MET TKIs and ADCs May Broaden Post-Osimertinib Treatment Options in EGFR-Mutant NSCLC

April 14, 2026 | Courtney Flaherty

Key Takeaways

• Final analyses from FLAURA2 and MARIPOSA demonstrated OS benefit with osimertinib- or amivanatmab-containing combination regimens over osimertinib alone in the first line.
• MET amplification represents a clinically actionable mechanism of osimertinib resistance, with the combinations of osimertinib plus the MEK TKI savolitinib showing improved PFS compared with chemotherapy in the post-osimertinib setting.
• TROP-2–directed ADCs, including Dato-DXd and Sac-TMT, are emerging as active later-line options with manageable safety profiles.

The treatment of patients with advanced or metastatic non–small cell lung cancer (NSCLC) harboring classical EGFR mutations has undergone a profound transformation over the past 2 years.¹ Final survival data from 2 pivotal phase 3 trials—FLAURA2 (NCT04035486) and MARIPOSA (NCT04487080)—have definitively established that combination approaches outperform osimertinib (Tagrisso) monotherapy in the first line.

Against this backdrop, a panel of experts convened at the 2nd Annual Hawaii Cancer Conference®, an event held by Physicians’ Education Resource, to examine the data on available treatment options in the post-osimertinib setting, emerging MET-directed combination strategies that could address osimertinib resistance, and the rapidly expanding portfolio of TROP-2–directed antibody–drug conjugates (ADCs) for potential use in later lines.

This session, highlighted below, was moderated by Sarah Goldberg, MD, MPH and Suma Reddy Satti, MD. Goldberg is an associate professor of medicine in the section of Medical Oncology, associate director of the Medical Oncology-Hematology Fellowship Program, co-director, and chief of thoracic oncology at the Yale School of Medicine in New Haven, Connecticut. Satti is a medical oncologist at Ochsner MD Anderson Cancer Center and the vice chair for Hematology/Oncology at St. Tammany Cancer Center – A Campus of Ochsner Medical Center and at Ochsner Cancer Center Baton Rouge, in New Orleans, Louisiana.

What are the current first-line standards of care in EGFR-mutant NSCLC?

Osimertinib Plus Chemotherapy

In February 2024, the FDA approved osimertinib in combination with platinum-based chemotherapy for patients with locally advanced or metastatic EGFR-mutated NSCLC harboring exon 19 deletions or exon 21 L858R substitutions based on data from the FLAURA2 trial.²

Primary findings from FLAURA2 showed that osimertinib plus platinum-based chemotherapy and pemetrexed produced a significant progression-free survival (PFS) benefit over osimertinib alone in patients with previously untreated advanced NSCLC with EGFR exon 19 deletion or L858R mutations, meeting the primary end point (HR, 0.62; 95% CI, 0.49-0.79; P < .001).

The final overall survival (OS) analysis, presented during the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer, confirmed that this PFS advantage translated into a clinically meaningful and statistically significant survival benefit.³ At a median follow-up of 51.2 months (range, 0.2-60.4) for osimertinib plus chemotherapy and 51.3 months (range, 0.1-60.1) for osimertinib alone, the median OS was 47.5 months (95% CI, 41.0-not calculable [NC]) vs 37.6 months (95% CI, 33.2-43.2), respectively (HR, 0.77; 95% CI, 0.61-0.96; P = .02). Notably, OS benefit was observed across predefined subgroups.

Despite this efficacy benefit, grade 3 or higher adverse effects (AEs) were much more common with the combination (70% vs 34%). AEs led to discontinuation of osimertinib, pemetrexed, or platinum for 12%, 50%, and 17% of patients in the combination arm, respectively. AEs led to discontinuation of osimertinib for 7% of those in the monotherapy arm. No new safety signals emerged with extended follow-up.

Amivantamab Plus Lazertinib

The chemotherapy-free combination of amivantamab-vmjw (Rybrevant) and lazertinib (Lazcluze) was evaluated as a first-line alternative to frontline osimertinib plus chemotherapy in MARIPOSA and subsequently gained FDA approval in untreated locally advanced or metastatic EGFR-mutated NSCLC in August 2024 based on data from this trial.⁴

Updated data from MARIPOSA published in the New England Journal of Medicine showed a significant OS benefit with amivantamab plus lazertinib vs osimertinib.⁵ At a median follow-up of 37.8 months, the median OS with amivantamab plus lazertinib was not reached (95% CI, 42.9–not estimable [NE]) vs 36.7 months (95% CI, 33.4-41.0) with osimertinib alone (HR, 0.75; 95% CI, 0.61-0.92; P = .005). Grade 3 or higher AEs occurred in 80% and 52% patients in these respective arms, with skin-related AEs, venous thromboembolism, and infusion-related reactions among the most notable toxicities.

