Unpacking the Advantages and Limitations of Leading Frontline Regimens in EGFR-Mutated NSCLC

During a session at the 23rd Annual Winter Lung Cancer Conference®, an event held by Physicians’ Education Resource, LCC, titled “The EGFR Crossfire: Monotherapy, Intensification, and Beyond,” experts in the field of lung cancer debated the roles of osimertinib (Tagrisso) monotherapy, osimertinib plus chemotherapy, and amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze) as frontline treatment for patients with EGFR-mutated non–small cell lung cancer (NSCLC).¹ During this presentation, Susan Scott, MD, Julia Rotow, MD, and Enriqueta Felip, MD, PhD, respectively, offered their perspectives on the unique benefits of each regimen and argued why it is the ideal choice in the frontline setting.

Scott is a thoracic medical oncologist with the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center at Sibley Memorial Hospital in Washington, DC, and an assistant professor of oncology at the Johns Hopkins University School of Medicine in Baltimore, Maryland. Rotow is the clinical director of the Lowe Center for Thoracic Oncology, the director of clinical research, and a physician at Dana-Farber Cancer Institute, as well as an assistant professor of medicine at Harvard Medical School, both in Boston, Massachusetts. Felip is the section chief at the Vall d’Hebron University Hospital and the head of the Vall d’ Hebron Institute of Oncology’s Thoracic Tumors Group in Barcelona, Spain.

Why is osimertinib monotherapy still an essential option in the current treatment arsenal?

Scott began the session by defending the continued role of osimertinib monotherapy, which earned FDA approval in April 2018 for the frontline treatment of patients with metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.² The approval was supported by data from the phase 3 FLAURA trial (NCT02296125).

Scott explained that when she approaches selecting a frontline regimen, she considers patient-specific factors such as disease features, goals of care, risk tolerance, and comorbidities.

“When I look back after these discussions [with patients], they hear me, they understand the data, and, at the end of the day, so many of them choose osimertinib over combination [therapy],” Scott said. “Our patients are not making this decision based on the confidence interval for the HR of overall survival [OS]. For our patients, this is a big decision, and it's really about something much bigger. It's about freedom.”

Scott reviewed topline data from FLAURA, which demonstrated that patients who received osimertinib (n = 279) achieved a median progression-free survival (PFS) of 18.9 months (95% CI, 15.2-21.4) compared with 10.2 months (95% CI, 9.6-11.1) among those treated with a standard EGFR TKI (n = 277; HR, 0.46; 95% CI, 0.37-0.57; P < .001).³ Additionally, patients who received osimertinib had a median OS of 38.6 months (95% CI, 34.5-41.8) vs 31.8 months (95% CI, 26.6-36.0) in the control arm (HR, 0.80; 95% CI, 0.64-1.00; P = .046).

“Osimertinib just did a better job: better PFS, better OS, [and] less toxicity,” Scott said. “This is where we should be heading with subsequent innovations in therapy optimization, less toxicity. This is what we need to see from next-generation treatments, and we all agree that osimertinib is not enough.”

When putting the FLAURA data in context with findings from the phase 3 FLAURA 2 (NCT04035486) and MARIPOSA (NCT04487080) trials of osimertinib plus chemotherapy and amivantamab plus lazertinib, respectively, Scott noted that overall response rates (ORRs) were largely comparable between the 3 regimens, ranging from 80% to 86%.¹ “Unlike when you’re using immunotherapy and you want to introduce early chemotherapy to help get a quick benefit [and] relieve symptoms, you’re not going to make any patient feeling better feel any better by adding combination up front,” she noted.

