Targeted Therapy Pushes Into Locally Advanced NSCLC as Questions of Duration and Cure Persist

July 29, 2026 | Chris Ryan

Rachel E. Sanborn, MD, reviews how EGFR-, ALK-, RET-, and KRAS-directed strategies are reshaping locally advanced non–small cell lung cancer care.

As the role of targeted agents migrates from metastatic non–small cell lung cancer (NSCLC) management into the locally advanced and resectable settings, the pivotal question is shifting from whether they work to how long patients truly need them.

“We’ve left more questions than we have answers, but it’s an exciting time,” Rachel E. Sanborn, MD, of Providence Cancer Institute and Earle A. Chiles Research Institute in Portland, Oregon, said during a presentation at the 27th Annual International Lung Cancer Congress.¹

She organized her review around 4 biomarker-defined populations: patients with classical EGFR mutations, those with ALK/ROS1 rearrangements, those with RET fusions, and those with KRAS G12C mutations. Each carries distinct data and its own unresolved practice questions.

What is the role of consolidation osimertinib in classical EGFR-mutated NSCLC?

Sanborn opened with the phase 3 LAURA trial (NCT03521154), which randomly assigned patients with locally advanced, unresectable, stage III EGFR-mutated NSCLC who had not progressed after definitive concurrent chemoradiation to receive ongoing osimertinib (Tagrisso) or placebo. Consolidation osimertinib (n = 143) produced a median progression-free survival (PFS) of 39.1 months (95% CI, 31.5-not calculable) vs 5.6 months (n = 3.7-7.4) with placebo (n = 73; HR, 0.16; 95% CI, 0.10-0.24; P < .001), with this benefit maintained across all preplanned subgroups.^2,3

“The authors appropriately concluded from this trial that osimertinib after completion of chemoradiation for stage III NSCLC with classical EGFR mutations improved PFS,” she said, noting that final overall survival (OS) data are pending.

The result, she argued, also raised questions.

“Do all patients who have a classical EGFR mutation in stage III disease truly need a lifetime of osimertinib?” Sanborn poised. “This comes at a cost of physical toxicity. There are patients who are cured even without the agent, and [they] will be continuing to receive a chronic and ongoing treatment.”

She added that the “empirical financial toxicity of treatment in that setting” must also weigh on decision-making.

How should ALK- and ROS1-positive locally advanced NSCLC be managed?

In resected disease, Sanborn cited the phase 3 ALINA trial (NCT03456076), in which a defined course of adjuvant alectinib (Alecensa) significantly improved disease-free survival over 4 cycles of platinum-doublet chemotherapy in patients with stage IB (≥ 4 cm) to IIIA ALK-positive NSCLC (HR for recurrence or death, 0.24; 95% CI, 0.13-0.45; P < .001).⁴

She then turned to the locally advanced setting and the phase 2 LORIN study (NCT05740943), which tested 12 weeks of neoadjuvant lorlatinib (Lorbrena) followed by definitive therapy and up to 2 years of adjuvant/consolidation lorlatinib in 43 patients, most with N3 and stage IIIB disease.⁵ Among 32 patients who underwent surgery, the pathologic complete response rate was 47%, which Sanborn said was “much higher than we have expected to see in other studies.” Notably, 75% of the 24 initially unresectable patients became resectable, and nodal downstaging occurred in 90% of patients.

Tolerability tempered Sanborn’s enthusiasm. Although no new safety signals emerged, “there seem to be a relatively greater number of patients requiring dose reduction and switching treatment in the adjuvant or consolidation setting,” she observed. “Once we face the chronicity of a treatment, the toxicities may become more difficult to tolerate.”

She also reviewed a 67-patient, 17-institution real-world analysis in which patients receiving a consolidation ALK TKI had a PFS HR favoring that approach over durvalumab (Imfinzi), and in which durvalumab in turn outperformed observation.⁶

“The population that did best in relative comparison were patients who received an ALK TKI in the consolidation setting vs observation,” she said. “These are real-world data for individual treatment decisions.”

