Explicating Early-Line Treatment Considerations for EGFR-Mutant NSCLC

Following the approval of dato-DXd in untreated EGFR-mutant NSCLC, Jacob Sands, MD, discussed next steps for improving outcomes for this disease.

In a discussion with CancerNetwork®, Jacob Sands, MD, assistant professor of Medicine at Harvard Medical School, thoracic oncologist at the Dana-Farber Cancer Institute, and investigator of the phase 2 TROPION-Lung05 trial (NCT04484142) and phase 3 TROPION-Lung01 trial (NCT04656652), which supported the accelerated approval of datopotamab deruxtecan-dlnk (dato-DXd; Datroway) in pretreated EGFR-mutant metastatic NSCLC in June 2025, discussed safety and efficacy considerations for the agent’s use.1,2

He began by outlining a combined cohort of the TROPION-Lung05 and TROPION-Lung01 trials, which collectively showed an efficacy benefit with dato-DXd in patients with EGFR-mutant disease vs docetaxel.3 Furthermore, Sands highlighted the most common toxicities observed with dato-DXd in this population, which included stomatitis, interstitial lung disease (ILD), and ocular toxicities, as well as management strategies to mitigate their incidence and severity.

Sands concluded by highlighting next steps for research in this disease state, including the phase 2 ORCHARD trial (NCT03944772) evaluating dato-DXd with osimertinib (Tagrisso) in the second-line setting after progression on osimertinib and the phase 3 TROPION-Lung15 trial (NCT06417814), which is evaluating chemotherapy against dato-DXd alone or with osimertinib.4,5

CancerNetwork: What does the accelerated approval of dato-DXd mean for patients who received prior EGFR-directed therapy as well as platinum-based chemotherapy?

Sands: This is another treatment option for patients [and] a new one as well. Patients who have [received] prior EGFR TKI and prior chemotherapy, the standard of care, are then looking at next-line docetaxel. We have a randomized trial of dato-DXd vs docetaxel in all comers [for NSCLC]. This included squamous cell carcinoma, nonsquamous [disease] without actionable genomic alterations, as well as those with actionable genomic alterations beyond EGFR mutations. [A total of] 17% of patients that enrolled on that trial had tumors with actionable genomic alterations, and that is where we saw the greatest benefit.

To speak broadly about TROPION-Lung01, in the squamous cohort, we saw that dato-DXd underperformed [vs] docetaxel. In the nonsquamous cohort, we saw statistically significant improvement in PFS; we saw a trend of improvement in OS that matches the PFS benefit but did not reach statistical significance, meaning that the confidence interval crossed 1. In that group of those with actionable genomic alterations, that OS trend was much bigger. Amongst those in the actionable genomic alteration cohort, the EGFR-mutated [subgroup] represented the majority.

TROPION-Lung05 was a study that was similar. It was a single-arm trial, but patients who had previously [received] targeted therapy and platinum-based chemotherapy then ended up [receiving] dato-DXd. Only [patients with] tumors with actionable genomic alterations [were] enrolled. Again, the piece of the pie that was the biggest was the one of EGFR-mutated [disease], and the EGFR-mutated group did look better even than the ALK-rearranged group as well.

I know the focus is the EGFR group, per the recent FDA approval. We have a cohort of essentially combining all EGFR mutant subgroups from TROPION-Lung01 as well as TROPION-Lung05, and within that, we see a median [PFS] benefit of 5.8 months and a median [OS] of 15.6 months. As far as how it compares to docetaxel, I would say it compares favorably.

There are nuances to discuss, but overall, beating docetaxel on toxicity is not necessarily a high bar. As we look for opportunities to treat with something other than docetaxel, this represents a good option. After this, patients can then later go on to receive docetaxel at progression and other chemotherapy regimens that are important to consider, but this does represent an important third-line consideration as a treatment option.

Are there any particular toxicities associated with dato-DXd that clinicians should be aware of? What are some best practices for mitigating them?

Sands: I would highlight 3 in particular, one being stomatitis. Stomatitis, or mucositis, was common. Many were grade 1, which is asymptomatic.

There are ways of potentially trying to limit stomatitis or to treat it. One is for prophylaxis with steroid mouth rinses. This was implemented within the protocols, but it was at the tail end. The number of stomatitis [cases] within the data are not [reflective of using] steroid mouth rinses….Also, ice chips at the time of infusion to reduce the amount of flow to the mucous membranes may be helpful; it’s also for comfort if patients experience stomatitis. [Regarding] oral hygiene, using soft bristle brushes, brushing teeth well, maintaining good oral hygiene, [and] limiting spicy foods and alcohol can potentially be helpful. This is all still an area of ongoing work.

In dosing dato-DXd, I would want to see resolution of stomatitis before giving the next dose. In many cases, it is resolved by the time they get to the next dose anyway. You can redose and see how patients do. If they get severe stomatitis, or if you are having to delay dosing, then dose reductions can be considered.

Another one is ocular surface toxicities. Symptomatically or clinically, the way that it appears is more like dry eyes. I am saying like dry eyes because we have [not] yet defined the mechanism of what’s going on. I would say, clinically, it’s similar to what I see for patients receiving pemetrexed who have eye irritation. I recommend that they use preservative-free lubricating eye drops and that they see ophthalmology because we do not yet know entirely what is going on. They do need corneal exams in that setting.

The FDA approval suggests or recommends getting a baseline ophthalmology evaluation. Realistically, I know that there are sometimes delays in seeing ophthalmology, and I would not delay someone’s treatment because of that….If patients have changes in vision or beefy red eyes…those patients need urgent or emergent evaluation by ophthalmology. I have not seen that. Generally speaking, a referral saying, “Hey, I am going to start them on some preservative-free lubricating eye drops,” as long as they are seen in the next month, is fine, but they do need an evaluation by ophthalmology to look for something else.