What mechanisms drive resistance to osimertinib?

Despite the clinical activity of osimertinib, acquired resistance is nearly universal. These resistance mechanisms fall into 3 broad categories¹:

• On-target EGFR resistance mutations such as C797X, G796X, L792X, G724S, and L718Q.
• Off-target bypass signaling through MET amplification, HER2 amplification, KRAS/NRAS amplification or mutation, RET/NTRK1/ALK/BRAF/ROS1 rearrangements, PI3K pathway mutations, AXL overexpression, and IGF1R activation.
• Histologic transformation to small cell lung cancer, squamous cell, or epithelial-to-mesenchymal transition

Among off-target resistance mechanisms, MET amplification is one of the most clinically actionable, occurring in approximately 15% to 20% of patients. Combining osimertinib with a selective MET TKI such as savolitinib (Orpathys), capmatinib (Tabrecta), or tepotinib (Tepmetko) has emerged as a potential biomarker-driven strategy to address osimertinib resistance.

How could osimertinib resistance be overcome through MET TKI combination strategies?

The randomized, open-label, multicenter SACHI trial (NCT05015608) provided the first phase 3 evidence in support of this approach.⁶ Results shared during the 2025 ASCO Annual Meeting showed clinically meaningful and statistically significant PFS improvements with savolinib plus osimertinib over chemotherapy in patients with EGFR-mutated, MET-amplified advanced NSCLC who experienced disease progression after treatment with an EGFR TKI.

At a median follow-up of 16.5 months (95% CI, 9.7-24.9) in the intention-to-treat (ITT) population, the median investigator-assessed PFS with the combination (n = 106) was 8.2 months (95% CI, 6.9-11.2) vs 4.5 months (95% CI, 3.0-5.4) with chemotherapy (n = 105; stratified HR, 0.34; 95% CI, 0.23-0.49; P < .0001). At a median follow-up of 13.9 months (95% CI, 8.3-22.1), patients previously received a first- or second-generation EGFR TKI achieved a median PFS of 9.8 months (95% CI, 6.9-12.5) with the combination (n = 69) vs 5.4 months (95% CI, 4.2-6.0) with chemotherapy (n = 68; stratified HR, 0.34; 95% CI, 0.21-0.56; P < .0001).

Although savolitinib is not currently commercially approved in the United States, these data validate the broader approach of targeting MET amplification with an EGFR TKI plus a MET inhibitor beyond the first-line setting.¹

Do chemotherapy-based regimens still have a role in the post-osimertinib setting?

For patients with polyclonal or complex resistance profiles, chemotherapy-based regimens remain an important option. Data from the phase 3 MARIPOSA-2 trial (NCT04988295) demonstrated that amivantamab plus chemotherapy with or without lazertinib improved outcomes over chemotherapy alone in patients who progressed on osimertinib. ORR by blinded independent central review (BICR) was 6% for chemotherapy alone, 64% for amivantamab plus chemotherapy (OR vs chemotherapy, 3.1; P < .001), and 63% for amivantamab/lazertinib/ chemotherapy (OR vs chemotherapy, 3.0; P < .001).⁷ The median PFS was 6.3 months for amivantamab plus chemotherapy and 8.3 months for amivantamab/lazertinib/chemotherapy vs 4.2 months for chemotherapy.

Of note, the phase 3 COMPEL trial (NCT04765059) showed a numerical improvement in median PFS with osimertinib plus chemotherapy vs chemotherapy alone (8.4 vs 4.4 months; HR, 0.43; 95% CI, 0.27-0.70), as well as in median OS (15.9 vs. 9.8 months; HR, 0.71; 95% CI, 0.42-1.23), in the post-osimertinib setting.⁸ However, the study’s limited sample size (n = 23) meant that there were too few events to present the HR for CNS PFS for the subgroup of patients with central nervous system (CNS) metastases at baseline. Accordingly, chemotherapy rechallenge plus amivantamab remains the preferred post-osimertinib standard for systemic disease progression without an identified actionable mechanism based on the MARIPOSA-2 data.^1,8

How could TROP-2–directed ADCs reshape later-line treatment in EGFR-mutant NSCLC?

A major focus of NSCLC research is the emergence of TROP-2–directed ADCs as active, chemotherapy-like agents with a favorable toxicity profile relative to standard cytotoxics in EGFR-mutant NSCLC.¹ Two of such agents—datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) and sacituzumab tirumotecan (sac-TMT)—have shown substantial momentum.

