Findings from the phase 3 FLAURA2 trial (NCT04035486) confirmed the overall survival (OS) benefit with osimertinib (Tagrisso) plus chemotherapy vs osimertinib monotherapy in patients with EGFR-mutated non–small cell lung cancer (NSCLC), but the survival benefit alone may not be enough to warrant it’s use in every patient. Factors such as treatment toxicity, second-line sequencing, and patient goals and preferences must be considered when selecting the optimal therapy.
“There are a lot of new data [being made available] and we need to offer patients the opportunity to get the best outcomes,” Ticiana Leal, MD, said. “[We need to] have discussions about combinations and have a shared decision-making approach with patients in order to get their perspective on it.”
In an OncLive Peer Exchange filmed on-location in Barcelona, Spain, during the
How Should I Navigate the Choice Between Osimertinib Monotherapy and Combination Therapy?
In February 2024, osimertinib combination therapy solidified its place in the EGFR-mutated NSCLC treatment space, earning FDA approval in combination with platinum-based chemotherapy in patients with locally advanced or metastatic disease whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.1 During WCLC, investigators presented the final OS data from FLAURA2; prior data from this study supported the FDA approval of osimertinib plus chemotherapy.
At a median follow-up of 51.2 months (range, 0.2-60.4) in the osimertinib plus chemotherapy arm (n = 279) and 51.3 months (range, 0.1-60.1) in the osimertinib monotherapy arm (n = 278), the median OS values were 47.5 months (95% CI, 41.0-not calculable) and 37.6 months (95% CI, 33.2-43.2), respectively (HR, 0.77; 95% CI, 0.61-0.96; P = .02).2 The 3-year OS rates were 63% and 51%, respectively, and the 4-year OS rates were 49% and 41%, respectively.
“[These data] were the big news from this conference, [because] there was a real question where the [OS] HR would lie,” Helena Yu, MD, said. “Due to crossover, there was a possibility that the HR would be less significant, so I was pleasantly surprised. This was a measurable difference in outcomes for our patients, and I believe this will be practice changing.”
“We were waiting for the OS [data]; we knew they were going to be positive, but I believe these data solidify this combination strategy as a frontline option for our patients. Importantly, this benefit was seen in the key subgroups that were predefined,” Leal added.
Findings from a subgroup analysis of FLAURA2 showed that osimertinib plus chemotherapy showed a consistent OS benefit vs osimertinib monotherapy across patient subgroups. Notably, in patients with (HR, 0.72; 95% CI, 0.52-0.99) and without (HR, 0.77; 95% CI, 0.57-1.05) brain metastases as well as patients with disease harboring EGFR L858R mutations (HR, 0.76; 95% CI, 0.55-1.07) and EGFR exon 19 deletions (HR, 0.76; 95% CI, 0.56-1.02).
The panelists continued their conversation by further unpacking how they choose between osimertinib monotherapy and osimertinib plus chemotherapy for the frontline treatment of patients with EGFR-mutated NSCLC. Leal noted that the clinical trial population and patients treated in the real-world setting are often different and that older patients, those with a poor performance status, and/or those with significant comorbidities such as baseline renal dysfunction would not be good candidates to receive the chemotherapy-containing combination.
“It’s not a high-risk vs low-risk group. [We need to consider] all of these patient factors and patient preference together,” Zosia Piotrowska, MD, MHS, explained. “Different patients have different values, goals, and personal situations that affect [treatment]. Maybe they live farther away, and they don’t want to drive in or maybe they’ve had chemotherapy before. All these things are important in our decision-making. These are long and complicated discussions with patients. We have to provide them guidance, but we also want to hear what’s important to them.”
Findings from a real-world study of 235 adult patients with stage IV NSCLC who started first treatment with osimertinib plus chemotherapy or osimertinib monotherapy between February 19, 2024, and December 31, 2024, revealed that patients who were younger and those with more advanced disease received the combination more often.3 Specifically, patients less than 65 years old (n = 71) received combination therapy 42% of the time compared with 23% among patients who were at least 65 years of age (n = 164). Patients with stage IVA (n = 94) and stage IVB (n = 127) disease were treated with the combination at respective rates of 20% and 34%.
“[These data] are from a year after the initial results of FLAURA2 and there needs to be time to have a shift in practice patterns,” Leal said. “[We have] been very comfortable using osimertinib monotherapy and now having to shift to a higher intensity regimen takes a learning curve for many of us and for patients. In my community, I’m seeing quicker uptake of this combination than I was expecting. I’ve seen less uptake of the MARIPOSA regimen [amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze)] and higher uptake of the FLAURA2 regimen.”
