) and a median OS of 8.5 months (95% CI, 6.0-14.2).

Notably, ctDNA was not predictive of an improved ORR with telisotuzumab vedotin; the ORRs in the ctDNA-high and ctDNA-low subgroups were 28.6% (95% CI, 17.2%-43.6%) and 22.9% (95% CI, 14.4%-33.4%), respectively. Another ADC, the TROP2-directed agent datopotamab deruxtecan-dlnk (dato-DXd; Datroway), was granted accelerated approval by the FDA for the treatment of patients with EGFR-mutated NSCLC who had received prior EGFR-directed treatment and platinum-based chemotherapy in June 2025.8

The approval was based on pooled data from the phase 2 TROPION-Lung05 (NCT04484142) and phase 3 TROPION-Lung01 (NCT04656652) studies. At the time of the approval, patients who received dato-DXd at the recommended dose across the 2 studies (n = 114) achieved a confirmed ORR by BICR per RECIST 1.1 criteria of 45% (95% CI, 35%-54%). The median DOR was 6.5 months (95% CI, 4.2-8.4).

“My hope is we begin to see some of these ADCs being used in the front line, not just in the second or third line,” Levy said. “I also hope that we start to look at and deploy novel biomarkers that may help us to predict who responds to these drugs. I believe in the next year, we are going to have a lot of interesting data on how to use these in certain sequencing patterns and for which patient populations we should use them in.”

Investigators Set to Gather at CFS to Discuss the Latest Data in Lung Cancer and Other Malignancies

During the upcoming 43rd Annual Chemotherapy Foundation Symposium (CFS), hosted by Physicians’ Education Resource®, LLC, Levy will be joined by fellow cochairs John O. Mascarenhas, MD, and Tiffany A. Traina, MD, to discuss updates in hematologic malignancies, lung cancers, gastrointestinal (GI) cancers, and genitourinary (GU) cancers.9

The event will be held November 12 to 14, 2025, in New York, New York. “We’ve configured the meeting to include and incorporate feedback we’ve had from prior meetings [toward] where the field is moving and what we believe is relevant to someone practicing in the community who is trying to stay on top of this rapidly evolving landscape,” Mascarenhas said in an interview with OncologyLive. Mascarenhas is the director of the Center of Excellence for Blood Cancers and Myeloid Disorders and the adult leukemia program, leader of clinical investigation in the myeloproliferative disorders program, and a member of The Tisch Cancer Institute in New York, New York. He is also a professor of medicine at the Icahn School of Medicine at Mount Sinai.

Traina is the vice chair of outpatient operations in the Department of Medicine and the section head of the triple-negative breast cancer clinical research program at Memorial Sloan Kettering Cancer Center in New York, New York.

In the hematologic malignancies space, this year’s CFS will feature sessions on treatment sequencing and chimeric antigen receptor T-cell therapy selection for patients with multiple myeloma, updates in chronic lymphocytic leukemia, and novel immunotherapies in acute lymphoblastic leukemia. The sessions focused on GU cancers will include presentations on the evolving landscape of non–muscle-invasive bladder cancer, the current standing of ctDNA, and novel combination regimens for the treatment of patients with renal cell carcinoma. Presentations on the management of microsatellite instability–high colorectal cancer, anal carcinoma, and resectable esophageal cancer are set to headline the tracks in GI cancers.