Frontline Choice Anchors Sequencing Decisions in EGFR-Mutated NSCLC

When a patient with advanced EGFR-mutated non–small cell lung cancer (NSCLC) experiences disease progression, the most useful starting point regarding treatment selection is not the next drug but the last one, according to Edward B. Garon, MD, MS.

“The first question that one has to ask is: Relapsed or refractory to what?” Garonsit said during a presentation at the 27th Annual International Lung Cancer Congress.¹ “There are 3 main approaches that you will see [patients] receive in frontline therapy.”

Because the field’s clinical development has centered on patients whose disease advanced during frontline osimertinib (Tagrisso) monotherapy, Garon framed his overview of approved second- and later-line options around 3 distinct frontline scenarios: osimertinib monotherapy, osimertinib plus chemotherapy, and amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze), each of which reshapes what comes next in sequencing.

Garon is a professor in the Department of Medicine, Hematology/Oncology, director of the Thoracic Oncology Program, and co-director of Signal Transduction and Therapeutics at UCLA Health in Los Angeles, California.

Why does the frontline regimen dictate relapsed/refractory treatment selection in EGFR-mutated NSCLC?

Garon confined his overview to approaches with regulatory approval, either in the United States (US) or globally, and organized them by the frontline therapy a patient has already received.

Frontline osimertinib monotherapy accounts for most of the available randomized evidence, he noted, because second-line trials were designed when single-agent osimertinib was the standard-of-care starting therapy for patients with advanced EGFR-mutated disease. Patients who progress, whether after frontline metastatic osimertinib, adjuvant osimertinib, or consolidation following chemoradiotherapy, have the widest array of options, including carboplatin plus pemetrexed, that backbone plus amivantamab or osimertinib, datopotamab deruxtecan-dlnk (Dato-DXd; Datroway), and, in some regions, TROP2-directed and antiangiogenic combinations.

The later-line treatment algorithm shifts for patients whose frontline therapy already incorporated chemotherapy or amivantamab plus lazertinib, Garon explained, since those agents are no longer held in reserve.

What are the treatment options after frontline osimertinib monotherapy for EGFR-mutated NSCLC?

Carboplatin plus pemetrexed has served as the control arm across the pivotal second-line studies, and 2 randomized trials support intensifying that backbone, Garon outlined during his presentation.

In the phase 3 MARIPOSA-2 trial (NCT04988295), adding amivantamab to chemotherapy (n = 131) improved median progression-free survival (PFS) to 6.3 months (95% CI, 5.6-8.4) vs 4.2 months (95% CI, 4.0-4.40 with chemotherapy alone (n = 263; HR, 0.48; 95% CI, 0.36-0.64; P <.001); amivantamab plus lazertinib and chemotherapy extended median PFS to 8.3 months (n = 263; 95% CI, 6.8-9.1; HR vs chemotherapy alone, 0.44; 95% CI, 0.35-0.56; P <.001).² Overall survival (OS) data trended in favor of the amivantamab-containing arms without reaching statistical significance, and a final OS result is not yet available, Garon said.

Furthermore, the phase 3 COMPEL trial (NCT04765059) evaluated the addition of osimertinib to chemotherapy following progression on first-line osimertinib monotherapy, and data showed a median PFS of 8.4 months (95% CI, 5.7-11.8) for the combination (n = 49) vs 4.4 months (95% CI, 3.5-5.6) with chemotherapy plus placebo (n = 49; HR, 0.43; 95% CI, 0.27-0.70).³

Garon characterized the regimen as a “somewhat controversial topic,” noting that the study closed early once amivantamab plus chemotherapy was FDA approved and COMPEL’s chemotherapy-alone control arm became less appropriate.

“Many of my colleagues look at these curves and say, ‘Look, the tolerability here is better than what would be anticipated with amivantamab combinations, but the efficacy looks similar, so why not use [osimertinib plus chemotherapy after progression]?’” he said. “The efficacy looks similar [between osimertinib plus chemotherapy and amivantamab-based combinations], so why not use this?…[COMPEL] ended up being a small study [with] less than 100 patients [randomly assigned], and typically we have not compared data like this [with that from] a robust phase 3 study. However, [osimertinib plus chemotherapy] is of interest to many patients and comes up frequently in discussions.”

For patients seeking to defer additional chemotherapy, Dato-DXd offers a TROP2-directed antibody-drug conjugate (ADC) option. A pooled analysis of the phase 3 TROPION-Lung01 (NCT04656652) and phase 2 TROPION-Lung05 (NCT04484142) studies showed that in patients (n = 117) treated with a median of 3 prior lines of therapy, Dato-DXd elicited an objective response rate (ORR) of 43% (95% CI, 34%-52%), a median PFS of 5.8 months (95% CI, 5.4-8.2), and a median OS of 15.6 months (95% CI, 13.1-19.0).⁴

Responses to Dato-DXd spanned patients with common and uncommon EGFR mutations, as well as known resistance alterations, Garon noted.

He also overviewed sacituzumab tirumotecan (Sac-TMT), a second TROP2-directed ADC that is approved in China but not in the US.⁵

In the phase 3 OptiTROP-Lung04 trial (NCT05870319), sac-TMT (n = 188) improved median PFS and OS vs chemotherapy.⁶

“I get asked about [sac-TMT] a lot, in part because many of my patients read Chinese-language media, and this has generated great enthusiasm in China,” he said.