Scott explained that the most compelling argument for using upfront osimertinib monotherapy is the avoidance of risking unnecessary toxicities that often accompany combination approaches. She noted that data from the phase 3 COMPEL study (NCT04765059) shows that the use of frontline combination therapy is not clear cut.⁴

In COMPEL, patients who received osimertinib plus chemotherapy following non–central nervous system (CNS) disease progression on frontline osimertinib (n = 49) had a median PFS of 8.5 months (95% CI, 8.4-11.8) compared with 4.4 months (95% CI, 3.5-5.6) among those who received chemotherapy alone (n = 49; HR, 0.43; 95% CI, 0.27-0.70). The median OS values were 15.9 months (95% CI, 12.4-20.8) and 9.8 months (95% CI, 8.4-17.2), respectively (HR, 0.71; 95% CI, 0.42-1.23).

“This study showed that continuing osimertinib with chemotherapy upon progression is better than switching to chemotherapy by itself,” Scott said. “This leaves us wondering how to interpret the FLAURA 2 OS, when those patients had to stop osimertinib and went on to chemotherapy alone.”

In terms of safety, Scott noted that it is rare for patients to experience a high-grade adverse effect (AE) with osimertinib monotherapy. She emphasized that data from FLAURA 2 show that grade 3 or higher anemia, neutropenia, and fatigue occur in a significant portion of patients who receive osimertinib plus chemotherapy. In MARIPOSA, grade 3 or higher rash and other dermatologic toxicities are significant concerns for patients.

Scott concluded her portion of the presentation by asserting that osimertinib monotherapy also offers patients significant cost and time savings compared with the other 2 regimens.¹ In FLAURA, patients underwent approximately 7 clinical visits in the first year of treatment compared with approximately 19 in FLAURA 2 and approximately 30 in MARIPOSA. Moreover, she explained that the estimated annual costs for patients of the respective regimens were $180,000, $250,000, and $432,000.

“Osimertinib monotherapy is the people's choice. This regimen prioritizes quality over complexity. It provides excellent disease control with less toxicity, less time, less cost, [and] more living,” Scott said in her conclusion.

How does the addition of chemotherapy build on the success of osimertinib?

In February 2024, the FDA approved osimertinib plus platinum-based chemotherapy in patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.⁵ The approval was supported by data from FLAURA 2.

Rotow explained that data from FLAURA 2 demonstrated a significant PFS advantage with osimertinib plus chemotherapy compared with osimertinib alone.⁶ The median PFS in the combination arm (n = 279) was 25.5 months (95% CI, 24.7-not calculable [NC]) compared with 16.7 months (95% CI, 14.1-21.3) in the monotherapy arm (n = 278; HR, 0.62; 95% CI, 0.49-0.79). The combination arm also displayed a significant advantage in terms of OS compared with monotherapy (HR, 0.77; 95% CI, 0.61-0.96).⁷

“Outcomes are poor after acquired EGFR TKI resistance; first-line combinations are more effective than monotherapy for almost all patients, and many patients will never get a second-line option, so they really have to choose the most effective therapeutic combination first,” Rotow said. “There is a small fraction of patients who would do well on osimertinib [monotherapy] long term; unfortunately, we don't know who those patients are at diagnosis.”

Rotow also emphasized that osimertinib plus chemotherapy demonstrated a high magnitude of benefit in FLAURA 2. Significant PFS benefits were reported with the combination among patients with brain metastases (HR, 0.47; 95% CI, 0.33-0.66), detectable EGFR in plasma (HR, 0.60; 95% CI, 0.45-0.80), EGFR L858R mutations (HR, 0.63; 95% CI, 0.44-0.90), and TP53 mutations (HR, 0.57).

Rotow added that patients with traditional low-risk features should also be considered for combination therapy. “They’re still deriving a lot of benefit, [but] they’re just starting in a better place and then doing even better with a combination. In real life, risk stratification is not straightforward. This is not a clean situation where all patients' risk factors all line up. Many of these are different,” she explained.