Piotrowska noted that the fact that many patients do not make it to a second line of treatment in this setting could also influence the decision to choose between osimertinib plus chemotherapy or osimertinib monotherapy in the frontline setting. In FLAURA2, among patients who experienced progression on the combination (n = 127), 69% went on to receive a first subsequent treatment compared with 77% of those in the monotherapy arm who experienced disease progression (n = 185).2 In the combination group, subsequent treatment approaches included platinum-based chemotherapy (44%), non–platinum-based chemotherapy (30%), other EGFR-targeted therapy (8%), osimertinib plus a targeted or investigational agent (5%), and other approaches (14%). Comparatively, these subsequent therapies were given at respective rates of 72%, 3%, 7%, 3%, and 14% in the monotherapy group.
“We’ve known for a long time that chemotherapy is an effective therapy for these patients,” Piotrowska explained. “[Because] there’s no guarantee that patients will get chemotherapy in the second line, there is some appeal to giving them multiple agents that target the cancer in different ways and try to give them the best outcome. A point that is critically important here is the idea of shared decision-making with patients and taking into account their preferences and goals of care.”
Findings from a qualitative analysis of patient perspectives on osimertinib presented during WCLC showed that adult patients with advanced EGFR-mutated NSCLC were influenced by factors such as age, prior treatment experience, and life roles when considering treatment with the agent.4 Patients noted that they valued the convenience, tolerability, and ability to maintain independence provided by osimertinib.
How Should I Weigh the Risks and Benefits in First-Line Treatment Selection?
Beyond osimertinib plus chemotherapy, another regimen that is FDA approved for the frontline treatment of patients with EGFR-mutated NSCLC is the combination of the EGFR-MET bispecific antibody amivantamab plus the EGFR tyrosine kinase inhibitor lazertinib.5 In August 2024, the combination was approved in patients with untreated locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test. The regulatory decision was supported by data from the phase 3 MARIPOSA trial (NCT04487080).
At a median follow-up of 37.8 months (range, 0.0-48.1), updated data from MARIPOSA published in the New England Journal of Medicine showed that patients who received amivantamab plus lazertinib (n = 429) experienced a significant OS benefit vs osimertinib (n = 429; HR, 0.75; 95% CI, 0.61-0.92; P = .005).6 Specifically, the median OS values were not estimable (NE; 95% CI, 42.9 months-NE) and 36.7 months (95% CI, 33.4-41.0), respectively.
“We all agree that [osimertinib plus chemotherapy and amivantamab plus lazertinib] are similar in terms of efficacy,” Piotrowska said. “Where things start to differentiate themselves is in terms of their toxicity profiles and the practical aspects [such as] administration and frequency of visits.”
Data from a patient-level, head-to-head toxicity comparison presented during WCLC showed that patients who received amivantamab plus lazertinib were more likely to experience grade 3 or higher adverse effects (AEs; OR, 1.68; 95% CI, 1.21-2.34; P = .0022) and serious AEs (OR, 1.56; 95% CI, 1.15-2.13 P = .0052) vs osimertinib plus chemotherapy.7 The frequency of treatment discontinuation due to AEs was similar between the 2 arms (OR, 0.91; 95% CI, 0.56-1.50; P = .7064).
“We have to take these cross-trial comparisons with a grain of salt, but in my experience, there are a group of patients who have quality of life decrements for a substantial period of time with amivantamab,” Edward Garon, MD, MS, said. “How much a subcutaneous formulation in the future may may help with that is a bit hard to know, but [toxicities] are a factor, and you need to talk to patients about the possibility of them.”
Leal noted that the AE profile of the osimertinib plus chemotherapy is fairly well understood and toxicity management strategies are established. However, amivantamab plus lazertinib presents a unique toxicity profile, with AEs such as blood clots, infusion-related reactions, and rash that can be difficult to manage, she added.
The phase 2 COCOON trial (NCT06120140) evaluated enhanced vs standard dermatologic management in patients with EGFR-mutated NSCLC who received amivantamab plus lazertinib; mitigation strategies for dermatologic AEs were not evaluated in MARIPOSA.8 In COCOON, patients were randomly assigned 1:1 to receive oral doxycycline or minocycline during weeks 1 through 12, followed by topical clindamycin scalp lotion during weeks 13 through 52, with chlorhexidine on the nails, and a ceramide-based moisturizer (n = 99) or standard dermatologic management (n = 102), which included general skin prophylaxis and reactive treatment.
Findings from COCOON presented during WCLC demonstrated that patients in the investigational arm experienced a significantly lower incidence of grade 2 or higher dermatologic AEs of interest vs the control arm over the first 12 weeks, at 42% vs 75%, respectively (OR, 0.24; 95% CI, 0.13-0.45; P < .0001). Notably, the significant reduction of grade 2 or higher dermatologic AEs of interest was consistent across anatomic locations, excluding the incidence of paronychia which was comparable between the 2 arms during the first 12 weeks of treatment.
“The skin toxicities with [the MARIPOSA regimen] occur at a higher rate than what we see with chemotherapy,” Piotrowska said. “These are [AEs] that we need to get used to managing, no matter what the regimen is. This is a place where our entire team, especially our nurses and nurse practitioners, need to have clear materials for patients to follow and be as systematic as possible in giving patients directions.”
