Navigating EGFR Mutations and ALK Fusions in Early-Stage Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and the second most common cause of cancer-related mortality in men and women. Treatment has significantly advanced over the past few decades, leading to improved outcomes and better responses—a testament to the positively evolving therapeutic landscape of NSCLC. The emergence of biomarkers plays a critical role in the growing success of treatment, resulting in the development of novel agents with superior sensitivity and specificity compared with traditional standards of care therapies. Biomarker testing is making its way to the forefront of NSCLC diagnostics, risk stratification, and treatment decisions to guide health care practitioners and patients to the most efficacious, personalized regimens.

Visualization of human lungs with cancer | Image Credit: © iDoPixBox - stock.adobe.com

At the 2025 American Society of Clinical Oncology Annual Meeting, experts discussed genomic insights in perioperative decision-making in early-stage NSCLC, navigating EGFR ALK mutations, and the emergence of other biomarkers.

Biomarker Testing for NSCLC

“Molecular testing is the gateway to the right therapy in those with early-stage [NSCLC],” said Charu Aggarwal, MD, MPH, FASCO, from Penn Medicine Abramson Cancer Center.¹

Biomarker testing is relatively new in the treatment landscape for NSCLC but has proven to be incredibly important for personalizing patient care, transforming from a generic chemotherapy approach to a highly personalized, genomically driven treatment strategy. Initially, surgery was the primary treatment for early-stage disease, followed by platinum-based chemotherapy adjuvant therapy. For advanced disease, chemotherapy was the standard. However, these treatment approaches have a limited understanding of molecular subtypes with a one-size-fits-all approach without personalized targeting, leading to poorer responses and outcomes.¹

The introduction of molecular testing changed everything, leading to the discovery of driver mutations—such as EGFR and ALK—the development of targeted therapies, and the emergence of immunotherapies, leading to significant survival benefits. Precision medicine approaches replaced traditional chemotherapy, and molecular profiling has become the standard to guide targeted therapies for specific mutations.¹

“We need to test for EGFR and ALK for all of these patients if we are going to drive precision medicine to reality in our clinics,” Aggarwal said. “The first opportunity for biomarker testing is upon initial diagnosis. And I say that this is really important as we evaluate newer data for management and integration of EGFR TKI [Tyrosine kinase inhibitors] in the management of our patients.”¹

Targeting EGFR

EGFR mutations occur in about 10% to 15% of lung adenocarcinomas and are most common in nonsmokers, women, and Asian populations, with exon 19 deletion and exon 21 L858R being the most frequent mutations. In the adjuvant setting following surgery, osimertinib (Tagrisso; AstraZeneca), a TKI, is the standard of care with proven overall survival benefit in resected early-stage NSCLC. However, neoadjuvant approaches are showing promising results, and data from the NeoADAURA trial (NCT04351555) support this approach.^1,2

Molecular visualization of EGFR inhibition by osimertinib | Image Credit: © patsuda - stock.adobe.com

The randomized, controlled, 3-arm, multicenter phase 3 trial of neoadjuvant osimertinib as a monotherapy or in combination with chemotherapy, compared with standard of care chemotherapy alone in patients with resectable EGFR-mutated NSCLC. The data showed that neoadjuvant osimertinib was associated with a significantly superior major pathologic response—the study’s primary end point—compared with chemotherapy, which only had a 2% response rate. Additionally, the study results revealed a trend towards improved event-free survival.^1,2

Based on the trial results, neoadjuvant osimertinib, with or without chemotherapy, should be considered for resectable EGFR-mutant NSCLC; however, individualized treatment decisions remain crucial as not all patients will benefit from this therapeutic approach equally. Neoadjuvant osimertinib represents a potential new standard in treatment for patients with early-stage disease.¹

Aggarwal recommends mandatory molecular testing at diagnosis to more effectively guide and personalize treatment decisions based on specific EGFR mutations. Additionally, for patients with more aggressive, challenging-to-treat disease, oncologists and oncology pharmacists should consider clinical trials for emerging therapies.¹

