Understanding Underlying Resistance Mechanisms is Vital for Guiding Treatment Selection Post-Osimertinib in EGFR+ NSCLC

In a presentation at the 26th Annual International Lung Cancer Congress, Heather Wakelee, MD, highlighted therapeutic avenues in the second line after the development of resistance to first-line osimertinib (Tagrisso) or combination therapies for patients with non–small cell lung cancer (NSCLC) harboring EGFR mutations.¹

These included secondary mutation–targeted therapies; chemotherapy-based treatment, including the phase 3 MARIPOSA-2 trial (NCT04988295) regimen of amivantamab-vmjw (Rybrevant) plus chemotherapy, with or without lazertinib (Laclaza); and antibody-drug conjugates (ADCs) such as patritumab deruxtecan (HER3-DXd) and datopotamab deruxtecan (Dato-DXd; Datroway).

Throughout the presentation, Wakelee also emphasized the need for personalized treatment approaches based on specific mutations and patient characteristics.

“As we move away from the era where one size fits all for first-line EGFR-mutant NSCLC, we now have at least 3 sizes and probably more to come. That’s going to complicate what you do next, because what you do first, of course, has a big impact on that.” Wakelee stated.

Wakelee is a professor of medicine and chief of the Division of Oncology at Stanford University School of Medicine, deputy director and division chief of Medical Oncology at Stanford Cancer Institute in Palo Alto, California, and president of the International Association for the Study of Lung Cancer.

Key Mechanisms of Resistance in EGFR-Mutated NSCLC

Wakelee began her presentation by noting that although MET amplification remains a central driver of resistance in EGFR-mutant NSCLC, additional resistance alterations, including secondary mutations and fusions involving EGFR itself or other oncogenic pathways, are potentially actionable with targeted therapies.

The detection of secondary resistance mutations, such as RET fusions, may support consideration of combination approaches, provided there are safety data to guide selection, Wakelee stated. However, that EGFR mutations persist despite the emergence of new resistance drivers. As such, abandoning EGFR-targeted strategies entirely, except in the context of chemotherapy, may compromise efficacy, she cautioned.

Addition of Savolitinib to Osimertinib Shows Potential in Osimertinib-Resistant Disease

Wakelee next reviewed clinical data supporting MET inhibition in the setting of acquired resistance to osimertinib. Findings from the phase 2 SAVANNAH (NCT03778229) and phase 3 SACHI (NCT05015608) trials, both presented at the 2025 ASCO Annual Meeting, demonstrated progression-free survival (PFS) benefit with the combination of savolitinib and osimertinib. In SAVANNAH, patients treated with savolitinib plus osimertinib achieved a median PFS of 8.3 months (95% CI, 5.8-15.1) vs 3.6 months (95% CI, 1.4-5.7) with savolitinib plus placebo (HR, 0.27; 95% CI, 0.13-0.57). The median duration of response (DOR) was 9.9 months.²

Similarly, in SACHI, the median PFS with savolitinib plus osimertinib was 8.2 months (95% CI, 6.9-11.2) vs 4.5 months (95% CI, 3.0-5.4) with chemotherapy (HR, 0.34; 95% CI, 0.23-0.49; P <.0001).³ Median overall survival was 22.9 months (95% CI, 16.8-not evaluable) with the combination vs 17.7 months (95% CI, 14.9-26.3) with chemotherapy (HR, 0.84; 95% CI, 0.55-1.29), although these data are still evolving.

Wakelee acknowledged that combining MET inhibitors with osimertinib introduces MET-related adverse effects such as edema. She also underscored the heterogeneity of MET alterations, which often involve overexpression or amplification rather than point mutations.

“With MET, we’re often dealing with expression levels, amplification or protein levels, not just mutations. We all know about MET mutations in the setting of drug resistance, it’s not so much the mutations as those higher levels of expression,” Wakelee stated.

Current Arsenal of Chemotherapy-Based Regimens in the Post-Osimertinib Setting

Although savolitinib remains investigational, other MET-targeted agents with available safety data may be used off-label in combination with EGFR TKIs, Wakelee noted.

Amivantamab, a bispecific antibody targeting both EGFR and MET, is FDA approved and represents a relevant treatment option in this setting. Data from the MARIPOSA-2 trial, presented at the 2023 ESMO Congress, supported the addition of amivantamab to chemotherapy after progression on osimertinib.⁴ At a median follow-up of 8.7 months, amivantamab plus chemotherapy significantly improved PFS compared with chemotherapy alone (HR, 0.48; 95% CI, 0.36-0.64; P < .001). The combination also demonstrated a favorable trend for OS (HR, 0.77; 95% CI, 0.49-1.21), although OS data remain immature.

Furthermore, updated data from an analysis of outcomes with amivantamab based on osimertinib resistance mechanisms, which was presented at the 2025 ASCO Annual Meeting, showed that amivantamab plus chemotherapy improved PFS in patients with detectable ctDNA at baseline (HR, 0.49; 95% CI, 0.36-0.68; P < .0001) and those harboring TP53 co-mutations (HR, 0.63; 95% CI, 0.44-0.92; P = .014).⁵

Wakelee emphasized the role of platinum-based chemotherapy regimens such as carboplatin plus pemetrexed with or without continued osimertinib, a prominent area of debate prior to the emergence of other EGFR inhibitors. This decision is still largely dependent on patient-specific factors and underlying resistance mechanisms, she said.

