Surveying the Treatment Landscape for EGFR-Mutated Lung Cancer

Girindra Raval, MD

Medical College of Georgia

Numerous studies have redefined the treatment paradigm for patients with EGFR-mutated lung cancers, according to Girindra Raval, MD, associate professor of the Department of Medicine: Hematology and Oncology at the Medical College of Georgia at Augusta University.

In a discussion with CancerNetwork®, he outlined the evolution of therapies for patients undergoing treatment for diseases expressing this mutational status. Additionally, he highlighted key toxicities observed with standard-of-care treatment for these patients, as well as strategies for managing or mitigating them and for preserving quality of life.

Raval also discussed ongoing trials the Georgia Cancer Center he is involved with, highlighting both retrospective and interventional trials aiming to ascertain the impact of emerging and established modalities on patient outcomes. He concluded by touching upon his considerations for the future of the EGFR-mutated lung cancer landscape, emphasizing the importance of the effective sequencing of therapies given a vastness of available therapies.

CancerNetwork: How have treatment options for patients with EGFR-mutated lung cancer evolved over time, and what specific agents appear most promising in the treatment of this population?

Raval: The landscape of EGFR-mutated NSCLC—or adenocarcinoma, specifically—has evolved significantly over the last few years. We are seeing the whole evolution start from first-generation EGFR inhibitors [like] erlotinib [Tarceva] and gefitinib [Iressa] to the more recent osimertinib [Tagrisso], which was [assessed in the phase 3] FLAURA trial [NCT02296125] for the metastatic setting.1 We are also now seeing the [phase 3] FLAURA2 trial [NCT04035486] data, which is combining osimertinib with chemotherapy.2

There are the [phase 3] MARIPOSA trial [NCT04487080] data, which is combining amivantamab-vmjw (Rybrevant) and lazertinib (Lazcluze).3 Recently, there were data about datopotamab deruxtecan-dlnk [Datroway; dato-DXd] based on the TROPION-Lung studies in that same space, which is another tool that we now have for treatment of EGFR-mutated lung cancer in the metastatic setting.4

On the early-stage cancer side, we are awaiting results of the [phase 3] NeoADAURA trial [NCT04351555] in the neoadjuvant setting.5 We have the results of the [phase 3] ADAURA trial [NCT02511106], which showed an overall survival (OS) benefit in the adjuvant setting, and we have results of the [phase 3] LAURA study [NCT03521154], which showed efficacy of osimertinib after chemoradiation.6,7 A lot has happened in that space, and many trials are still ongoing. We have trials that we will talk about, hopefully, on where the field can go to eventually, but it is an exciting time, and a lot of things have moved in that space.

What are some notable toxicities that may occur during treatment for those with EGFR-mutated lung cancer? What are some best practices for mitigating these toxicities and protecting patient quality of life?

Let me start with the common one that we encounter most of the time, which is [with] osimertinib. We essentially use osimertinib as [a] backbone right now. It has been that way for most EGFR-mutated cancers, be it early- or late-stage [disease]. The toxicities we face most often with osimertinib are skin toxicities; we [advise] patients [to] be on the lookout for those. We are careful in ensuring that the patients have adequate heart [and] lung function, and we monitor their echocardiograms and their EKGs on a regular basis while they are on treatment with osimertinib.

We also have a high index of suspicion to be on the lookout for a rare but more serious toxicity, which is interstitial lung disease [ILD]. In my clinic, we practice what is called a “distance to dyspnea,” a metric where, before we start patients on osimertinib, we try to get them to walk a certain distance and make sure that they are not out of breath. And then we try to replicate that on subsequent clinical interactions to make sure that distance to dyspnea has not decreased. These are some subtle changes that can then trigger us to look for ILD or pneumonitis toxicities from osimertinib.

Then, we have amivantamab and lazertinib, which has now been approved as a frontline [therapy] for EGFR-mutated NSCLC in the metastatic setting, based on the MARIPOSA study. [Many] toxicities are mainly from infusion of amivantamab. We also see patients develop edema and swelling in the legs. [They also] developed skin toxicities and cytopenias in the amivantamab/lazertinib arm [of MARIPOSA and] in the FLAURA2 trial, where patients were receiving chemotherapy with osimertinib.

We tell most of our patients who are on chemotherapy [to not] expose themselves to infections, especially during the time when the [blood] counts are at the nadir. With amivantamab, there are specific SKIPPirr protocols where we try to premedicate patients with dexamethasone 2 days prior, a day prior, and an hour prior to giving the infusion. There are also protocols in place to decrease skin toxicities: sunscreens; avoiding sun exposure to the extent possible, if that is triggering the skin rash; and topical steroids.

These are some common [adverse] effects. This list is by no means exhaustive. We could be talking a lot more about these toxicities and the prevention thereof. One main toxicity [with] MET inhibition…is leg swelling and edema. We try to encourage our patients, when they develop the toxicity, to elevate their legs to decrease the swelling. Also, compression stockings go a long way. In rare cases, if they are refractory to these interventions, we get them on furosemide [Lasix] to see if that helps.

Regarding your campus and your group, what kinds of perioperative chemotherapy approaches may have a role in the treatment of patients with lung cancer?