Renal dysfunction and a risk of cytopenias represent a risk of the FLAURA2 regimen due to the long-term administration of pemetrexed, Piotrowska noted. During FLAURA2, patients who received osimertinib plus chemotherapy experienced a median pemetrexed exposure of 8.3 months (range, 0.7-58.9).2
“In my practice, there’s always a discussion about how long a patient needs to be on maintenance pemetrexed,” Leal explained. “As we monitor patients, they do seem to tire out over time and get more chronic fatigue, chronic anemia, lower extremity edema, and pseudo cellulitis that can bother some eye symptoms. Importantly, you will start to see their creatinine [levels] creep a little bit each time over time and there’s going to be a point where we need to reduce and [eventually] stop the pemetrexed dose because you want to make sure that you save that kidney function for later. It’s a real issue that we have to monitor and counsel patients for.”
How Should I Sequence Treatments in the Second-Line Setting?
The panelists shifted the focus of their conversation to the second-line setting, where they discussed which patients should receive a platinum-based doublet with osimertinib following disease progression on frontline osimertinib. Findings from the phase 3 COMPEL study (NCT04765059) presented during WCLC showed that patients who received osimertinib plus cisplatin or carboplatin with pemetrexed (n = 49) experienced a median progression-free survival (PFS) of 8.4 months (95% CI, 5.7-11.8) compared with 4.4 months (95% CI, 3.5-5.6) among those who received placebo with chemotherapy (n = 49; HR, 0.43; 95% CI, 0.27-0.70).9 The 6-month PFS rates were 64% and 32%, respectively.
“A lot of us were waiting for these data and think they are relevant,” Yu commented. “Our practice patterns were changed based on the [phase 3] IMPRESS [NCT01544179] data of the earlier generation EGFR TKIs and the lack of benefit with continuing chemotherapy. [COMPEL] showed a benefit. I suspect a lot of that is [from] the maintenance of central nervous system [disease] control. [These findings] do complicate things moving forward. Should there be some targeted therapy that’s paired with platinum-based chemotherapy? Is it going to be better to continue osimertinib indefinitely [vs] novel therapies?”
“I have not routinely incorporated osimertinib into my treatment plan after chemotherapy. There are some patients with brain metastases [for whom] I have done it, but it has not been my routine approach. The data were enough in that setting to give me confidence that this is not likely to be similar to IMPRESS, where the data looked worse by going to that,” Garon added.
In terms of amivantamab-containing regimens in the second-line setting, findings from the phase 3 MARIPOSA-2 study (NCT04988295) showed that patients who received amivantamab plus chemotherapy (n = 131) following disease progression on osimertinib experienced a numerical OS benefit compared with those who received chemotherapy alone (n = 263; HR, 0.73; 95% CI, 0.54-0.99; P = .039).10 The 18-month OS rates were 50% (95% CI, 40%-59%) and 40% (95% CI, 33%-46%), respectively.
“If I start with the FLAURA2 [regimen], I’m going to be less enthusiastic about using the COMPEL [regimen] in the second line,” Yu said. “As much as we say that amivantamab is a hard drug, when you’re adding it to chemotherapy, I find that it is somewhat better tolerated than with a TKI. The dexamethasone premedication can help with the infusion reaction and some of the toxicities. I am also comfortable with lowering the dose for toxicity. This regimen has surprised me in being reasonably well tolerated in the second line.”
References
- 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.
- Santos ES, Patel T, Divers S, et al. Real-world treatment of osimertinib monotherapy versus combination therapy in stage IV non-small cell lung cancer patients.Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract P3.12.24.
- Seeger R, Stacey D, Bossio E, Wheatley-Price P. Demographic influences on treatment preferences in advanced EGFR+ mNSCLC: a qualitative analysis of patient perspectives on osimertinib. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract EP.12.25.
- 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. Overall survival with amivantamab-lazertinib in EGFR-mutated advanced NSCLC. N Engl J Med. Published online September 7, 2025. doi:10.1056/NEJMoa2503001
- Resuli B, Kauffmann-Guerrero D, Mertsch P, et al. Redefining tolerability: a head-to-head IPD toxicity comparison of amivantamab+lazertinib vs osimertinib+chemotherapy in EGFR-mutant NSCLC. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract P3.12.67.
- Cho BC, Li W, Spira AI, et al. Enhanced vs standard dermatologic management with amivantamab-lazertinib in EGFRm advanced NSCLC: the COCOON global RCT. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract P3.12.46.
- Pasello G, Zhao J, Tufman A, et al. COMPEL: osimertinib + platinum-based chemotherapy in patients with EGFRm advanced NSCLC and progression on 1L osimertinib. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract OA08.03.
- Popat S, Reckamp KL, Califano R, et al. Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutated, advanced non-small cell lung cancer after disease progression on osimertinib: second interim overall survival from MARIPOSA-2. Ann Oncol. 2024;35(suppl 2):S1244-S1245. doi:10.1016/j.annonc.2024.08.2296