Evolving Treatment Landscape in First-Line EGFR-Mutant NSCLC: New Insights Into Combination Therapies

Despite recent advances in targeted therapy for NSCLC, survival outcomes among patients with EGFR-mutant advanced NSCLC remain poor, and many patients develop treatment resistance following TKI monotherapy.9-12 Combination treatments in the first-line setting have been explored as a strategy to improve survival outcomes and address the mechanisms of resistance in EGFR-mutant NSCLC.13

Epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) represents a considerable subset of lung cancer cases, with EGFR mutations occurring in 3% to 19% of patients with NSCLC in Western populations and up to 48% in Asian populations.1 EGFR mutations are most commonly observed in adenocarcinoma histology and are more frequent in women, never-smokers, and younger patients.2,3 These mutations are primarily located in the tyrosine kinase domain of the EGFR gene (exons 18–21) and drive tumor growth by promoting ligand-independent activation of the EGFR signaling pathway.4 Exon 19 deletions and exon 21 L858R substitutions are the two most common activating mutations in NSCLC, accounting for approximately 45% and 40% of EGFR mutations, respectively.5,6 Together, these classical mutations constitute approximately 90% of all EGFR mutations in NSCLC and are associated with sensitivity to targeted therapies.5,6

The treatment landscape for EGFR-mutant advanced NSCLC has evolved considerably in recent years, with targeted therapies, particularly EGFR tyrosine kinase inhibitors (TKIs), becoming part of the standard of care in the first-line setting.7 Despite advances in targeted therapy for NSCLC, there remain several clinical challenges associated with the treatment of EGFR-mutant advanced NSCLC.8 Survival outcomes among patients with EGFR-mutant advanced NSCLC remain poor, with a 5-year survival rate lower than 20%.9 Additionally, 29% to 63% of patients develop treatment resistance following TKI monotherapy.10-12 Combination treatments in the first-line setting have been explored as a strategy to improve survival outcomes and address the mechanisms of resistance in EGFR-mutant NSCLC.13

EGFR TKI Monotherapy as First-Line Treatment for EGFR-Mutant Advanced NSCLC

First-Generation EGFR-TKIs

First-generation EGFR-TKIs, including gefitinib and erlotinib, were the first to demonstrate significant clinical benefits in patients with EGFR-mutant NSCLC. These agents typically achieve objective response rates (ORRs) of 64% to 74% and median progression-free survival (PFS) of 6 to 11 months.11,14-16 However, responses to these TKIs among patients with EGFR-mutant NSCLC do not translate into a significant overall survival (OS) benefit.11,14-16 In addition, monotherapies using first-generation EGFR-TKIs are limited by high rates of acquired resistance due to second-site EGFR mutations.11,12 The EGFR T790M mutation accounts for approximately 50% of cases with acquired resistance to first-generation TKIs.11

Second-Generation EGFR-TKIs

Second-generation TKIs, such as afatinib and dacomitinib, offer broader inhibition than first-generation TKIs by irreversibly binding to EGFR and other ErbB/HER family members.17 In clinical trials, afatinib and dacomitinib demonstrated a median progression-free survival (PFS) of 2.4 to 11.1 and 2.6 to 18.2 months, respectively.17 However, the clinical superiority of second-generation TKIs over first-generation TKIs is unclear, and second-generation agents are associated with higher toxicity.17

Third-Generation EGFR-TKIs

However, acquired resistance to osimertinib is common, occurring in approximately 29% of patients with NSCLC within 8 months of treatment initiation.10 Common mechanisms of acquired resistance include loss of the EGFR T790M mutation, emergence of second-site EGFR mutations (eg, C797S), and gain of MET amplification.10,21 Survival in patients with acquired osimertinib resistance is poor, with a median real-world OS of 11.4 months after progression.22

Combination Therapies for First-Line Treatment of EGFR-Mutant Advanced NSCLC

Recent clinical trials have explored combination strategies to overcome resistance to TKI monotherapy and improve clinical outcomes in patients with EGFR-mutant advanced NSCLC.23