Can adjuvant selpercatinib set a treatment standard in RET fusion–positive NSCLC?

For RET fusions, Sanborn highlighted the adjuvant phase 3 LIBRETTO-432 trial (NCT04819100), which randomly assigned patients with resected RET fusion–positive NSCLC to receive selpercatinib (Retevmo) or placebo after appropriate adjuvant therapy. A defined course of selpercatinib significantly improved event-free survival (EFS; HR, 0.172; 95% CI, 0.058-0.509; P = .0003), with 24-month EFS rates of 91.5% (95% CI, 75.4%-97.2%) vs 61.1% (95% CI, 44.2%-74.3%), respectively.⁷

The data, she said, sharpen a recurring dilemma for rare drivers of NSCLC.

“Do we need a randomized phase 3 consolidation trial for patients with RET fusions to be able to apply this knowledge?” she asked. “Would completion of that study ever be feasible and timely?”

Do KRAS G12C mutations offer a different path for NSCLC management?

KRAS mutations reframe the early-stage discussion, Sanborn said, citing their sensitivity to immune checkpoint inhibitors.

The accruing phase 3 SUNRAY-02 trial (NCT06890598) includes a cohort of patients with unresectable KRAS G12C–mutant NSCLC who, after concurrent chemoradiation, are being randomly assigned to receive consolidation checkpoint inhibition alone or with the addition of olomorasib (LY3537982).

“I would encourage people to enroll patients into that trial,” she said, noting that the broader pipeline remains thin regarding KRAS-direct therapy.

What unmet needs remain for targeted NSCLC treatment strategies?

Looking ahead, Sanborn called for trials that distinguish immunotherapy-sensitive from immunotherapy-insensitive alterations and that weigh efficacy against differences in tolerability among targeted agents. The field must also expand to emerging targets, including KRAS G12D, BRAF, HER2, and MET exon 14, she said.

Above these sits the question of duration: How long do patients truly need to receive treatment?

“Which patients have been cured with that targeted therapy, and which have already been cured without?” Sanborn asked.

Minimal residual disease testing could be a path toward better identifying these patients, she concluded, adding that the current state of targeted therapies represents an exciting building block.

References

Sanborn RE. Targeted therapy in locally advanced NSCLC. Presented at: 27th Annual International Lung Cancer Congress; July 24-26, 2026; Huntington Beach, CA.

Lu S, Kato T, Dong X, et al. Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC. N Engl J Med. 2024;391(7):585-597. doi:10.1056/NEJMoa2402614

Ramalingam SS, Kato T, Dong X, et al. Osimertinib (osi) after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage (stg) III epidermal growth factor receptor-mutated (EGFRm) NSCLC: primary results of the phase 3 LAURA study. J Clin Oncol. 2024;42(suppl 17):LBA4. doi:10.1200/JCO.2024.42.17_suppl.LBA4

Wu YL, Dziadziuszko R, Ahn JS, et al. Alectinib in resected ALK-positive non-small-cell lung cancer. N Engl J Med. 2024;390(14):1265-1276. doi:10.1056/NEJMoa2310532

Zhang C, Hu Y, Jiang B-Y, et al. LORIN: neoadjuvant and adjuvant/consolidation lorlatinib in locally advanced ALK-positive NSCLC. J Clin Oncol. 2026;44(suppl 16):8002. doi:10.1200/JCO.2026.44.16_suppl.800

Nassar AH, Jayakrishnan R, Feng J, et al. Consolidation ALK tyrosine kinase inhibitors versus durvalumab or observation after chemoradiation in unresectable stage III ALK-positive NSCLC. J Thorac Oncol. 2025;20(1):109-118. doi:10.1016/j.jtho.2024.09.1379

Wu YL, Hochmair M, Yang Y, et al. Selpercatinib in early-stage RET fusion-positive non-small-cell lung cancer. N Engl J Med. Published online May 31, 2026. doi:10.1056/NEJMoa2602628