Patient Preferences Steer Decisions as Options Multiply Across EGFR-Mutated NSCLC

With 3 category 1 preferred frontline regimens and a growing roster of agents for resistant and uncommon disease, treatment selection in EGFR-mutated non–small cell lung cancer (NSCLC) increasingly hinges on the patient rather than the tumor.¹

“Unfortunately, I don’t have an answer of how to make the best selection,” Sarah Goldberg, MD, MPH, a professor of medicine and chief of thoracic oncology at Yale School of Medicine and Yale Cancer Center in New Haven, Connecticut, said during a presentation at the 21st Annual New York Lung Cancers Symposium.

Goldberg walked through first-line therapy, treatment at resistance, and antibody-drug conjugates (ADCs) for common mutations before turning to atypical and exon 20 insertion mutations.

How should clinicians choose among 3 category 1 frontline options?

For patients with EGFR exon 19 deletions or L858R mutations, NCCN guidelines list osimertinib (Tagrisso) monotherapy, osimertinib plus platinum-based chemotherapy and pemetrexed, and amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze) as preferred category 1 options.¹ In the phase 3 FLAURA2 trial (NCT04035486), osimertinib plus chemotherapy (n = 279) produced a median overall survival (OS) of 47.5 months vs 37.6 months with osimertinib alone (n = 278; HR, 0.77; 95% CI, 0.61-0.96; P = .02).² Moreover, in the phase 3 MARIPOSA trial (NCT04487080), the median OS was not estimable with amivantamab plus lazertinib (n = 429) vs 36.7 months with osimertinib (n = 429; HR, 0.75; 95% CI, 0.61-0.92; P = .005).³

“I think these really look more similar than different,” Goldberg said. “It would be hard to select a combination regimen just based on efficacy with this data that we have.”

Regarding, high-risk features, in MARIPOSA, detectable baseline circulating tumor DNA (ctDNA), TP53 comutations, persistent ctDNA on treatment, and liver or brain metastases were common, and both combinations outperformed osimertinib monotherapy regardless of these features.^4,5

“Almost every patient with an EGFR-mutant lung cancer will have [one of these features], really more than 80% of patients,” she said. For patients without these features, she noted, “Can they get away with single agent? It may be the case, but we don’t know that for sure yet.”

Toxicity comparisons favor the chemotherapy-based combination. Across trials, rates of grade 3 or higher adverse effects (AEs) were 75% with amivantamab plus lazertinib vs 64% with osimertinib plus chemotherapy, and discontinuations due to AEs were 35% vs 11%, respectively.⁶ However, in the phase 2b COPERNICUS trial (NCT06667076), which paired subcutaneous amivantamab and lazertinib with dermatologic and venous thromboembolism prophylaxis (n = 274), reported a 1-year cumulative incidence of amivantamab discontinuation due to selected AEs of special interest of less than 1% vs 9% in MARIPOSA (n = 421).^7,8 “We are clearly doing better, but [it] still can be a difficult regimen for some of our patients,” she said.

Absent tumor-based selectors, Goldberg said performance status, comorbidities, and especially patient preferences guide her choice. “Some people, don’t want chemotherapy. Some people don’t want a rash,” she explained. “It sometimes becomes clear what the best first-line regimen is for any individual patient in front of us.”

What options exist after progression on an EGFR TKI?

Since resistance may be EGFR dependent, EGFR independent, histologic, or unknown, Goldberg often obtains a tissue biopsy, specifically in efforts to look for histologic transformations.”⁹

For MET-driven resistance, the phase 3 SAFFRON trial (NCT05261399) enrolled patients with MET overexpression and/or amplification after osimertinib. In The trial osimertinib plus savolitinib (Orpathys) improved median progression-free survival (PFS; n = 171) vs platinum-pemetrexed (n = 167) with rates being 7.6 months vs 5.4 months, respectively (HR, 0.55; 95% CI, 0.42-0.72; P < .001).¹⁰ The combination also improved median OS, with respective rates of 17.8 months vs 12.9 months (HR, 0.68; 95% CI, 0.50-0.91; P = .010).

Patients with both MET amplification and overexpression appeared to derive the greatest benefit with a PFS hazard ratio of 0.39 (95% CI, 0.26-0.59).

“We’re used to looking at amplification status, but I think using an immunohistochemistry to select for a TKI is something unusual,” Goldberg noted. EU and Japanese applications have since been submitted for the combination.¹¹

Regarding biomarker-agnostic options, Goldberg turned to the phase 3 MARIPOSA-2 trial (NCT04988295) in which amivantamab plus chemotherapy (n = 131) improved PFS vs chemotherapy alone (n = 263; HR, 0.48; 95% CI, 0.36-0.64; P < .001).¹² In the phase 3 COMPEL trial (NCT04765059), continuing osimertinib with chemotherapy (n = 49) improved median PFS rates to 8.4 months vs 4.4 months with placebo plus chemotherapy (n = 49; HR, 0.43; 95% CI, 0.27-0.70).¹³ “The [COMPEL strategy] is a strategy that I think many of us were using in clinic for a long time, where we would continue osimertinib at the time of progression and add on chemotherapy, and that's what this study did” Goldberg said, adding that both approaches are reasonable.