Amivantamab Plus Lazertinib

The MARIPOSA trial (NCT04487080) is a phase III, global, randomized, controlled study evaluating the efficacy and safety of amivantamab in combination with lazertinib compared to osimertinib monotherapy as a first-line treatment for patients with EGFR-mutant (exon 19 deletion or exon 21 L858R) advanced NSCLC.24 Amivantamab is a bispecific antibody targeting EGFR and MET, and lazertinib is an oral, third-generation EGFR TKI that inhibits exon 19 deletion, exon 21 L858R, and the EGFR T790M resistance mutation.24 By targeting both activating and resistance mutations in EGFR and MET, this combination aims to synergistically inhibit tumor growth and delay treatment resistance.24 Moreover, first-line treatment with this combination aims to prevent or delay central nervous system (CNS) metastasis, a common challenge in EGFR-mutant NSCLC, due to the ability of lazertinib to penetrate the blood–brain barrier.24,25

Efficacy Data

The MARIPOSA trial met its primary endpoint, demonstrating a statistically significant improvement in PFS for the combination therapy.26 The median PFS was 23.7 months (95% confidence interval [CI] = 19.1–27.7 months) for amivantamab plus lazertinib vs 16.6 months (95% CI = 14.8–18.5 months) for osimertinib, with a hazard ratio (HR) of 0.70 (95% CI = 0.58–0.85 months; P < .001).26

At a median follow-up of 37.8 months, OS was significantly longer with amivantamab plus lazertinib than with osimertinib monotherapy.27 The median OS was not reached (95% CI = 42.9 to not estimable) in the amivantamab plus lazertinib combination therapy arm and 36.7 months (95% CI = 33.4–41.0) in the osimertinib arm (HR = 0.75; 95% CI = 0.61–0.92; P < .005).27 OS curves continue to widen over time, and based on an exponential distribution assumption of OS in both arms, the improvement in median OS is projected to exceed 1 year.27 The combination therapy provided a longer duration of response (DOR), with a median DOR of 25.8 months (95% CI = 20.1 to not estimable) for amivantamab plus lazertinib vs 16.8 months (95% CI = 14.8–18.5) for osimertinib monotherapy.26

The MARIPOSA trial included assessments of intracranial outcomes, with all participants undergoing serial brain imaging.26 In patients with brain metastases at baseline (median follow-up of 37.8 months), the median intracranial PFS was 25.4 months (95% CI = 20.1–29.5) for the combination therapy vs 22.2 months (95% CI = 18.4–26.9) for osimertinib (HR = 0.79; 95% CI = 0.61–1.02; P = .07).27 The 3-year intracranial PFS rate was 36% (95% CI = 28%–43%) for amivantamab plus lazertinib compared to 18% (95% CI = 12%–25%) for osimertinib.27

Safety Profile

Grade 3 or higher adverse events occurred in 80% of patients in the amivantamab plus lazertinib group vs 52% in the osimertinib group.27 Paronychia, infusion-related reactions, and rash were the most common any-grade adverse events in the amivantamab plus lazertinib group, with frequencies of 69%, 65%, and 64%, respectively.27 Thromboembolism was reported in 40% of the patients in the amivantamab plus lazertinib group and in 11% of those in the osimertinib group.27

Serious adverse events were reported in 55% of patients receiving amivantamab plus lazertinib combination therapy and in 41% of those receiving osimertinib monotherapy.27 Grade ≥ 3 adverse events resulting in death were reported in 9% of patients in the amivantamab plus lazertinib arm and 8% of those in the osimertinib arm.27

Given the increased risk of venous thromboembolism (VTE) and infusion-related reactions in patients receiving amivantamab plus lazertinib combination therapy in the MARIPOSA trial,27  ongoing trials focus on identifying risk factors and strategies to mitigate these adverse events (Table 1).28-33

Table 1. Adverse Event Management Strategies in EGFR-Mutant NSCLC Treated With First-Line Amivantamab Plus Lazertinib: Ongoing Clinical Trials