Rounding out the setting, the PD-1/VEGF bispecific antibody ivonescimab plus chemotherapy (n = 172) improved median PFS to 6.8 months vs 4.4 months for chemotherapy alone (n = 173; HR, 0.52; 95% CI, 0.41-0.66; P <.0001) in the phase 3 HARMONi trial (NCT06396065).⁷ However, the ivonescimab combination did not meet its OS end point at the scheduled analysis (HR, 0.79; 95% CI, 0.62-1.01; P = .0570).

The ivonescimab regimen is under FDA review.⁸ Although HARMONi featured patients from China and others enrolled globally, Garon cautioned that this study had an unusual design in which patients in China enrolled years earlier than those elsewhere. Notably, an updated analysis with longer-term follow-up data for Western patients showed a consistent OS benefit in both the intention-to-treat population and the Western subgroup, with an HR of 0.76 for each.⁹

How should treatment sequencing proceed after frontline EGFR-directed combination regimens in NSCLC?

When the frontline regimen comprises the combination of osimertinib, carboplatin, and pemetrexed, the number of reasonable next steps narrows, Garon said.

Returning to chemotherapy is generally unappealing for patients, although rechallenge with carboplatin plus pemetrexed, with or without osimertinib, remains an option if enough time has elapsed since the last exposure, he explained.

Dato-DXd also represents an option. Amivantamab with or without lazertinib has shown activity in this setting, but the combination is only FDA approved in the frontline setting, he noted. For patients whose frontline therapy was amivantamab plus lazertinib, Dato-DXd and the carboplatin- and pemetrexed-based regimens remain the principal choices.

What factors beyond efficacy shape treatment decision-making for EGFR-mutated NSCLC?

Garon closed by adding that because patients generally spend a comparable amount of time receiving second-line and later therapy as they do frontline treatment, “It remains important to look at both efficacy and tolerability in this setting. In our practice, many of us are using liquid biopsy and, in some cases, tissue biopsy, to determine additional treatments.”

These biopsies could identify additional oncogenic drivers, such as MET amplifications, but Garon acknowledged the practical burden of conducting these tests. He said that for clinicians who treat only a handful of patients with lung cancer alongside the rest of their general oncology practice, expecting them “to mix and match a bunch of TKIs is maybe a lot to ask.”

“The frontline therapy determines what is appropriate in previously treated patients with EGFR mutations,” Garon concluded. “Further data and regulatory decisions are going to refine treatment options further.”

References

1. Garon EB. Treatment of patients with relapsed/refractory EGFR-mutated NSCLC. Presented at: 27th Annual International Lung Cancer Congress; July 24-25, 2026; Huntington Beach, California.
2. 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
3. Peled N, Tufman A, Sequist LV, et al. COMPEL: osimertinib plus platinum-based chemotherapy in patients with EGFR-mutated advanced NSCLC and progression on first-line osimertinib. ESMO Open. 2025;10(10):105807. doi:10.1016/j.esmoop.2025.105807
4. Ahn MJ, Lisberg A, Goto Y, et al. A pooled analysis of datopotamab deruxtecan in patients with EGFR-mutated NSCLC. J Thorac Oncol. 2025;20(11):1669-1682. doi:10.1016/j.jtho.2025.06.002
5. Kelun-Biotech’s TROP2 ADC sacituzumab tirumotecan (sac-TMT) approved for marketing in second indication by NMPA for EGFRm NSCLC. Kelun-Biotech. March 10, 2025. Accessed July 24, 2026. https://www.prnewswire.com/news-releases/kelun-biotechs-trop2-adc-sacituzumab-tirumotecan-sac-tmt-approved-for-marketing-in-second-indication-by-nmpa-for-egfrm-nsclc-302396917.html
6. Fang W, Wu L, Meng X, et al. Sacituzumab tirumotecan in EGFR-TKI-resistant, EGFR-mutated advanced NSCLC. N Engl J Med. 2026;394(1):13-26. doi:10.1056/NEJMoa2512071
7. Goldman JW, 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. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract 4808.
8. Summit Therapeutics announces US FDA acceptance of biologics license application (BLA) seeking approval for ivonescimab in combination with chemotherapy in treatment of patients with EGFRm NSCLC post-TKI therapy. News release. Summit Therapeutics Inc. January 29, 2026. Accessed July 24, 2026. https://www.smmttx.com/news/press-releases/news-details/2026/Summit-Therapeutics-Announces-U-S--FDA-Acceptance-of-Biologics-License-Application-BLA-Seeking-Approval-for-Ivonescimab-in-Combination-with-Chemotherapy-in-Treatment-of-Patients-with-EGFRm-NSCLC-Post-TKI-Therapy/default.aspx
9. Ivonescimab plus chemotherapy shows consistent, favorable overall survival results in Western and Asian patients in updated analysis from global phase III HARMONi study. News release. Summit Therapeutics. July 22, 2026. Accessed July 24, 2026. https://smmttx.com/news/press-releases/news-details/2026/Ivonescimab-Plus-Chemotherapy-Shows-Consistent-Favorable-Overall-Survival-Results-in-Western-and-Asian-Patients-in-Updated-Analysis-from-Global-Phase-III-HARMONi-Study/default.aspx