Since many patients now receive osimertinib/chemotherapy upfront, she noted how she often uses amivantamab plus lazertinib in later lines after progression. In the phase 3 PALOMA-3 study (NCT05388669), subcutaneous amivantamab plus lazertinib (n = 206) was noninferior to intravenous dosing (n = 212).¹⁴ Ivonescimab may also be approaching the clinic; in the phase 3 HARMONi trial (NCT06396065), adding it to chemotherapy (n = 173) improved median PFS compared with placebo plus chemotherapy (n = 173; HR, 0.52; 95% CI, 0.41-0.66) in addition to a numerical OS trend (HR, 0.79; 95% CI, 0.62-1.01).¹⁵

Where do ADCs fit in EGFR-mutated disease?

In a pooled analysis of the phase 3 TROPION-Lung01 trial (NCT04656652) and the phase 2 TROPION-Lung05 trial (NCT04484142), datopotamab deruxtecan (Datroway; Dato-DXd) produced an objective response rate (ORR) of 43% and median duration of response (DOR) of 7 months.¹⁶ In the phase 2 ORCHARD study (NCT03944772), a 6-mg/kg dose of Dato-DXd combined with osimertinib ( n = 33) yielded a median DOR of 20.5 months.¹⁷

Phase 3 data for other ADCs are also emerging; in OptiTROP-Lung04 (NCT05870319), sacituzumab tirumotecan (Sac-TMT; n = 188) achieved a median PFS of 8.3 months vs 4.3 months with chemotherapy (n = 188) (HR, 0.49; 95% CI, 0.39-0.62). Additionally, median OS rates with Sac-TMT were 25.9 months vs 17.4 months with chemotherapy (HR, 0.69; 95% CI, 0.54-0.89; Nominal one-sided P = .0021).^18,19

“We now have seen several ADCs vs platinum-based chemotherapy that really do look like this might be practice-changing for our patients in the future,” Goldberg said.

How is management evolving for uncommon EGFR mutations?

In the phase 1/1b CHRYSALIS-2 trial (NCT04077463), amivantamab plus lazertinib (n = 105) yielded an ORR of 52% and median PFS of 11.1 months in patients with atypical EGFR-mutated NSCLC, rising to an ORR of 57% and median PFS of 19.5 months, specifically in patients being treated int eht first-line setting.^20,21

“[Amivantamab plus lazertinib] is something that I’m considering for first-line treatment for my atypical EGFR mutation–positive patients,” she said.

For exon 20 insertions, amivantamab plus chemotherapy remains standard based on the phase 3 PAPILLON trial (NCT04538664), though OS was not significantly improved (HR, 0.87; 95% CI, 0.66-1.14; P = .307).²²

“[The OS results were] probably because many of these patients crossed over to receive amivantamab at progression,” Goldberg said; the crossover-adjusted HR was 0.57 (95% CI, 0.39-0.82).

Sunvozertinib (Zegfrovy) produced an an ORR of 45.9% in patients with EGFR exon 20 insertions who had recieved at least one prior line of therapy, and improved frontline PFS vs chemotherapy in the phase 3 WU-KONG28 study (NCT05668988) with a median PFS of 10.3 months vs 7.5 months, respectively (HR, 0.65; 95% CI, 0.50-0.85; P = .0008).^23,24

Zipalertinib plus chemotherapy (n = 140) also improved frontline PFS to 14.5 months vs 8.5 months in chemotherapy alone (n = 139; HR, 0.50; 95% CI, 0.34-0.73) in the phase 3 REZILIENT3 trial (NCT05973773), “although toxicity is something we have to think about,” she said.²⁵ An NDA for that combination has since been submitted.²⁶

What questions remain unanswered?

Goldberg concluded that although clinicians now have options across EGFR subtypes, the field still lacks tumor-based markers for choosing between frontline combinations, evidence on whether lower-risk patients can safely receive monotherapy, and clarity on how best to sequence chemotherapy, TKIs, and amivantamab.