Trial (Identifier) CHRYSALIS (NCT02609776), CHRYSALIS-2 (NCT04077463), LASER201 (NCT04075396)
Design Open-label trials
Key Findings/Objectives
  • Higher VTE incidence with combination therapy (21%) vs monotherapies (11%)
  • 64% of VTE events occurred within the first 4 months
  • Risk factors: age ≥ 60, ECOG PS 1, positive treatment response

Trial (Identifier) COCOON (NCT06120140)
Design Phase II, open-label, randomized
Key Findings/Objectives
  • Evaluating enhanced vs standard dermatologic care
  • Enhanced care: prophylactic oral antibiotics, topical treatments
  • Primary endpoint: reduction in grade ≥ 2 dermatologic AEs by week 12
  • In the first 12 weeks: significant reduction in grade ≥ 2 dermatologic AEs with COCOON dermatologic management vs standard dermatologic care (42% vs 75%; P < .0001), with benefit maintained at 6 months and patient-reported outcomes favoring COCOON dermatologic management

Trial (Identifier) SKIPPirr (NCT05663866)
Design Phase II, open-label
Key Findings/Objectives
  • Dexamethasone at 8 mg BID reduced first infusion IRRs approximately threefold (22.5% vs 67.4%)
  • ORR of 28% maintained with dexamethasone
  • No new safety signals identified
AE = adverse event; BID = twice daily; ECOG PS = Eastern Cooperative Oncology Group Performance Status; IRR = infusion-related reaction; IV = intravenous; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetic; SC = subcutaneous; VTE = venous thromboembolism.

Osimertinib Plus Chemotherapy

The FLAURA2 trial (NCT04035486) investigated the combination of osimertinib with platinum-based chemotherapy (pemetrexed plus cisplatin or carboplatin) in patients with EGFR-mutant (exon 19 deletion or L858R mutation) advanced NSCLC.34 The median PFS was 25.5 months in the combination arm vs 16.7 months in the monotherapy arm (P < .001).34 The median ORR was 83% (95% CI = 78%–87%) in the combination arm vs 76% (95% CI = 70%–80%) in the monotherapy arm, and the median DOR was 24.0 months (95% CI = 20.9–27.8 months) with the combination therapy compared to 15.3 months (95% CI = 12.7–19.4 months) with monotherapy.34 Overall survival data were still immature (27% maturity) at the data cutoff date, with a hazard ratio for death of 0.90 (95% CI = 0.65–1.24; P = .52).34

The addition of chemotherapy increased the incidence of grade 3 or higher adverse events (64% in the combination arm vs 27% in the monotherapy arm).34 Serious adverse events were reported in 38% of patients in the combination arm and 19% of those in the monotherapy arm; treatment-related deaths occurred in 5 patients and 1 patient, respectively.34 Despite the higher incidence of adverse events in the combination therapy group, the safety profile aligned with expectations for the individual agents, and no new safety concerns were identified. The most common adverse events in the combination arm were anemia (46%), diarrhea (43%), nausea (43%), decreased appetite (31%), and constipation (29%).34

EGFR-TKIs Plus Anti-Angiogenic Agents

The phase III RELAY trial (NCT02411448) demonstrated that adding ramucirumab to erlotinib improved PFS in patients with previously untreated EGFR-mutant (exon 19 deletion or exon 21 substitution) metastatic NSCLC (19.4 months vs 12.4 months; HR = 0.59 [95% CI = 0.46–0.76]; P < .0001).35 The median duration of response was also longer with combination therapy than with monotherapy (18.0 months vs 11.1 months; HR = 0.62 [95% CI = 0.48–0.81]; P = .0003).35 However, the overall response rate (76% vs 75%) and the disease control rate (95% vs 96%) were similar in the two groups; the median OS was not yet reached in either arm.35

Grade 3 to 4 toxicities were more frequent in the ramucirumab plus erlotinib group than in the control group (72% vs 54%).35 Serious treatment-emergent adverse events were reported in 29% of patients in the combination therapy arm and 21% of those in the monotherapy arm.35 The frequency of treatment discontinuation due to treatment-emergent adverse events was 13% with ramucirumab plus erlotinib combination therapy and 11% with erlotinib monotherapy.35 The most frequent grade 3 or worse treatment-emergent adverse events in the combination therapy group were hypertension (24%) and dermatitis acneiform (15%).35