Dato-DXd

On June 23, 2025, the FDA granted accelerated approval to Dato-DXd for adult patients with locally advanced or metastatic EGFR-mutated NSCLC who have received prior EGFR-directed therapy and platinum-based chemotherapy.⁹ This approval was supported by a pooled efficacy analysis of 114 patients meeting the labeled criteria from the phase 2 TROPION-Lung05 (NCT04484142) and the phase 3 TROPION-Lung01 (NCT04656652) trials.

In this analysis, the confirmed ORR with Dato-DXd was 45% (95% CI, 35%-54%), comprising a complete response rate of 4.4% and a partial response rate of 40.0%. The median duration of response (DOR) was 6.5 months (95% CI, 4.2-8.4).^1,9  Additional safety data from the pooled analysis shared at the 2024 ESMO Asia Congress showed that any-grade treatment-related AEs (TRAEs) were reported in 95% of patients in the pooled population, and the rate of grade 3 or higher TRAEs was 23%.¹⁰ TRAEs led to dose reductions in 22% of patients, dose delays in 23% of patients, and treatment discontinuation in 5% of patients. No TRAEs led to death, and serious TRAEs occurred in 8% of patients.

In addition to the TROPION trials, the phase 2 ORCHARD study (NCT03944772) further explored the combination of Dato-DXd and osimertinib in patients with EGFR-mutant NSCLC. Findings from module 10 of the phase 2 ORCHARD study (NCT03944772) were shared during the ¹¹ At the 4-mg/kg dose of Dato-DXd in combination with osimertinib (n = 35), the ORR was 43% (80% CI, 31%-55%), the median PFS was 9.5 months (95% CI, 7.2-9.8), and the median DOR was 6.3 months (95% CI, 3.8–8.2). At the 6-mg/kg dose (n = 33), the ORR was 36% (80% CI, 25%-49%), with a longer median PFS of 11.7 months (95% CI, 8.3-NC) and a notably longer median DOR of 20.5 months (95% CI, 6.2-NC).

These combination data have informed the ongoing phase 3 TROPION-Lung14 trial (NCT06350097), which is evaluating Dato-DXd plus osimertinib vs osimertinib alone in the first-line setting for EGFR-mutated NSCLC.

Sac-TMT

Data from the phase 3 OptiTROP-Lung04 trial (NCT05870319) published in the New England Journal of Medicine showed significant improvements in both PFS and OS with Sac-TMT (n = 188) vs chemotherapy (n = 188) in patients with EGFR-mutant nonsquamous NSCLC who had progressed on 1 or more prior EGFR TKIs.¹² At a median follow-up of 18.9 months, the median PFS by BICR was 8.3 months (95% CI, 6.7-9.9) with Sac-TMT vs 4.3 months (95% CI, 4.2-5.5) with chemotherapy (HR, 0.49; 95% CI, 0.39-0.62; P < .0001). Twelve-month PFS rates were 32.3% and 7.9%, respectively. The median OS with Sac-TMT was not reached (95% CI, 21.5 months to NE) vs 17.4 months (95% CI, 15.7-20.4) with chemotherapy (HR, 0.60; P < .0001).

Regarding safety, hematologic toxicities were the most common TRAEs in both arms, with similar incidence between groups. No patients in the Sac-TMT arm experienced treatment-related interstitial lung disease/pneumonitis, and ocular surface AEs were reported in 9.6% of patients in the Sac-TMT arm, all of which were grade 1/2.

Additionally, data from the final OS analysis of the phase 2 OptiTROP-Lung03 study (NCT05631262) presented during ELCC 2026 showed that Sac-TMT (n = 91) displayed a significant OS benefit vs docetaxel (n = 46) in patients with pretreated EGFR-mutated NSCLC (HR, 0.63; 95% CI, 0.40-0.98).¹³ Sac-TMT also met the primary PFS end point of the phase 3 OptiTROP-Lung05 trial (NCT06448312) in combination with pembrolizumab (Keytruda) for patients with PD-L1–positive advanced NSCLC.¹⁴

In December 2024, the FDA granted breakthrough designation to Sac-TMT for the treatment of patients with advanced or metastatic nonsquamous NSCLC harboring EGFR mutations whose disease has progressed on or following a TKI and platinum-based chemotherapy.¹⁵

Sac-TMT is also currently approved in China for patients with EGFR-mutated, locally advanced or metastatic nonsquamous NSCLC whose disease has progressed following EGFR TKI therapy and platinum-based chemotherapy, as well as for those with EGFR-mutant locally advanced or metastatic nonsquamous NSCLC whose disease has progressed after prior EGFR TKI therapy.^14,16

Overall, Dato-DXd’s approval and strong phase 3 data with Sac-TMT support a rapidly evolving role for this therapeutic class in later lines, though sequencing with amivantamab-based regimens and combination strategies with EGFR TKIs remain active areas of investigation. ¹

References

Goldberg S, Satti SM, Neal JW, et al. Treatment of Advanced/Metastatic NSCLC with EGFR Mutations. Presented at: 2nd Annual Hawaii Cancer Conference; January 24-January 25, 2026; Honolulu, Hawaii.