Other chemotherapy-based combinations include carboplatin, paclitaxel, bevacizumab (Avastin), and atezolizumab (Tecentriq), as well as carboplatin, pemetrexed, and ivonescimab (Akeso).¹

“[That first approach] hearkens back to a lot of other drugs that are combining VEGF and immunotherapy in the setting of EGFR-mutant disease. We’ve now had multiple [positive] trials in that setting. Every trial that looked at chemotherapy plus or minus VEGF and immunotherapy was positive. The trials that were chemotherapy plus a VEGF TKI plus or minus immune therapy were not positive. We really need to think about that VEGF component and question what immunotherapy or VEGF TKIs are [individually adding [to these regimens],” Wakelee, emphasized.

MET-, HER3- and TROP2-Targeted ADCs: The Next Frontier

Wakelee then turned her attention to the growing landscape of ADCs in development or under investigation in EGFR-mutant NSCLC after resistance to standard therapies, some of which have demonstrated notable efficacy in early-phase trials.

One such agent is telisotuzumab vedotin-tllv (Emrelis), which demonstrated an overall response rate (ORR) of 58% in patients with MET-overexpressing, EGFR-mutant NSCLC in the post-osimertinib setting.¹ Despite its compelling clinical activity and durable responses, Wakelee cautioned that this agent also has a distinct toxicity profile, including ocular toxicities, appetite suppression, or peripheral edema.

Wakelee also highlighted other emerging ADCs in the post-osimertinib space, including patritumab deruxtecan and Dato-DXd.

Patritumab deruxtecan has demonstrated moderate clinical activity in this setting. Preliminary findings from the phase 2 HERTHENA-Lung01 trial (NCT04619004) published in the Journal of Clinical Oncology, showed that the agent produced an ORR of 29.8% (95% CI, 23.9%-36.2%) at a fixed dose of 5.6 mg/kg, as assessed by blinded independent central review, in patients with advanced EGFR-mutant NSCLC who had received prior EGFR TKI therapy and platinum-based chemotherapy.⁶ The median DOR was 6.4 months (95% CI, 4.9-7.8), and median PFS was 5.5 months (95% CI, 5.1-5.9).

In the phase 3 HERTHENA-Lung02 trial (NCT05338970), median PFS with patritumab deruxtecan was 5.8 months compared with 5.4 months with chemotherapy (HR, 0.77; 95% CI, 0.63-0.94; P = .011), and median overall survival (OS) was 16.0 vs 15.9 months, respectively (HR, 0.98; 95% CI, 0.79-1.22).⁷

“We had a lot of enthusiasm about this agent,” Wakelee added. “There were some early data showing efficacy especially in the [later lines], and this seemed to be regardless of the mechanism of resistance. People were excited but also puzzled. Some questions were also raised about whether [its activity] was target-dependent. Unfortunately, [the OS data from HERTHENA-Lung-2] were completely negative.”

Based on its modest OS benefit in HERTHENA-Lung02, the biologics license application seeking FDA approval of patritumab deruxtecan for use in this setting was withdrawn.⁸

Conversely, Dato-DXd has shown more robust efficacy. A pooled analysis of the phase 2 TROPION-Lung05 (NCT04484142) and phase 3 TROPION-Lung01 (NCT04656652) trials, presented at the 2024 ESMO Asia Congress, reported a confirmed ORR of 42.7% (95% CI, 33.6%-52.2%) in previously treated patients with advanced EGFR-mutated NSCLC (n = 117), including a 4.3% complete response rate.⁹ The median DOR was 7.0 months (95% CI, 4.2-9.8), median PFS was 5.8 months (95% CI, 5.4-8.2), and median OS was 15.6 months (95% CI, 13.1-19.0).

“[HRs for PFS and OS with Dato-DXd] have shown that in patients [with actionable] mutations, there seemed to be higher efficacy,” Wakelee noted, adding that, “Mechanistically, this is a little bit harder to think through, but it was seen in a couple of different trials.”

These findings supported the FDA’s decision to grant 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 in June 2025.¹⁰

Wakelee finished by emphasizing the need to understand and manage ADC-specific toxicities—such as ocular effects, mucositis, and edema—as these agents become more integrated into post-osimertinib treatment strategies.

The Million-Dollar Question: How Do Underlying Resistance Mechanisms Affect Second-Line Decision-Making?

Wakelee concluded by underscoring that treatment selection following first-line osimertinib should be guided by the underlying resistance mechanism. For patients with MET amplification, multiple targeted therapies are available. In cases of histologic transformation to small cell lung cancer, platinum plus etoposide remains standard, with ongoing discussion about the role of immunotherapy. For resistance mutations such as EGFR C797S, earlier-generation EGFR TKIs may be considered depending on allelic configuration, and investigational agents such as fourth-generation TKIs may offer future options.

The optimal sequencing of therapies is less clear for patients who have progressed after receiving patritumab deruxtecan or bispecific antibodies like amivantamab, Wakelee noted. Questions also remain about whether to rechallenge with osimertinib plus chemotherapy if patients previously received this combination.

Although these novel approaches are promising, Wakelee reminded her audience that conventional chemotherapy remains an essential backbone for patients who have exhausted targeted therapies or who lack identifiable resistance mechanisms.

“Plain old, vanilla chemotherapy is still very effective,” she concluded.

References

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6. Yu HA, Goto Y, Hayashi H, et al. HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy. J Clin Oncol. 2023;41(35):5363-5375. doi:10.1200/JCO.23.01476
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8. Datopotamab deruxtecan new BLA submitted for accelerated approval in the US for patients with previously treated advanced EGFR-mutated non-small cell lung cancer. News release. AstraZeneca. November 12, 2024. Accessed July 23, 2025. https://www.astrazeneca.com/media-centre/press-releases/2024/dato-dxd-new-bla-submitted-nsq-bla-withdrawn.html
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10. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. FDA. June 23, 2025. Accessed July 23, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-datopotamab-deruxtecan-dlnk-egfr-mutated-non-small-cell-lung-cancer