Conclusion

Recent advances in the first-line treatment of advanced NSCLC with common EGFR mutations have broadened the therapeutic landscape, offering several promising options tailored to patient-specific factors.36  The current standard, single-agent osimertinib, is now complemented by combination therapies such as osimertinib with platinum-pemetrexed (FLAURA2 regimen) and amivantamab with lazertinib (MARIPOSA regimen), which may be particularly beneficial for high-risk patient subgroups.36-38 These include individuals with TP53 co-mutations or liver metastases, where the MARIPOSA regimen has shown potential in extending progression-free survival.39

The choice of first-line therapy should be guided by a comprehensive evaluation of patient characteristics, including performance status, age, comorbidities, brain metastasis status, and specific biomarkers such as EGFR mutations in ctDNA.36,38 This personalized approach is crucial for optimizing efficacy, managing potential toxicities, and planning subsequent treatment strategies.36,38 The evolving role of biomarkers, such as MET mutation status and ctDNA, further underscores their importance in refining treatment decisions and enhancing the precision of first-line therapies.38

References

  1. Dearden S, Stevens J, Wu YL, et al: Mutation incidence and coincidence in non small-cell lung cancer: Meta-analyses by ethnicity and histology (mutMap). Ann Oncol 24:2371-2376, 2013.
  2. Rosell R, Moran T, Queralt C, et al: Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361:958-967, 2009.
  3. He CH, Shih JF, Lai SL, et al: Non-small cell lung cancer in the very young: higher EGFR/ALK mutation proportion than the elder. J Chin Med Assoc 83:461-465, 2020.
  4. Iyer RS, Needham SR, Galdadas I, et al: Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers. Nat Commun 15:2130, 2024.
  5. Stewart EL, Tan SZ, Liu G, et al: Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review. Transl Lung Cancer Res 4:67-81, 2015.
  6. Li AR, Chitale D, Riely GJ, et al: EGFR mutations in lung adenocarcinomas: Clinical testing experience and relationship to EGFR gene copy number and immunohistochemical expression. J Mol Diagn 10:242-248, 2008.
  7. Marin-Acevedo JA, Pellini B, Kimbrough EO, et al: Treatment strategies for non-small cell lung cancer with common EGFR mutations: A review of the history of EGFR TKIs approval and emerging data. Cancers (Basel) 15:629, 2023.
  8. Passiglia F, Bironzo P, Bertaglia V, et al: Optimizing the clinical management of EGFR-mutant advanced non-small cell lung cancer: A literature review. Transl Lung Cancer Res 11:935-949, 2022.
  9. Bazhenova L, Minchom A, Viteri S, et al: Comparative clinical outcomes for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Lung Cancer 162:154-161, 2021.
  10. Oxnard GR, Hu Y, Mileham KF, et al: Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib. JAMA Oncol 4:1527-1534, 2018.
  11. Bethune G, Bethune D, Ridgway N, et al: Epidermal growth factor receptor (EGFR) in lung cancer: An overview and update. J Thorac Dis 2:48-51, 2010.
  12. Yu HA, Arcila ME, Rekhtman N, et al: Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 19:2240-2247, 2013.
  13. Zhou C, Yao LD: Strategies to improve outcomes of patients with EGRF-mutant non-small cell lung cancer: Review of the literature. J Thorac Oncol 11:174-186, 2016.
  14. Maemondo M, Inoue A, Kobayashi K, et al: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 362:2380-2388, 2010.
  15. Rosell R, Carcereny E, Gervais R, et al: Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13:239-246, 2012.
  16. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-957, 2009.
  17. Karachaliou N, Fernandez-Bruno M, Bracht JWP, et al: EGFR first- and second-generation TKIs-there is still place for them in EGFR-mutant NSCLC patients. Transl Cancer Res 8(suppl 1):S23-S47, 2019.