That [is] a 2-part question. There are data for neoadjuvant osimertinib; hopefully, we will get the results read out soon with the NeoADAURA trial. There’s a category 1 recommendation for adjuvant osimertinib based on the ADAURA trial. Then, there are the ALK inhibitors, where we have data on adjuvant alectinib [Alecensa] based on the [phase 3] ALINA trial [NCT03456076] that was done recently.8 There are other trials underway in the early-stage setting with patients who have RET mutations, ROS1 mutations, and exon 20 insertion mutations as well; we are waiting for the results of those trials to be read out.

For patients who do not have targets, there is a plethora of data based on the [phase 3] KEYNOTE-671, CheckMate 77T, and AEGEAN studies [NCT03425643, NCT04025879, NCT03800134] about the use of perioperative immunotherapy in this space.9-11 We have been early adopters, thanks to our coordination with our surgical colleagues, to get these patients on the right therapy from the get-go. That usually translates, at our institution, with the [regimen from the] neoadjuvant [phase 3] CheckMate 816 trial [NCT02998528], which has shown an OS benefit after 3 to 4 cycles of neoadjuvant treatment.12 There, we have good data that if the patients develop a complete response [CR], they do not need any adjuvant immunotherapy afterwards.

Most of the trials and most of the therapy that we give now, based on the state of the field, are tailored according to what we find at the time of surgery, after the patients have received neoadjuvant chemoimmunotherapy. These patients would then, if they have developed a [pathological] CR, probably not benefit from receiving any further adjuvant treatment. If they did not, there is a role for continuing nivolumab [Opdivo], pembrolizumab [Keytruda], or durvalumab [Imfinzi] based on the trials that we have read out so far.

What kinds of clinical trials or research are you involved with here at Georgia Cancer Center, and how might these initiatives help improve patient outcomes?

The research we have going on can be classified under 2 sections. One is the intervention arm, where we are trying to talk about new drugs [and] molecules that are in development, and see how they can impact and move the needle on the state of cancer treatment for lung cancer. The other trials that we have are what we are calling retrospective trials, where we are looking back at our own data to see where we can optimize treatment for these [patients with] cancer. In that category, we have trials that are looking at the impact of the patient‘s ethnicity, demographics, zip code, and their distance from our cancer center [on] their overall outcomes. [These trials] can be used to then tailor patients’ treatments or patient recommendations to improve their outcomes.

The other trials that we have ongoing are the trials that are based on the effect of radiation in combination with maintenance therapy in metastatic NSCLC. We are trying to see if local therapy with radiation can improve the outcomes in patients who are already on maintenance therapy [for] metastatic lung cancer. There‘s also a trial that we recently completed about the role of biomarker-driven treatment in patients with small cell lung cancer, where [those] with Schlafen 11 [SLFN11] were given a PARP inhibitor to see if that improves outcomes [in extensive-stage disease].

We are also part of the study that is looking at molecules to augment the effect of immunotherapy by combining them with interleukin [IL] or pegylated interleukin [PEG-IL]. We are also looking at trials that are using tumor-infiltrating lymphocytes [TILs] to see if they can improve their efficacy in second-, third-, or even further lines of treatment down. We are in the process of trying to get trials that [may] address the role of adjuvant immunotherapy after the patient has received neoadjuvant immunotherapy. These are parts of the cooperative group trials: the SWOG and ECOG [trials].

We have trials that are retrospective, and we have trials that are looking at brain metastases and the importance of imaging to evaluate how the PD-L1 status affects imaging in patients with brain metastases [who have] lung cancer. We have a retrospective trial looking at social determinants of health, trials that are looking at combining targeted therapies, [and trials] combining…other molecules that can augment the effect of immunotherapy in the metastatic and early-stage settings. We are looking at novel therapies [such as] TILs to see if those can move the needle on cancer treatment.

When you look towards the future, where does the field as a whole need to head to further improve outcomes for patients with EGFR-mutated lung cancer or other cancer populations?

Thankfully, we have many treatments that have come to the forefront that have shown OS data. We have the [FLAURA2, MARIPOSA, and FLAURA1 regimens]. We have the PFS data from the TROPION-Lung studies [with] dato-DXd, and we have some other ongoing trials, like the HARMONi [trials] looking at patients who had bispecific VEGF and PD-L1 inhibition, to see if those will be impactful in patients with EGFR-mutated lung cancer.13 We also have some data that was read out at the 2025 European Society for Medical Oncology (ESMO) Congress about patients who received sacituzumab govitecan-hziy [Trodelvy] for lung cancer.

We have a problem of plenty, in some ways. We have many trials in this space that are vying for attention, and it’s [quite] difficult to then figure out on which niche should these patients be treated, or which patient should be treated with which frontline treatment. The bigger question now that I can see in the field is about sequencing: “What would you start with? Who do you escalate the treatment in?” More specifically, “In who do you deescalate, where you see that there is no advantage of adding the other component of the therapy?” The future in EGFR-mutated lung cancer would be about sequencing, and in what sequence you start and what sequence you would give treatment to these patients.

References

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2. Jänne PA, Planchard D, Kobayashi K, et al. Survival with osimertinib plus chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. Published October 17, 2025. doi:10.1056/NEJMoa2510308
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4. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. News release. FDA. June 23, 2025. Accessed December 3, 2025. https://tinyurl.com/mvtyhnjf
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13. Ivonescimab plus chemotherapy demonstrates consistent global benefit: HARMONi data update shows OS HR=0.78, nominal P=0.0332. News release. Akeso, Inc. September 7, 2025. Accessed December 3, 2025. https://tinyurl.com/32msamur