Targeting ALK

ALK fusions occur in 1% to 4% of lung cancers, typically in adenocarcinomas. They are more common in younger patients and are often associated with a minimal smoking history. Standard of care treatment for patients with ALK fusions is alectinib (Alecensa; Genentech), a TKI that was approved by the FDA in 2024 for adjuvant treatment following tumor resection in patients with ALK-positive NSCLC. This decision was based on data from the ALINA trial (NCT03456076), where alectinib showed significant superiority in disease-free survival (DFS) benefit compared with chemotherapy.^1,3,4

The randomized phase 3 trial evaluated alectinib versus chemotherapy in 257 patients with stage 1B to 3A (tumors ≥ 4 cm or node-positive) resected ALK fusion-positive NSCLC. Although it was the primary end point, DFS was not reached, the hazard ratio (0.24) strongly favored alectinib over chemotherapy (DFS approximately 45 months). This benefit was consistent across disease stages—fifteen patients in the alectinib arm had disease recurrence compared with 49 patients in the chemotherapy arm. Central nervous system DFS outcomes were also favorable (alectinib: 98%; chemotherapy: 86%).¹

TKIs binding to target enzymes | Image Credit: © Justlight - stock.adobe.com

Following the ALINA trial data, the investigators recommend waiting to initiate adjuvant alectinib 2 years after surgery and to avoid immunotherapy. Mandatory ALK fusion testing should become part of the standard of care to better personalize treatments to a patient’s specific ALK variant.¹

"Immunotherapy given neoadjuvantly may not be the appropriate treatment strategy for patients with high fusion,” said Kaushal Parikh, MD, from Mayo Clinic. “In fact, it is not the appropriate treatment strategy for ALK fusion-positive early-stage lung cancers."¹

Ongoing trials, such as AlNEO (NCT05015010), are exploring neoadjuvant alectinib, which shows promising early results. In ALNEO, preemptive treatment with alectinib yielded a 42% pathologic response rate.^1,5

Future Directions

As biomarker testing becomes increasingly integrated into the standard of care, its role in refining perioperative strategies for NSCLC cannot be overstated. Molecular profiling has ushered in a new era of precision medicine, enabling clinicians to move beyond conventional one-size-fits-all models toward approaches that consider each tumor’s unique genetic landscape. Trials like NEODORA and ALINA provide compelling evidence that targeted therapies such as osimertinib and alectinib can significantly improve outcomes when used in appropriately selected early-stage patients. However, these advances hinge on timely and comprehensive molecular testing at diagnosis, which must become the norm across all clinical settings.

“Perioperative treatment should be tailored today based on individual clinical and genomic features for patients with EGFR- and ALK-type [NSCLC],” concluded Biagio Ricciuti, MD, PhD, from the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School. “Chemotherapy should remain some of the care in the neoadjuvant or perioperative setting.”¹

Looking ahead, the future of NSCLC treatment lies in the continued refinement of biomarker-driven treatment selection, increased trial enrollment for patients with complex mutations, and multidisciplinary collaboration between oncologists, surgeons, pathologists, and pharmacists.

REFERENCES

1. Aggarwal C, Parikh K, Ricciuti B. Genomic insights in perioperative decision-making in non–small cell lung cancer: Navigating EGFR, ALK, and emerging biomarkers. 2025 ASCO Annual Meeting. May 30, 2025, to June 3, 2025. Chicago, IL.

2. A study of osimertinib with or without chemotherapy versus chemotherapy alone as neoadjuvant therapy for patients with EGFRm positive resectable non-small cell lung cancer (NeoADAURA). Updated May 23, 2025. Accessed June 19, 2025. https://clinicaltrials.gov/study/NCT04351555

3. A study comparing adjuvant alectinib versus adjuvant platinum-based chemotherapy in patients with ALK positive non-small cell lung cancer. Updated April 22, 2025. Accessed June 19, 2025. https://clinicaltrials.gov/study/NCT03456076

4. FDA approves alectinib as adjuvant treatment for ALK-positive non-small cell lung cancer. FDA. April 18, 2024. Accessed June 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-alectinib-adjuvant-treatment-alk-positive-non-small-cell-lung-cancer

Alectinib in neo-adjuvant treatment of stage III NSCLC (ALNEO). Updated August 9, 2024. Accessed June 19, 2025. https://www.clinicaltrials.gov/study/NCT05015010