The third is ILD. ILD is something we have seen with all the deruxtecan payload antibody drug conjugates: dato-DXd [for] TROP2, patritumab deruxtecan for HER3, ifinatamab deruxtecan for B7-H3, and trastuzumab deruxtecan (Enhertu) for HER2. With dato-DXd in the EGFR-mutant population, with the combined analysis from TROPION-Lung01 and TROPION-Lung05, there were 5 patients, or 4%, that had adjudicated drug-related ILD. There was 1 grade 3 event, although we have to highlight that in other populations on Dato-DXd—not the cohort with EGFR mutations specifically—there are others that have had an adjudicated grade 5 ILD. There’s a lot of attention to recognizing ILD to treat it early.

I would also highlight that understanding what [is] drug-related ILD can be challenging. If you see a classic [case]––bilateral lungs, multiple areas of inflammatory findings, shortness of breath––that’s highly concerning and needs to be treated immediately; hold [the] drug. Deciphering what’s truly a drug-related ILD or not is something that can be challenging. Deciphering who you are holding drugs [for], giving steroids, and monitoring for improvement before starting [treatment] is something that needs to be considered.

It’s encouraging that there were no grade 5 [events], but we need to be attentive that there were others that did have worse [toxicity], so this is another [toxicity to monitor]. Fortunately, these are low numbers, but in the setting of treating multiple patients, those percentages get higher [for] an oncologist seeing a patient that has ILD and even worsening ILD. I would also highlight that although we look attentively and closely to try and monitor for catching ILD early, if there’s a patient that you see who may have a drug-related ILD, it’s important to then consider what other things might be going on so that you rule out or catch anything else that could potentially be happening.

There are other toxicities that can be seen, but those 3 are unique. This is not the only drug that causes those, but stomatitis [and] mucositis are a bit higher in percentage than what we see in some of the other regimens. Ocular surface toxicity is similar to what we see from pemetrexed in clinical experience, but there might be something more going on to that, and we need to be attentive to that. The ILD has low numbers, but the fact that there have been grade 5 [instances] in other cohorts makes this something that we need to be attentive to.

What are the next steps for researching dato-DXd or improving outcomes among those with EGFR-mutated NSCLC?

Sands: There’s still a lot of work ongoing around dato-DXd in the EGFR space and beyond. In the EGFR space, we have the [phase 2] ORCHARD data, which was looking at a combination of dato-DXd at 2 different dose levels combined with osimertinib, and those data have been quite encouraging. That’s in the second line after progression on osimertinib alone. We [also] have a randomized trial in the second-line setting, TROPION-Lung15, which is after progression on osimertinib. [Patients received] either chemotherapy, dato-DXd alone, or dato-DXd plus osimertinib; a 3-arm randomized trial. We also have a first-line trial of osimertinib or osimertinib plus dato-DXd as well.

In the EGFR space, [you have] ongoing studies [in the] first line and second line after osimertinib alone, and they will add to the already complex picture….There’s a lot of data still to come out.

What should others take away from this conversation?

Sands: As the medical community gains more experience using this drug, they will find that these [toxicities] are more manageable than on paper. That’s not to say there are not concerns. These are things to be attentive to and to manage, but it then provides patients with the efficacy benefit from the drug as well. There are people that go well beyond what we see on the median, like any drug that we give, and I have seen patients go [on to have] 2 years of benefit with ongoing disease control that are still working and active in their lives. The toxicity profile for [this] subset of patients can be more severe, and doses need to be reduced or potentially even stopped.

Thankfully, those are low numbers, and there are people on the other end of the spectrum who carry on without much in the way of toxicities and [can] carry on with their lives and [experience] real durability from this. The experience, like any of these drugs, is quite broad. I specify that because we oftentimes discuss the medians. Sometimes, I see the discussion steered as if everyone is experiencing that median. It’s quite broad, and this represents an important consideration for patients.

References

1. Sands J, Ahn MJ, Lisberg A, et al. Datopotamab deruxtecan in advanced or metastatic non-small cell lung cancer with actionable genomic alterations: results from the phase II TROPION-Lung05 study. J Clin Oncol. Published online January 6, 2025. doi:10.1200/JCO-24-01349
2. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. News release. FDA. June 23, 2025. Accessed July 29, 2025. https://tinyurl.com/mtay7ab9
3. Ahn MJ, Tanaka K, Paz-Ares L, et al. Datopotamab deruxtecan versus docetaxel for previously treated advanced or metastatic non-small cell lung cancer: the randomized, open-label phase III TROPION-Lung01 study. J Clin Oncol. Published online September 9, 2024. doi:10.1200/JCO-24-01544
4. Yu HA, Goldberg SB, Le X, et al. Biomarker-directed phase II platform study in patients with EGFR sensitizing mutation-positive advanced/metastatic non-small cell lung cancer whose disease has progressed on first-line osimertinib therapy (ORCHARD). Clin Lung Cancer. 2021;22(6):601-606. doi:10.1016/j.cllc.2021.06.006
5. A study to investigate the efficacy and safety of dato-DXd with or without osimertinib compared with platinum based doublet chemotherapy in participants with EGFR-mutated locally advanced or metastatic non-small cell lung cancer (TROPION-Lung15). ClinicalTrials.gov. Updated July 16, 2025. Accessed July 29, 2025. https://tinyurl.com/56z3dmsp