How Do Experts Think Dato-DXd Should Be Used in NSCLC?

Datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) was recently approved as a treatment for patients with EGFR-mutated non–small cell lung cancer (NSCLC) who received prior EGFR-directed therapy and platinum-based chemotherapy.¹ In the wake of this approval, experts seek to find the proper placement for Dato-DXd among different disease subpopulations in the treatment paradigm and how best to manage its toxicities.

CancerNetwork^® hosted an Around the Practice^® program, during which a panel of experts discussed all things Dato-DXd in NSCLC. The panel was led by Ana Velázquez Mañana, MD, MSc, FASCO,assistant professor of medicine at the University of California San Francisco (UCSF) and Matthew Gubens, MD, MS, FASCO, professor of medicine and medical director of thoracic medical oncology at UCSF. Fellow panel members were Akshiv Malhotra, MD, medical oncologist at UCSF-John Muir Health Center in Berkeley; Bogdan Eftimie, MD, hematologist/oncologist at UCSF-Washington Cancer Center in Fremont; Rebecca DeBoer, MD, MA, associate professor of medicine in the Division of Hematology/Oncology at UCSF and attending medical oncologist at Zuckerberg San Francisco General Hospital and Trauma Center; Gigi Chen, MD, hematologist/oncologist at John Muir Health; Cindy Ludovico, NP, nurse practitioner at UCSF; Malti Sharma, NP, nurse practitioner at UCSF; Alan Chin, PharmD, BCOP, pharmacist at UCSF; Howard J. Lee, MD, hematologist/oncologist at UCSF in San Mateo; and Carlo Legasto, PharmD, BCOP, thoracic oncology pharmacist at UCSF.

The Efficacy and Safety Data

Mañana / What are your different perspectives on this data from the phase 2 TROPION-Lung05 trial (NCT04484142), and what particularly stands out regarding the efficacy and safety of Dato-DXd in the EGFR-positive population compared with other options?

Chen / It’s a much better option than docetaxel, which would be our line of therapy if this were not approved in terms of efficacy, as well as in terms of the [adverse] effects. Docetaxel is very hard to tolerate for many reasons, with the edema and the neuropathy, and all that. I think the efficacy and the tolerability will be much better.

I had a patient who I was going to start [on Dato-DXd], but I haven’t had a chance to use it. For breast cancer and for other cancers, we use a lot of [fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu)], but I have not had a chance to use the Dato-DXd.

Lee / I was a fellow in a breast cancer clinic [during the phase 2 I-SPY trial (NCT01042379)]. The stomatitis was real for the patients. I had limited experience with it, as a fellow, but one thing that stood out to me was that I was always looking at the [interstitial lung disease (ILD)] pneumonitis because, especially for a lung cancer cohort compared with a breast cancer cohort, I expected there to be a much higher rate of ILD. At least, it wasn’t magnitudes higher. It seemed at least within the realm of reason to compare it with [patients with] breast cancer.

DeBoer / I agree that [Dato-DXd is given] after a patient with breast cancer has had [sacituzumab govitecan-hziy (Trodelvy)] and T-DXd. I haven’t had anybody who’s been eligible for another ADC [antibody-drug conjugate]. I have heard that using the steroid mouthwash prophylactically is important because it’s harder to catch up [to the stomatitis]; it’s much easier to prevent. The mouthwash doesn’t work as well once it starts. I’ve also heard mixed things about the cryotherapy and whether [my colleagues] think it does anything.

If we could use it earlier or…if it’s possible in the second line after the [phase 3 FLAURA2 trial (NCT04035486) regimen of osimertinib (Tagrisso) with chemotherapy], then it does seem tolerable with the mouthwash and appropriate dose reductions.

Ludovico / The one patient who we had on this drug was struggling with stomatitis; however, the steroid rinses did help control it. She was doing the ice chips, but she wasn’t sure if that was helpful or not.

Mañana / Which patients would you consider using Dato-DXd for, based on the data?

Chen / After first-line EGFR therapy, whether it’s [osimertinib] or [osimertinib] plus chemotherapy or [amivantamab-vmjw (Rybrevant)], we would get a molecular profile to see what the resistance pattern is. If you pick up a MET [mutation], would you then direct it that way vs if you don’t pick up something like a RAS [alteration]? Does Dato-DXd work better in that setting?

Chin / In terms of safety, with the stomatitis, just extrapolating from everolimus [Afinitor] in the breast setting, they’ve been using [dexamethasone] mouth rinses since 2017 or 2018. Now that we have incorporated the [Beacon treatment] plans, the only thing we’ve noticed from pharmacies is that a lot don’t standardly carry [the dexamethasone mouth rinse]. It takes some time for them to get it. For a patient with [gynecological disease] where we’re trying to get them a steroid mouth rinse, the patient got their everolimus way before their steroid mouth rinse—like a week before. They didn’t start their steroid mouth rinse until a week after everolimus was started.

Mañana / How is this being implemented in community settings?

DeBoer / I had that exact problem last week with [the] mouthwash not being available at Walgreens. That’s why I sent it to UCSF’s pharmacy.

