Interview Summary
The introduction of third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) significantly improved outcomes for people with EGFR-mutant advanced non-small cell lung cancer (aNSCLC). Yet, unmet needs, most notably acquired TKI resistance and central nervous system metastasis, persist. Moreover, 25–30% of patients die before they reach a second-line treatment. Recent advances in the health community’s understanding of the mechanisms of resistance, however, have led to intensification strategies that are reshaping the treatment landscape.INTRODUCTION
EGFR-sensitising mutations are detected in 10–15% of aNSCLC cases in Western countries.1 Together, exon 19 deletions and exon 21 L858R mutations account for the majority of EGFR alterations.1 Patients tend to be light or never smokers, and have adenocarcinoma histology.2 Califano explained that EGFR-positive NSCLC is a heterogeneous disease that is “very prone to spread to the brain”.2,3 “Not uncommonly, people with EGFR-positive NSCLC will present with neurological symptoms related to brain metastasis,” he said, adding that these patients, along with those with liver metastasis at baseline, or TP53 co-mutation, have the poorest outcomes among all patients with aNSCLC.3,4,5
Despite the advances of recent years, most notably the introduction of EGFR-TKIs,6 “there are still a number of unmet needs”. These include addressing the central nervous system (CNS) involvement and overcoming the “intrinsic resistance which we see with some of the specific mutations,” said Califano.2
Until recently, Califano explained, the standard first-line treatment was the third-generation EGFR-TKI, osimertinib. Despite it being “a very effective drug”, the progression-free survival (PFS) is only around 19 months, he said.1 “The disease, which was initially responding to the TKI, starts to grow. This results in increased morbidity, and often we see rapid CNS progression.” In addition, real-world data suggest that up to 30% of patients treated with a TKI at first line, as a single agent, will not receive second-line therapy.7 “There’s a substantial attrition rate from first to second line, and a need to intensify first line strategies.”
EGFR-mutant lung cancer is a rapidly evolving disease landscape. Given that unmet needs remain, different strategies to intensify the first-line treatment have emerged. One option is to add chemotherapy to the standard of care, osimertinib. Another is the novel combination treatment amivantamab plus lazertinib, which was approved in 2024 in the USA and in 2025 in Europe and in the UK.8-10 In addition, a wealth of data presented at the recent 2025 European Lung Cancer Congress (ELCC) point to a promising pipeline.11-15
A growing understanding of the mechanisms of acquired resistance, which often drives disease progression, is paving the way for personalised management that may improve patient outcomes. It is also presenting clinicians with new questions and considerations, such as how best to monitor disease activity or choose the most appropriate treatment regimen.
ACQUIRED RESISTANCE TO EGFR-TYROSINE KINASE INHIBITORS
EGFR-TKIs are molecules that bind to the adenosine triphosphate (ATP) binding domain of the EGFR protein, thereby interrupting the downstream signalling pathway.1 They have significantly improved outcomes, yet, even with third-generation options, the majority of patients will eventually develop disease progression due to acquired resistance.16
MECHANISMS OF RESISTANCE
“For patients who have been exposed to osimertinib, we have a wealth of evidence that demonstrates the most common mechanisms of resistance,” said Califano. These can “be roughly divided” into two categories: EGFR-dependent, or on target, and EGFR-independent, or off target. “The EGFR-dependent mechanisms of resistance are the presence of secondary EGFR mutations, mostly C797S. The most common non-EGFR-dependent mechanism is mesenchymal-epidermal transition factor (MET) amplification, though there may also be KRAS activation, ALK fusion, or BRAF mutations. In addition, “we see transformation into squamous cell carcinoma or small cell lung cancer,” explained Califano.1
Growing understanding of the underlying mechanism of disease and the drive to tackle unmet needs have led to the development of new approaches. Intensification strategies, for example, aim to enhance the effectiveness of EGFR-targeted therapies by combining TKIs with other therapies or agents.17,18
The FLAURA2 trial, for example, compared osimertinib alone to osimertinib plus chemotherapy as first-line treatment in EGFR-mutated (exon 19 deletion or exon 21 L858R) locally advanced or metastatic NSCLC.17 In the study, osimertinib plus chemotherapy improved PFS to 25.5 months compared to 16.7 months with osimertinib alone (p<0.001). There was consistent benefit across subgroups, including patients with CNS metastatic disease.17 The MARIPOSA study compared the chemotherapy-free regimen of amivantamab, a dual MET and EGFR inhibitor, plus lazertinib, a third-generation EGFR-TKI, to osimertinib in locally advanced or metastatic NSCLC with common EGFR mutations (exon 19 deletion or exon 21 L858R). The median progression-free survival (PFS), the primary study endpoint, was significantly longer in the amivantamab plus lazertinib group than in the osimertinib group (23.7 versus 16.6 months; p<0.001).18 “This was consistent across high-risk subgroups, such as CNS or liver metastasis at baseline, or TP53 co-mutation,” said Califano.