  18. Attili I, Corvaja C, Spitaleri G, et al: New generations of tyrosine kinase inhibitors in treating NSCLC with oncogene addiction: Strengths and limitations. Cancers (Basel) 15:5079, 2023.
  19. Soria JC, Ohe Y, Vansteenkiste J, et al: Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 378:113-125, 2018.
  20. Ramalingam SS, Vansteenkiste J, Planchard D, et al: Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 382:41-50, 2020.
  21. Chmielecki J, Mok T, Wu YL, et al: Analysis of acquired resistance mechanisms to osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer from the AURA3 trial. Nat Commun 14:1071, 2023.
  22. Rotow JK, Lee JK, Madison RW, et al: Real-world genomic profile of EGFR second-site mutations and other osimertinib resistance mechanisms and clinical landscape of NSCLC post-osimertinib. J Thorac Oncol 19:227-239, 2024.
  23. Liu A, Wang X, Wang L, et al: EGFR-TKIs or EGFR-TKIs combination treatments for untreated advanced EGFR-mutated NSCLC: A network meta-analysis. BMC Cancer 24:1390, 2024.
  24. Cho BC, Felip E, Hayashi H, et al: MARIPOSA: Phase 3 study of first-line amivantamab + lazertinib versus osimertinib in EGFR-mutant non-small-cell lung cancer. Future Oncol 18:639-647, 2022.
  25. Supavavej A, Chayangsu C, Benjawongsathien D, et al: A multicenter study of central nervous system (CNS) metastasis in EGFR-mutated advanced non–small-cell lung cancer in Thailand: CNS progression-free survival analysis. J Clin Oncol 41(suppl 16):e14002
  26. Cho BC, Lu S, Felip E, et al: Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med 391:1486-1498, 2024.
  27. Yang JC, Lu S, Hayashi H, et al: Overall survival with amivantamab-lazertinib in EGFR-mutated advanced NSCLC. N Engl J Med. September 7, 2025 (early release online).
  28. Girard N, Cho BC, Spira AI, et al: Risk factors for venous thromboembolism (VTE) among patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) receiving amivantamab plus lazertinib versus either agent alone. J Clin Oncol 41(suppl 16):9137, 2023.
  29. Spira AI, Paz-Ares L, Han JY, et al: Preventing infusion-related reactions with intravenous amivantamab-results from SKIPPirr, a phase 2 study: A brief report. J Thorac Oncol 20:809-816, 2025.
  30. Minchom AR, Krebs MG, Cho BC, et al: Subcutaneous amivantamab (ami) in patients (pts) with advanced solid malignancies: The PALOMA study—Updated safety and identification of the recommended phase 2 dose. J Clin Oncol 41(suppl 16):9126, 2023.
  31. Lim SM, Tan J-L, Mourão Dias J, et al: Subcutaneous amivantamab and lazertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Results from the phase 2 PALOMA-2 study. J Clin Oncol 42(suppl 17):LBA8612, 2024.
  32. 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 42:3593-3605, 2024.
  33. Cho BC, Li W, Spira AI, et al: Enhanced versus standard dermatologic management with amivantamab-lazertinib in EGFR-mutated advanced NSCLC: The COCOON global randomized controlled trial. J Thorac Oncol. September 9, 2025 (early release online).
  34. Planchard D, Janne PA, Cheng Y, et al: Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med 389:1935-1948, 2023.
  35. Nakagawa K, Garon EB, Seto T, et al: Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 20:1655-1669, 2019.
  36. Gridelli C, Mok T, Janne P, et al: Debate on first-line treatment strategies in advanced non-small cell lung cancer with EGFR mutation: An expert panel meeting by the Italian Association of Thoracic Oncology (AIOT). Lung Cancer 201:108100, 2025.
  37. Hasan N, Nagasaka M. Amivantamab plus lazertinib vs. osimertinib in first-line EGFR-mutant advanced non-small cell lung cancer. Expert Rev Respir Med 19:223-232, 2025.
  38. Brazel D, Nagasaka M. MARIPOSA: Can amivantamab and lazertinib replace osimertinib in the front-line setting? Lung Cancer (Auckl) 15:41-47, 2024.
  39. Felip E, Cho BC, Gutierrez 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 35-805-816, 2024.

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