April 16, 2026
The addition of local consolidative therapy (LCT) to osimertinib (Tagrisso) significantly prolonged progression-free survival (PFS) compared with osimertinib monotherapy in patients with EGFR-mutated non–small cell lung cancer (NSCLC), according to findings from a secondary analysis of the phase 2 NorthStar trial (NCT03410043) presented during the 2026 European Lung Cancer Congress.1 Moreover, consolidative radiotherapy led to excellent local control rates, with disease recurrence primarily occurring outside of the radiotherapy field at new distant metastatic sites.
Prior data from NorthStar presented during the 2025 ESMO Congress showed that patients who received LCT plus osimertinib (n = 56) achieved a median PFS of 25.3 months (95% CI, 19.4-45.0) compared with 17.5 months (95% CI, 14.5-24.4) among patients who received osimertinib monotherapy (n = 63; HR, 0.66; 95% CI, 0.50-0.87; 1-sided log-rank P = .025).2
Findings from the secondary analysis revealed that patients who received radiation BED therapy at a minimum dose of 75 Gy (n = 14) achieved a median PFS of 49.1 months (95% CI, 21.6-not estimable [NE]) vs 22.3 months (95% CI, 11.6-39.7) among those who received radiation BED therapy at less than 75 Gy (n = 16; HR, 0.31; 95% CI, 0.14-0.70; P = .006).1
“[The] addition of LCT to osimertinib prolonged PFS [and] post-induction clearance of thoracic nodes, as well as pleural effusion, were potential predictors of benefit from LCT,” Saumil N. Gandhi, MD, PhD, an associate professor in the Department of Radiation Oncology, Division of Radiation Oncology, at The University of Texas MD Anderson Cancer Center in Houston, said during the presentation.
Although acquired resistance to first-line EGFR-targeted therapy remains a major obstacle in patients with EGFR-mutated non–small cell lung cancer (NSCLC), findings from real-world datasets and circulating tumor DNA (ctDNA) assessments can be used by oncologists to combat this resistance, according to Christine M. Lovly, MD, PhD, FASCO.
“Molecular insights into acquired resistance to first-line EGFR-directed therapy are evolving and depend on the specific regimen [that is used],” Lovly, a professor of medical oncology and the division chief of thoracic medical oncology at City of Hope Cancer Center in Duarte, California, said. “We need more data. It speaks to the need to have rigorous biospecimen collection during protocols. I routinely request tissue and liquid [biopsy] at progressing sites to do biomarker studies. It doesn’t always affect my treatment decision making, but it’s important to have that information.”
In a session at the 23rd Annual Winter Lung Cancer Conference®, an event held by Physicians’ Education Resource, LCC, Lovly discussed the mechanisms that lead to acquired resistance, the evolution of molecular insights into acquired resistance, and future research directions in the space.1
What are the mechanisms of acquired resistance?
Lovly explained that data from an analysis of the phase 3 FLAURA trial (NCT02296125) of frontline osimertinib (Tagrisso) in patients with EGFR-mutated NSCLC revealed that 35% of evaluable patients (n = 38 of 109) had a detectable acquired resistance mechanism.2 The most common acquired resistance mechanisms that were reported in the analysis included MET amplification (16%) and EGFR mutations (10%), including those in C797S (6%), L71Q (2%), and G796S (1%). Fourteen percent of patients had more than 1 acquired resistance mechanism.
Additional data from the analysis demonstrated that in a subset of patients in FLAURA (n = 23), patients with tumors enriched for alterations in TP53 missense, RBM10, MET, SMARCA4, and RICTOR experienced a suboptimal response to first-line osimertinib. An alteration in at least 1 of these genes were significantly enriched in suboptimal response tumors (87%) compared with 22% (n = 18 of 81) of tumors without a suboptimal response (2-sided P < .001).
Findings from an analysis of the phase 3 FLAURA 2 (NCT04035486) of osimertinib plus chemotherapy vs osimertinib monotherapy in patients with untreated EGFR-mutated NSCLC (n = 129) showed that MET amplification (16%) and transformation to small cell lung cancer (13%) were the most common resistance mechanisms per tissue biopsy.1 The median time to the initiation of osimertinib therapy to tissue biopsy was 14.5 months (range, 1-52). Resistance mechanisms were found to be similar across the 2 treatment arms, and no novel mechanisms were reported.