Final survival analysis from the MARIPOSA trial, presented at ELCC 2025, showed an overall survival (OS) advantage favouring amivantamab plus lazertinib, with a hazard ratio of 0.75, at a median follow-up of 37.8 months (p<0.005).19 “The median has not been reached, but there’s a projected advantage of at least 1 year for amivantamab plus lazertinib compared to osimertinib,” said Califano, adding that this was the first time an intensification strategy had demonstrated an OS benefit over single agent osimertinib in EGFR-mutant disease.19 “Together with the benefit in high-risk subgroups for PFS, this is practice changing,” said Califano.
EMERGING STRATEGIES
Further strategies for second-line treatments are also emerging. The MARIPOSA-2 Phase III trial, for example, compared chemotherapy (carboplatin/pemetrexed) to amivantamab plus chemotherapy (ami-chemo) and amivantamab plus lazertinib and chemotherapy (ami-lazer-chemo). Participants were patients with EGFR exon 19 deletions or exon 21 L858R mutations whose tumours had progressed on osimertinib. “Primary results showed improved PFS and overall response rate in the ami-chemo and ami-laze plus chemotherapy arms compared to those receiving chemotherapy alone,” said Califano. “The PFS benefit was consistent across subgroups, including patients with brain metastases, the number of prior lines of therapy, and EGFR mutation types.” Intracranial PFS also improved in the amivantamab-containing arms, and was consistent across subgroups with brain metastases at baseline, he added.20
At a median follow-up of 18.1 months, OS was numerically improved for ami–chemo versus chemotherapy, but did not reach the prespecified significance threshold: 50% of patients receiving ami-chemo were alive at 18 months compared to 40% on chemotherapy.20 On the basis of the MARIPOSA-2 trial, carboplatin/pemetrexed plus amivantamab is now approved by the U.S FDA and EMA as a second-line option.21,22
The pipeline looks promising, as demonstrated by a number of studies reported at ELCC 2025. Savolitinib, for example, is a highly selective MET-TKI that, when combined with osimertinib, may overcome acquired MET-driven resistance. In the Phase II SAVANNAH trial, which included patients with aNSCLC with MET overexpression and/or amplification following progression on osimertinib, savolitinib plus osimertinib was well tolerated and “demonstrated clinically meaningful and durable response”.15 The savolitinib plus osimertinib combination is now under investigation in the Phase III SAFFRON study (NCT05261399).23 Researchers also presented the latest data from the first-in-human study of osimertinib plus datopotamab deruxtecan (Dato-DXd), which formed part of the ORCHARD study.24 Dato-DXd is a TROP2-directed antibody-drug conjugate, recently granted U.S FDA breakthrough therapy designation for patients with pre-treated EGFR-mutant aNSCLC.25 Osimertinib plus Dato-DXd showed promising efficacy and a manageable safety profile in patients who had progressed on osimertinib alone, and further data are awaited.25
MONITORING TOOLS
Monitoring tools are another hot topic of debate in the EGFR-mutated aNSCLC arena. Mechanisms of resistance can only be detected if patients with progressive disease are adequately monitored, explained Califano, adding that it is also important to identify high-risk groups, such as those with brain or liver metastasis at baseline, or TP53 co-mutation.
Imaging is vital. Many patients will have CNS metastasis at baseline, yet “a significant proportion” will have asymptomatic disease, said Califano. “It is very important that we understand whether we are dealing with CNS metastatic disease at the outset, because this group has a worse prognosis. Therefore, it is even more important to have an effective first-line strategy,” Califano explained. Current European Society for Medical Oncology (ESMO) guidelines recommend brain imaging at baseline for all patients. In the presence of brain involvement, scans and re-grading of extra-cranial disease should be repeated every 3 months. In the absence of brain involvement, 6-monthly scans are advised.26 This is important as some patients may be eligible to stay on first line therapy, and also receive local therapy, such as stereotactic surgery, Califano added.
During follow up, tissue biopsy is particularly relevant for detecting transformations, which may indicate the need for “a different kind of chemotherapy regimen”, whereas molecular iterations are important “because they may steer patients into a clinical trial with the appropriately targeted therapy”, said Califano. While tissue biopsy is the current standard for lung cancer genotyping and detection of resistance mechanisms, it is obtained by invasive methods and provides only small amounts of DNA. It provides a snapshot of the disease that does not fully reflect the tumour’s temporal and spatial heterogeneity.27 In addition, said Califano, re-biopsy is not always feasible, in the case of brain involvement, for example. Plasma testing, he went on, can identify circulating EGFR mutations, and aid with prognosis.28 Califano explained, “This means the tumours are shedding quite a lot of tumour cells in the plasma. When you have a high level of circulating tumour-DNA (ctDNA) showing an EGFR mutation, we know the tumour is more aggressive.” Liquid biopsies have limitations in everyday practice, as current assays lack sensitivity in early disease, though the technology is advancing rapidly.28
“I think we need to become more proactive, potentially using ctDNA to detect molecular resistance early, at minimal residual disease, even before we see it clinically on a scan,” said Califano. Such approaches, while not ready for routine practice, are being investigated in clinical trials, he added. “If we were able to pick up resistance at a molecular level, this would allow for timely treatment modification. Sometimes, when you have new symptoms, or a scan showing a massive increase in the size of the cancer lesion, the patient may not be well enough for what comes next.”