Rotow added that osimertinib plus chemotherapy also produced a significant CNS response in patients with EGFR-mutated NSCLC. Patients with measurable and non-measurable brain metastases who received the combination (n = 118) experienced a CNS ORR of 73% (95% CI, 64%-81%) compared with 69% (95% CI, 59%-78%) in the monotherapy arm (n = 104).⁸ The respective complete response rates were 59% and 43%. The median duration of response (DOR) was not reached (NR; 95% CI, 23.8-NC) and 26.2 months (95% CI, 19.4-NC), respectively. Patients with CNS metastases at baseline also experienced a significant PFS benefit with the combination (HR, 0.47; 95% CI, 0.33-0.66).⁶

“The first-line of therapy may be the only line of therapy a patient receives,” Rotow concluded. “Nearly all subgroups, even lower-risk subgroups may derive benefit from combination therapy, and while efficacy outcomes are similar in MARIPOSA to FLAURA 2 in the overall population, FLAURA 2 may offer better efficacy in some subgroups, and FLAURA 2 has more manageable AEs and a better cost efficacy profile for our patient as a whole.”

What sets amivantamab plus lazertinib apart in the space?

Felip concluded the debate by arguing for the merits of amivantamab plus lazertinib, which was approved by the FDA in August 2024 for the first-line treatment of adult patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.⁹ The regulatory decision was supported by data from MARIPOSA, which showed that, at a median follow-up of 36.7 months, the median OS was NR (95% CI, 42.9-NR) with amivantamab plus lazertinib (n = 429) vs 36.7 months (95% CI, 33.4-41.0) with osimertinib monotherapy (HR, 0.75; 95% CI, 0.61-0.92; P < .005).¹⁰

“I believe we need to treat patients with the strongest combination upfront because there are a number of patients who never receive second-line treatment, and we have learned that in patients treated with osimertinib, MET amplification and EGFR secondary mutations are mechanisms of resistance,” Felip stated.

Felip explained that MET pathway activations and EGFR pathway alterations are known mechanisms of resistance to third-generation EGFR TKIs, and approximately 25% to 40% of patients who receive a third-generation EGFR TKI as monotherapy do not go on to receive second-line therapy, she continued.

However, both amivantamab and lazertinib bind extra- and intracellularly to EGFR, in addition to amivantamab’s extracellular binding of MET.¹ Amivantamab binding also triggers EGFR and MET receptor degradation by the tumor cell, leading to receptor inactivation.

Additional data from MARIPOSA revealed that, at a median follow-up of 22.0 months, amivantamab plus lazertinib led to a median PFS of 23.7 months (95% CI, 19.1-27.7) compared with 16.6 months (95% CI, 14.8-18.5) in the osimertinib arm (HR, 0.70; 95% CI, 0.58-0.85; O < .001).¹¹ The combination also produced a PFS benefit across key subgroups, including in those with (HR, 0.69; P = .01) and without (HR, 0.69; P = .005) a history of brain metastases, with (HR, 0.58; P = .017) and without (HR, 0.74; P = .004) liver metastases, with (HR, 0.65; P = .003) and without (HR, 0.75; P = .114) TP53 comutations, and with (HR, 0.68; P = .002) and without (HR, 0.72; P = .132) detectable EGFR mutations per circulating tumor DNA analysis.¹²

In the safety-evaluable population of MARIPOSA (n = 421), the most common any-grade AEs related to EGFR inhibition included paronychia (69%), rash (64%), and diarrhea (32%). Any-grade infusion-related reactions were reported in 65% of patients. Venous thromboembolic events (VTEs) events occurred in 40% of patients in the combination arm compared with 11% in the osimertinib arm.

“There are some issues with safety, and perhaps what is most relevant is that rash, paronychia, and infusion-related reaction occur in [approximately] 60% of the patients,” Felip said. “But [these AEs] were predictable and occurred only in the first cycle. We know now how to manage [these AEs and] we know that we should give prophylactic anticoagulation for the first 4 months [to] reduce the VTEs. Even with osimertinib, [approximately] 10% of patients had VTEs.”

Disclosures: Scott received research funding direct to institution from AstraZeneca, Black Diamon Therapeutics, Johnson & Johnson, and Nuvalent. She also received consulting fees and honoraria from AstraZeneca, Daiichi Sankyo, EMD Serono, Genentech-Roche, Johnson & Johnson, and Merus.