Legasto / In terms of eye [adverse] effects, the [gynecologic] world has been seeing a lot of drugs such as disitamab vedotin, and it seems like the eye drops are doing a good job in terms of prophylaxis. Our patients have the same problem that you mentioned: It is difficult to get them seen [by ophthalmology] before their next cycle of therapy. It’s important, when you’re checking in with patients, to make sure that they’re not having significant visual changes or any pain with their eyes. Other than eye drops, I don’t know a lot about what the ophthalmologists are doing. In most cases, we’re just continuing therapy with possible dose modifications, etc. I don’t know if it’s the same with Dato-DXd, with the patients who had eye changes.

Mañana / That’s where education, as suggested, would come in handy. The oncologist in the room, would you feel comfortable making those decisions without an ophthalmologist seeing somebody [and you] prescribing steroid eye drops in the meantime?

Chen / It’s OK to prescribe the steroid eye drops, but you still want them to get seen in a timely manner.

Sharma / I’ve had good luck [contacting] ophthalmology. I refer to Bayfront Urgent Care [in San Francisco, California], and they will have the patients see ophthalmology the same day. I’ve had 2 or 3 [symptomatic] patients for whom it’s happened.

Sequencing Dato-DXd

Mañana / How would you sequence Dato-DXd in patients who have EGFR-mutated lung cancer?

Malhotra /If we can check the mechanism of resistance, that would be the first thing I would do. Based on that, if there’s no MET amplification and even though it is technically targeted chemotherapy, the other option is amivantamab. However, it is also quite toxic. We will discuss both options and have a discussion with the patient about [adverse] effects, and then make a decision together.

Chen / After [osimertinib] alone, it’s reasonable to introduce the chemotherapy. The question is whether you add chemotherapy to [osimertinib] or whether you switch to [amivantamab] plus chemotherapy. I would use one of those as a second line before switching to Dato-DXd.

Mañana / How about the patients who are now starting on a FLAURA2 regimen and are getting chemotherapy with osimertinib in the first line? We have approvals for more chemotherapy with amivantamab in the second line. Now, Dato-DXd has an open label including those 2 [agents].

DeBoer / The patient has started with first-line [osimertinib] plus chemotherapy, and they don’t have MET amplification. We don’t have data to compare second-line Dato-DXd with second-line [amivantamab] plus chemotherapy. I have very little experience with either for lung cancer. It seems like you’d have to do cross-trial comparisons with the toxicity data.

Eftimie / It looked as though the response of Dato-DXd in [patients who are] MET amplified was lower. My question is, if you find somebody who is MET amplified, do you treat them with a MET inhibitor? Would you still treat them with Dato-DXd, even though the response rates don’t seem that great?

Gubens / What else do you have to [treat the patient with]? To be a purist, even when you talk about [amivantamab] plus chemotherapy, that approval was in the chemotherapy-naive setting. It’s not a wrong assumption. To add to the complexity, a lot of people who do FLAURA2 stop chemotherapy before the end of their benefit. We saw a paper at [the World Conference on Lung Cancer] last week where the average patient on FLAURA2 had a progression-free survival [PFS] of 25 months, and the median patient only got 8 months of chemotherapy.² They’re not chemotherapy naive, but they also [have not had direct progression on chemotherapy]. I’m not sure what the right answer is.

Chen / For that individual, you may have to look at their PFS. It would be nice if [subcutaneous amivantamab] gets approved; then the [adverse] effects will be less. If somebody has a long PFS, then one might consider [amivantamab] plus chemotherapy as a second-line therapy and save Dato-DXd as a third-line therapy.

Mañana / What do we think [about treating] patients who may start [amivantamab and lazertinib (Lazcluze)] in the first line? How would that affect your decision-making in this puzzle of timing?

Lee / If I had started with [amivantamab plus lazertinib], I still gravitate toward using platinum doublet chemotherapy, maybe more out of familiarity, but also from the fact that the approval for Dato-DXd was in comparison with docetaxel. Maybe this is not completely evidence based, but I feel like I would gravitate toward platinum and then save Dato-DXd for the third line.

Mañana / We’re hearing that the burden of disease is one of those factors that you would [consider during your] decision- making. What other patient factors would you [investigate] at the time you’re making this decision?

Lee / Pemetrexed has some [central nervous system (CNS)] activity, but not many of the other chemotherapies really do. For the patient with the rare squamous [cancer] with an EGFR mutation, I might gravitate more toward Dato-DXd. I don’t have a great comparison of the exact magnitude of difference in intracranial response that I would expect from Dato-DXd, but that might be one thing that could push me more toward Dato-DXd earlier.

Chen / Is Dato-DXd safe in patients who have some cardiomyopathy? Because [osimertinib] would not be safe.

Mañana / To my knowledge, no concerns are flagged.

Gubens / I don’t think so. It’s not like T-DXd, where there are concerns about cardiotoxicity.

Mañana / What additional data would help you better define the role of [Dato-DXd] in that algorithm? Does Dato-DXd fit?

Eftimie / I would love to see a better quality-of-life measurement tool so a patient could say, “You know what, my quality of life is actually really good.” Because we only infer, we can see the rate of neutropenia and stomatitis, but for these medications, or for any medications, I would love to see a patient-specific quality of life. If the data tell me that [the patient’s] quality of life truly is better, that would really move me toward doing this.

Chen / I would agree with that.

References

1. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. FDA. June 23, 2025. Accessed October 14, 2025. https://tinyurl.com/46vh3dwb
2. 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.