Targeted Therapy Expands Into Adjuvant and Neoadjuvant Settings for Oncogene-Driven Early-Stage NSCLC

Phase 3 randomized trials have established osimertinib (Tagrisso) and alectinib (Alecensa) as adjuvant standards of care for surgically resected EGFR-mutant and ALK-positive non–small cell lung cancer (NSCLC), respectively, with the phase 3 ADAURA trial (NCT02511106) the first to demonstrate a positive overall survival (OS) benefit at 5 years in this setting, according to a presentation by David R. Gandara, MD, during the 27th Annual International Lung Cancer Congress.¹

“It's increasingly important to know the next-generation sequencing [NGS] status in early-stage NSCLC. Should we be testing for things we don't have therapy for yet, but they're oncogenes?” Gandara said.

Gandara is the chief medical officer of the International Society of Liquid Biopsy, the co-director of the Center for Experimental Therapeutics in Cancer, and senior advisor to the director at the University of California Davis Comprehensive Cancer Center, as well as an adjunct clinical professor in the Translational and Clinical Research Program at the University of Hawaii Cancer Center.

During the presentation, Gandara reviewed the current landscape of targeted therapy across adjuvant and neoadjuvant settings in oncogene-driven, early-stage NSCLC, raising open questions about how the perioperative paradigm established for checkpoint immunotherapy may or may not translate to oncogene-driven disease.

What Questions Arise When Applying Perioperative Paradigms to Oncogene-Driven NSCLC?

Gandara framed several open questions facing the field as it extends the perioperative treatment paradigm established for checkpoint immunotherapy to oncogene-driven cancers, including whether curative intent is achievable in the oncogene-targeted TKI setting. He also discussed whether clinical utility established for one oncogene is applicable across all oncogenes, or only some and how important platinum-based chemotherapy is in the adjuvant and neoadjuvant oncogene setting. Gandara also covered whether adjuvant, neoadjuvant, or perioperative treatment is the preferred approach for oncogene-driven disease and how to best identify early-stage patients with oncogene-driven cancers who are candidates for targeted therapy, underscoring the growing importance of NGS testing in early-stage NSCLC.

What Is the Current Standard of Care for Adjuvant Targeted Therapy in EGFR-Mutant and ALK-Positive NSCLC?

Randomized phase 3 trials have established both osimertinib, with or without chemotherapy, in EGFR-mutant NSCLC and alectinib in ALK-positive NSCLC as approved adjuvant approaches in resectable disease. Gandara noted that the importance of platinum-based chemotherapy in this setting remains an open question and may be oncogene-specific, commenting that "the jury is still out" on its role based on disease-free survival (DFS) and OS data from the phase 3 ALINA trial (NCT03456076) of alectinib and ADAURA, which examined osimertinib.

Findings from ADAURA demonstrated that patients who received osimertinib with adjuvant chemotherapy experienced a significant OS benefit compared with those who received placebo with adjuvant chemotherapy (HR, 0.49; 95% CI, 0.30-0.79). An OS benefit was also reported in favor of the osimertinib arm among patients who did not receive adjuvant chemotherapy (HR, 0.47; 95% CI, 0.25-0.83).

In ALINA, a DFS benefit was reported with alectinib vs chemotherapy in patients with stage II to IIIA disease (HR, 0.36; 95% CI, 0.23-0.56). A DFS benefit was also observed with alectinib vs chemotherapy among those with stage IB to IIIA disease (HR, 0.35; 95% CI, 0.23-0.54).

What Do the LIBRETTO-432 Data Show for RET Fusion-Positive NSCLC?

The phase 3 LIBRETTO-432 trial (NCT04819100) evaluated adjuvant selpercatinib (Retevmo) in patients with stage IB to IIIA, RET fusion-positive NSCLC, with investigator-assessed event-free survival (EFS) reported in both the overall stage IB to IIIA population and the primary analysis population of patients with stage II to IIIA disease.²

Findings from LIBRETTO-432 revealed that patients with stage II to IIIA disease who received selpercatinib (n = 54) experienced a 24-month EFS rate of 91.5% (95% CI, 75.4%-97.2%) compared with 61.1% (95% CI, 44.2%-74.3%) among those who received placebo (HR, 0.172; 95% CI, 0.058-0.509). Patients with stage IB to IIIA also experienced a significant EFS benefit with selpercatinib (HR, 0.165; 95% CI, 0.056-0.485).

Gandara said the trial establishes a new standard of care in surgically resected, RET fusion-positive NSCLC, while raising the question of whether this approach can reasonably be extrapolated to other oncogenes.

What Do Early Neoadjuvant Targeted Therapy Trials Show?

Several early studies have evaluated neoadjuvant, or perioperative, targeted therapy in resectable EGFR-mutant and ALK-positive NSCLC. In the phase 3 Neo-ADAURA trial (NCT04351555), which used major pathologic response (mPR) as its primary end point, neoadjuvant osimertinib alone showed an mPR rate of 26% and complete pathologic response (cPR) rate of 4%, while osimertinib plus chemotherapy showed a cPR rate of 12%.¹

In the phase 3 ALNEO trial (NCT05015010) of neoadjuvant alectinib, also using mPR as the primary end point, the mPR rate was 42% (n = 14 of 33) and cPR rate was 12% (n = 4 of 33). In the single-arm phase 2 NAUTIKA trial (NCT04302025) of neoadjuvant alectinib, the mPR rate was 61% (n = 17 of 28) and cPR rate was 12% (n = 7 of 28).

Gandara offered the opinion that none of these studies, including Neo-ADAURA, currently sets a new standard of care, noting that mPR remains an unproven primary end point in this setting and that relatively few cPRs have been observed compared with checkpoint inhibitor–based neoadjuvant approaches; he added that the trials demonstrated feasibility, nodal downstaging, and surgical resectability, but that longer-term efficacy end points are needed before a new standard of care can be established. An interim analysis of Neo-ADAURA further characterized EFS by mPR status.

What Does the LORIN Study Suggest for Neoadjuvant Lorlatinib in ALK-Positive NSCLC?

The phase 2 LORIN trial (NCT05740943) evaluated neoadjuvant lorlatinib (Lorbrena) in patients with ALK-positive, stage III NSCLC, both resectable and unresectable. The trial showed a pathologic complete response (pCR) rate of 47% (n = 15 of 32) and an objective response rate (ORR) of 84% (n = 36 of 43), along with a 75% conversion rate (n = 18 of 24) from unresectable to resectable disease. Gandara characterized this small trial as proof-of-principle for neoadjuvant lorlatinib, highlighting its high pCR rate and conversion rate alongside what he described as impressive biologic correlates.

References

1. Gandara DR. Targeted therapies in early-stage NSCLC. Presented at: 27th Annual International Lung Cancer Congress; July 24-25, 2026; Huntington Beach, CA.
2. Goldman J, Yang XN, Hochmair M, et al. Event-free survival with adjuvant selpercatinib in stage IB-IIIA RET fusion-positive NSCLC: Primary results of the phase 3 LIBRETTO-432 trial. J Clin Oncol. 2026;44(suppl 17):LBA3. doi:10.1200/JCO.2026.44.17_suppl.LBA3