MANAGING SIDE EFFECTS
From what we have seen, we are “moving towards earlier intensification strategies”, Califano said, adding that, “realistically”, the choice is between the two currently approved options: the FLAURA2 (osimertinib + chemotherapy) and the MARIPOSA (amivantamab + lazertinib) regimens.
The first consideration, Califano believes, should be patient preference on their tolerance of side effects. “Chemotherapy plus osimertinib and amivantamab plus lazertinib are better regimens when compared to standard single agent osimertinib, but these intensification strategies come at a price,” Califano said. While osimertinib is “usually well tolerated”, the FLAURA2 regimen adds potential chemotherapy side effects. In the FLAURA2 trial, 128 (46%) of those treated with osimertinib and chemotherapy experienced anaemia, 120 (43%) experienced diarrhoea, and 119 (43%) experienced nausea. A total of 68 (25%) developed neutropenia, and 51 (18%) developed thrombocytopenia.17
In the MARIPOSA trial, common adverse events included nail toxicity, experienced by 288 of 421 patients (68%), infusion-related reactions, seen in 265 patients (63%), and rash, which was recorded in 260 (62%), Califano went on. A total of 73 patients (17%) experienced pulmonary embolism during the study, in which anticoagulation was not mandated.9 However, said Califano, many of these events are “potentially manageable and preventable”. “We know that patients on amivantamab plus lazertinib should have at least 4 months of prophylactic anticoagulation, which dramatically reduces the risk of thromboembolic events,” he said.29 The prophylactic COCOON dermatological management regimen, consisting of antibiotics, a nail cleaning agent, and long-acting skin moisturisation has been shown to reduce both Grade ≥2 and ≥3 dermatological adverse events by 50% when compared with standard-of-care dermatologic management.30 The SKIPPirr regimen of 2 days of additional oral steroids ahead of the first amivantamab infusion has been shown to reduce the risk of infusion-related reactions, with no severe reactions (Grade ≥3) being reported during the trial.31 In addition, subcutaneous amivantamab, which reduced administration-related reactions and demonstrated non-inferior exposure pharmacokinetics and efficacy to the intravenous formulation in the PALOMA-3 study,13 was approved by the European Commission in April 2025.32 Initial findings from the PALOMA-2 study, presented at ELCC 2025, suggest that switching from IV to SC amivantamab is feasible and well tolerated.13
PATIENT EDUCATION
Patient education is critical for several reasons, said Califano. It can aid with adherence to treatment, as well as help to ensure the timely reporting of treatment side effects. “We need to educate the patients; to explain the rationale for choosing that strategy. It is important to talk to the patient about the need for re-biopsy or re-liquid biopsy early on, so that it doesn’t come as a shock or upset them when it is needed.” He added, “As doctors, we are educators of our patients, and the more informed they are about what’s available to them, the better able they will be to ask relevant questions.”
Explaining the OS,19 as well as the PFS,18 which quantify the benefits of the chosen first-line intensified treatment option is important “both clinically and emotionally”, he said. Continued monitoring, he reiterated, also plays a huge role in ongoing personalised care. “There are a number of research streams that are looking at potential ways of overcoming resistance, so it is very important that, after intensification strategies, we re-biopsy to see how the biology of the tumour has changed. Then you can select the most appropriate strategy going forward.”
THE FUTURE OF EGFR CARE
At the moment, we are “shooting all bullets at everyone”, but we are moving towards more personalised care. “From a research point of view, we are developing strategies to prevent or manage the acquired resistance. We need a more tailored treatment approach to manage this heterogeneous disease, and, therefore, optimise long-term outcomes,” Califano said.
In the future, Califano believes ctDNA will “become routine in guiding the treatment algorithm”, alongside considerations around factors such as patient comorbidities, age, and frailty. “As the data mature, we should be able to refine how we select patients for different upfront combinations, but we’re not there yet. A lot is still ongoing, and a number of studies are due to read out.”
As more treatments and strategies become available, the “real challenge” for clinicians will be the optimal sequencing of post-intensification strategies. “At present, it is completely undefined. That is why we really need to continue to enrol patients into clinical trials and continue to collect real-world data because they are essential in guiding best practice,” concluded Califano.