FDA approves osimertinib with chemotherapy for EGFR-mutated non–small cell lung cancer. FDA. Updated February 20, 2024. Accessed September 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer

Planchard D, Jänne PA, Kobayashi K, et al. First-line osimertinib + chemotherapy versus osimertinib monotherapy in EGFRm advanced NSCLC: FLAURA2 final overall survival. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract PL02.06.

FDA approves lazertinib with amivantamab-vmjw for non-small lung cancer. FDA. Updated August 20, 2024. Accessed September 12, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer

Yang JCH, Lu S, Hayashi H, et al; MARIPOSA Investigators. Overall survival with amivantamab-lazertinib in EGFR-mutated advanced NSCLC. N Engl J Med. Published online September 7, 2025. doi:10.1056/NEJMoa2503001

Lu S, Wang J, Yang N, et al. Savolitinib (savo) combined with osimertinib (osi) versus chemotherapy (chemo) in EGFR-mutant (EGFRm) and MET-amplification (METamp) advanced NSCLC after disease progression (PD) on EGFR tyrosine kinase inhibitor (TKI): results from a randomized phase 3 SACHI study. J Clin Oncol. 2025;43(suppl 17):LBA8505. doi:10.1200/JCO.2025.43.17_suppl.LBA8505

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;35:77–90. doi:10.1016/j.annonc.2023.10.117.

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

FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. FDA. June 23, 2025. Accessed April 13, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-datopotamab-deruxtecan-dlnk-egfr-mutated-non-small-cell-lung-cancer

Ahn M-J, Sands J, Lisberg AE, et al. Efficacy and safety of datopotamab deruxtecan (Dato-DXd) in patients (pts) with previously-treated EGFR-mutated advanced non-small cell lung cancer (NSCLC): a pooled analysis of TROPION-Lung01 and TROPION-Lung05. Ann Oncol. 2024;35(suppl 4):S1630-S1631. doi:10.1016/j.annonc.2024.10.656

Le X, Hendriks L, Morabito A, et al. Osimertinib + datopotamab deruxtecan in patients with EGFR-mutated advanced NSCLC whose disease progressed on first-line osimertinib: ORCHARD. J Thorac Oncol. 2025;20(suppl 3):S2-S4. doi:10.1016/S1556-0864(25)00196-0

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

Fang W, Li Z, Wang Q, et al. Sacituzumab tirumotecan (sac-TMT) in patients (pts) with previously treated advanced EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC): final overall survival (OS) analysis from the randomized OptiTROP-Lung03 study. Presented at: 2026 European Lung Cancer Congress; March 25-28, 2026; Copenhagen, Denmark. Abstract LBA4.

Kelun-Biotech announces phase 3 trial of sac-TMT in combination with Keytruda (pembrolizumab) as first-line treatment for PD-L1–positive NSCLC met primary endpoint. News Release. PR Newswire. November 24, 2025. Accessed April 13, 2026. https://www.prnewswire.com/news-releases/kelun-biotech-announces-phase-iii-trial-of-sac-tmt-in-combination-with-keytruda-pembrolizumab-as-first-line-treatment-for-pd-l1-positive-nsclc-met-primary-endpoint-302624279.html

FDA grants breakthrough designation to sacituzumab tirumotecan (sac-TMT) for the treatment of certain patients with previously treated advanced or metastatic nonsquamous non-small cell lung cancer with EGFR mutations. News release. Merck. December 3, 2024. Accessed April 13, 2026. https://www.merck.com/news/fda-grants-breakthrough-therapy-designation-to-sacituzumab-tirumotecan-sac-tmt-for-the-treatment-of-certain-patients-with-previously-treated-advanced-or-metastatic-nonsquamous-non-small-cell-lung-ca/

Kelun-Biotech’s TROP2 ADC sacituzumab tirumotecan (sac-TMT) approved for marketing in second indication by NMPA for EGFRm NSCLC. Sichuan Kelun-Biotech Biopharmaceutical. March 10, 2025. Accessed April 16, 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