In the phase 3 MARIPOSA trial (NCT04487080) of frontline amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze), the combination regimen (n = 148) reduced the incidence of acquired MET amplifications by approximately 4-fold compared with osimertinib monotherapy (n = 198); EGFR resistance mechanisms were reduced by approximately 5-fold in the combination arm.3 Specifically, patients who received the combination experienced MET amplifications at a rate of 3.4% vs 13.1% in the monotherapy arm (P = .002); secondary EGFR resistance mutations were reported at respective rates of 1.4% and 7.6% (P = .01). No notable increases in other molecular escape pathways between the 2 arms were reported.
“[This is] still an evolving topic, especially for resistance to first-line osimertinib plus chemotherapy and amivantamab plus lazertinib,” Lovly said. “I would emphasize the need for biopsy and rigorous match tissue plasma collection protocols to further study this. I recognize that this is hard in clinical practice [but] it is the only way we will move the field forward.”
How can markers of acquired resistance inform treatment approaches?
Lovly transitioned her presentation to discussing how clinical, radiographic, and/or molecular features can potentially be used to determine which patients will benefit the most from frontline treatment monitoring and intensification strategies.1 In FLAURA 2, she noted that patients with non-detected plasma EGFR mutations (HR, 0.79; 95% CI, 0.44-1.44) and TP53 wild-type disease (HR, 0.70; 95% CI, 0.32-1.54) experienced a significant overall survival (OS) benefit with osimertinib plus chemotherapy compared with osimertinib alone.
Moreover, data from an analysis of FLAURA revealed that disease progression per ctDNA analysis preceded radiographic disease progression.4 ctDNA disease progression preceded or co-occurred with RECIST-defined disease progression in 64% of patients (n = 93 or 146). The median time from ctDNA progression to RECIST-defined progression was 3.4 months in the osimertinib arm and 2.6 months in the comparator arm. The median times from ctDNA progression to the first subsequent treatment were 6.0 months and 4.7 months, respectively.
“We can use ctDNA in patients with metastatic disease to think about molecular progression of disease or molecular relapse,” Lovly commented.
Lovly added that local consolidative therapy (LCT) could be used as a potential mechanism for evaluation and early treatment of patients with acquired resistance. In the phase 2 NorthStar trial (NCT05115630), patients with polymetastatic disease who received complete (n = 23) and partial (n = 16) LCT achieved a median progression-free survival of 27.9 months (range, 16.6-48.3) and 14.5 months (range, 10.2-21.6), respectively. Complete LCT was achieved in 59% of patients who presented with polymetastatic disease (n = 84).
What strategies are being developed to overcome acquired resistance?
Lovly concluded her presentation by discussing emerging novel approaches in TKI-resistant, EGFR-mutated NSCLC. The phase 3 MARIPOSA-2 trial (NCT04988295) evaluated amivantamab plus chemotherapy with or without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib.6 Findings from MARIPOSA-2 showed that amivantamab plus chemotherapy (HR, 0.48; 95% CI, 0.36-0.64; P < .001) and amivantamab plus lazertinib and chemotherapy (HR, 0.44; 95% CI, 0.35-0.56; P < .001) both displayed a significant PFS advantage vs chemotherapy alone.
In the phase 3 HARMONi trial (NCT05184712), investigators examined the VEGF-PD1 bispecific antibody ivonescimab in combination with chemotherapy in patients with EGFR-mutated locally advanced or metastatic non-squamous NSCLC who progressed following EGFR-TKI treatment.7 Data from the study revealed that the median OS in the combination arm (n = 219) was 16.8 months compared with 14.0 months in the chemotherapy-only arm (n = 219; HR, 0.79; 95% CI, 0.62-1.01; P = .0570). The median PFS values were 6.8 months and 4.4 months, respectively (HR, 0.52; 95% CI, 0.41-0.66; P < .0001).