Rotow received consulting fees or honoraria from Amgen, AstraZeneca, BioAtla, Blossom Hill, Bristol Myers Squibb, Boehringer Ingelheim, Catalyst, Daiichi Sankyo, Genentech, G1 Therapeutics, Guardant Health, Jazz Pharmaceuticals, Johnson and Johnson, Merus, Novocure, Nuvalent, Nuvation Bio, Pfizer, Regeneron, Sanofi-Genzyme, Summit Therapeutics, and Takeda. Travel from AstraZeneca, Bristol Myers Squibb, Daiichi-Sankyo, Johnson and Johnson, and Merus. She has been contracted for institutional research with AbbVie, Altor Bioscience, AstraZeneca, Bicycle Therapeutics, BioAtla, Black Diamond, Blossom Hill, Blueprint Medicines, Bristol Myers Squibb, Duality, Enliven Therapeutics, EpimAb, Immunity Bio, LOXO Oncology, ORIC Pharmaceuticals, RedCloud Bio, Summit, Synthekine, and Regeneron.

Felip served as an advisory board/invited speaker for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Ellipses Pharma, Grifols, Gilead, GSK, ITeos Therapeutics, Johnson & Johnson / Janssen, Medical Trends, Medscape, Merck Sharp & Dohme, Moderna, PeerVoice, Pfizer, PharmaMar, Pierre Fabre, Regeneron, Roche–Genentech, Seagen, and Tubulis. She is on the board of directors of Grifols and holds local PI/institutional/financial interest/clinical trial rolse with AbbVie, Amgen, AstraZeneca AB, Bayer Consumer Care AG, BeiGene, Boehringer Ingelheim GmbH, Bristol Myers Squibb International Corporation, Daiichi Sankyo, Exelixis Inc, F. Hoffmann-La Roche Ltd, Genentech Inc, GSK, Janssen Cilag International NV, Merck KGAA, Merck Sharp & Dohme Corp, Mirati Therapeutics Inc, Novartis Pharmaceutica SA, Nuvalent, Pfizer, and Takeda Pharmaceuticals International.

References

1. Scott S, Rotow, J, Felip E. The EGFR crossfire: monotherapy, intensification, and beyond Presented at: 23rd Annual Winter Lung Cancer Conference; January 23-January 25, 2026; Hollywood, FL.
2. FDA approves osimertinib for first-line treatment of metastatic NSCLC with most common EGFR mutations. FDA. Updated April 19, 2018. Accessed April 14, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-first-line-treatment-metastatic-nsclc-most-common-egfr-mutations
3. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662
4. Pasello G, Zhao J, Tufman A, et al. COMPEL: osimertinib + platinum-based chemotherapy in patients with EGFRm advanced NSCLC and progression on 1L osimertinib. J Thorac Oncol. 2025;20(suppl 1):S27. doi:10.1016/j.jtho.2025.09.056
5. FDA approves osimertinib with chemotherapy with chemotherapy for EGFR-mutated non-small cell lung cancer. FDA. Updated February 20, 2024. Accessed April 14, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer
6. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
7. 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
8. Safety and CNS outcomes of first-line (1L) osimertinib (osi) ± chemotherapy (CTx) in EGFRm advanced NSCLC. Ann Oncol. 2023;34:S1311-S1312. doi:10.1016/j.annonc.2023.10.069
9. FDA approves lazertinib with amivantamab-vmjw for non-small lung cancer. FDA. Updated August 20, 2024. Accessed April 14, 2026. http://fda.gov/drugs/resources-information-approved-drugs/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer
10. Yang JC, 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
11. Cho BC, Lu S, Felip E, et al. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498. doi:10.1056/NEJMoa2403614
12. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced non-small cell lung cancer (NSCLC) with biomarkers of high-risk disease: a secondary analysis from the phase 3 MARIPOSA study. J Clin Oncol. 2024;42(suppl 16):8504. doi:10.1200/JCO.2024.42.16_suppl.8504