References

1. Goldberg SB. EGFR: how to make the best decision. Paper presented at: New York Lung Cancers Symposium; November 14, 2026; New York, NY
2. Jänne PA, Planchard D, Kobayashi K, et al. Survival with osimertinib plus chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2026;394(1):27-38. doi:10.1056/NEJMoa2510308
3. Yang JCH, Lu S, Hayashi H, et al. Overall survival with amivantamab-lazertinib in EGFR-mutated advanced NSCLC. N Engl J Med. 2025;393(17):1681-1693. doi:10.1056/NEJMoa2503001
4. Felip E, Cho BC, Gutiérrez V, et al. Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA. Ann Oncol. 2024;35(9):805-816. doi:10.1016/j.annonc.2024.05.541
5. Jänne PA, Planchard D, Kobayashi K, et al. FLAURA2: exploratory overall survival analyses in patients with poorer prognostic factors treated with osimertinib ± platinum-pemetrexed as first-line treatment for EGFR-mutated advanced NSCLC. Paper presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA77
6. Resuli B, et al. Redefining tolerability: a head-to-head IPD toxicity comparison of amivantamab+lazertinib vs osimertinib+chemotherapy in EGFR-mutant NSCLC. Paper presented at: IASLC 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract P3.12.67
7. Goldberg SB, et al. COPERNICUS, a pragmatic phase 2b study of first-line subcutaneous amivantamab + lazertinib with supportive care in EGFR-mutated advanced NSCLC: early safety results. Paper presented at: 2026 ASCO Annual Meeting; May 29-June 2, 2026; Chicago, IL
8. Halmos B, Tu J, Goldberg SB, et al. Subcutaneous amivantamab + lazertinib with supportive care in EGFR-mutant NSCLC: longer follow-up from the pragmatic COPERNICUS study. Paper presented at: IASLC 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract M012.09
9. Le X, Popat S, Heymach JV, et al. Treatment options and considerations for acquired resistance in EGFR mutation-positive non-small-cell lung cancer. ESMO Open. 2026;11:106027. doi:10.1016/j.esmoop.2025.106027
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11. EU, Japanese approval is sought for savolitinib plus osimertinib in MET-driven EGFR-mutated NSCLC. OncLive. November 2, 2026. Accessed November 14, 2026. https://www.onclive.com/view/eu-japanese-approval-is-sought-for-savolitinib-plus-osimertinib-in-met-driven-egfr-mutated-nsclc
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13. 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
14. Leighl NB, Akamatsu H, Lim SM, et al. Subcutaneous versus intravenous amivantamab, both in combination with lazertinib, in refractory epidermal growth factor receptor-mutated non-small cell lung cancer: primary results from the phase III PALOMA-3 study. J Clin Oncol. 2024;42(30):3593-3605. doi:10.1200/JCO.24.01001
15. Le X, Passaro A, Zhao Y, et al. Ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated non-small cell lung cancer after EGFR-TKI progression (HARMONi): a randomised, double-blind, multi-centre phase 3 trial. Lancet Oncol. 2026;27(9):1094-1109. doi:10.1016/S1470-2045(26)00282-2
16. Ahn MJ, Lisberg AE, 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
17. Le X, Hendriks LEL, Morabito A, et al. Osimertinib (osi) + datopotamab deruxtecan (Dato-DXd) in patients (pts) with EGFR-mutated (EGFRm) advanced NSCLC (aNSCLC) whose disease progressed on first-line (1L) osi: ORCHARD. J Thorac Oncol. 2025;20(3 suppl 1):S2-S4. doi:10.1016/S1556-0864(25)00196-0
18. 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
19. Zhang L, Fang WF, Wu L, et al. Final OS analysis of sacituzumab tirumotecan (sac-TMT) versus platinum-based chemotherapy in EGFR-mutated non-small cell lung cancer (NSCLC) after progression on EGFR-TKI: phase III OptiTROP-Lung04 study. Paper presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA67
20. Tomasini P, Wang Y, Li Y, et al. Amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer: results from CHRYSALIS-2. J Clin Oncol. 2026;44(1):54-65. doi:10.1200/JCO-24-02835
21. Neal JW, Yang JCH, Cho BC, et al. Overall survival of first-line amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer (NSCLC): updated results from the CHRYSALIS-2 study. J Clin Oncol. 2026;44(suppl 16):8501. doi:10.1200/JCO.2026.44.16_suppl.8501
22. Kim C, Tang KJ, Cho BC, et al. First-line amivantamab-chemotherapy vs chemotherapy in NSCLC with EGFR exon 20 insertions: overall survival from PAPILLON. Paper presented at: IASLC 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract PL03.03
23. Yang JCH, Wang M, Doucet L, et al. Phase II dose-randomized study of sunvozertinib in platinum-pretreated non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations (WU-KONG1B). J Clin Oncol. 2025;43(29):3198-3208. doi:10.1200/JCO-25-00788
24. Heymach JV, Liu G, Xing L, et al. Sunvozertinib monotherapy versus platinum-based chemotherapy as first-line treatment for advanced NSCLC with EGFR exon20ins: primary analysis of a multinational phase 3 randomized study (WU-KONG28). J Clin Oncol. 2026;44(suppl 17):LBA8500. doi:10.1200/JCO.2026.44.17_suppl.LBA8500
25. Tan DSW, Danchaivijitr P, Shinno Y, et al. Zipalertinib plus chemotherapy for 1st-line NSCLC with EGFR exon 20 insertions: results from the phase 3 trial (REZILIENT3). Paper presented at: IASLC 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract PL03.04
26. NDA submission completed for zipalertinib plus chemotherapy in frontline EGFR exon 20 insertion–positive NSCLC. OncLive. November 13, 2026. Accessed November 14, 2026. https://www.onclive.com/view/nda-submission-completed-for-zipalertinib-plus-chemotherapy-in-frontline-egfr-exon-20-insertion