The Chinese phase 3 OptiTROP-Lung04 trial (NCT05870319) evaluated the TROP2-directed antibody drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT) against chemotherapy in patients with EGFR-mutated NSCLC following progression on EGFR-TKIs.8 Finding from OptiTROP-Lung04 revealed that patients who received Sac-TMT (n = 168) experienced a median PFS of 8.3 months (95% CI, 6.7-9.9) compared with 4.3 months (95% CI, 4.2-5.5) in the chemotherapy arm (n = 188; HR, 0.49; 95% CI, 0.39-0.62; P < .0001). The median OS values were not reached (95% CI, 21.5-not evaluable) and 17.4 months (95% CI, 15.7-20.4), respectively (HR, 0.60; 95% CI, 0.44-0.82; 2-sided P = .001).
“We are actively awaiting further data on this TROP2 ADC,” Lovly said. “This is a rapidly evolving field, more data are needed. [Ideal treatment of patients with acquired resistance] depends on the treatment the patient received in the first line, prior chemotherapy exposure, duration of chemotherapy, chemotherapy-free interval, and residual toxicities. Most of the regimens that are being evaluated involve some kind of chemotherapy, whether it’s platinum-based or the payload on an ADC.”
Disclosures: Lovly holds consulting roles for AbbVie, Amgen, AnHeart, Astra Zeneca, Black Diamond, BMS, Boehringer Ingelheim, Daiichi Sankyo, Exact, Foresight, Foundation Medicine, Guardant, Genentech, Gilead, Guardant, Immunity Bio, Jazz, JNJ, Merck, Nuvalent, Nuvation, Onviv, Pfizer, Regeneron, Summit, Takeda, Taiho, and Tempus. She also received honoraria from AbbVie, Amgen, AnHeart, Astra Zeneca, Black Diamond, BMS, Boehringer Ingelheim, Daiichi Sankyo, Exact, Foresight, Foundation Medicine, Guardant, Genentech, Gilead, Guardant, Immunity Bio, Jazz, JNJ, Merck, Nuvalent, Nuvation, Onviv, Pfizer, Regeneron, Summit, Takeda, Taiho, and Tempus.
References
Lovly CM. Battling EGFR Resistance: Overcoming the Next Frontier. Presented at: 23rd Annual Winter Lung Cancer Conference; January 23-January 25, 2026; Hollywood, FL.
Chmielecki J, Gray JE, Cheng Y, et al. Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer. Nat Commun. 2023;14(1):1070. doi:10.1038/s41467-023-35961-y
Hayashi H, Besse B, Lee SH, et al. Mechanisms of acquired resistance to first-line amivantamab plus lazertinib vs osimertinib: updated analysis from MARIPOSA. J Throac Oncol. 2025;20(10):S592. doi:10.1016/j.jtho.2025.09.1118
Gray JE, Markovets A, Reungwetwattana T, et al. Longitudinal analyses of circulating tumor DNA for the detection of EGFR mutation-positive advanced NSCLC progression during treatment: data from FLAURA and AURA3. J Thorac Oncol. 2024;19(11):1525-1538. doi:10.1016/j.jtho.2024.07.008
Elamin YY, Gandhi S, Antonoff MB, et al. NorthStar: a phase II randomized study of osimertinib (OSI) with or without local consolidative therapy (LCT) for metastatic EGFR-mutant non-small cell lung cancer (NSCLC). Ann Oncol. 36:S1729. doi:10.1016/j.annonc.2025.09.086
Passaro A, Wang J, Wang Y, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024;35(1):77-90. doi:10.1016/j.annonc.2023.10.117
Goldman J, Passaro A, Laskin J, et al. Ivonescimab vs placebo plus chemo, phase 3 in patients with EGFR+ NSCLC progressed with 3rd gen EGFR-TKI treatment: HARMONi. J Thorac Oncol. 2025;20(10):S2-S3. doi:10.1016/j.jtho.2025.09.017
Zhang L, Fang WF, Wu L, et al. Sacituzumab tirumotecan (sac-TMT) vs platinum-based chemotherapy in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) following progression on EGFR-TKIs: results from the randomized, multi-center phase III OptiTROP-Lung04 study. Ann Oncol. 2025;36(suppl 2):S1613-S1614. doi:10.1016/j.annonc.2025.09.085
