DESTINY-Lung04: Frontline T-DXd Efficacy and ILD Management in HER2-Mutant NSCLC

Drs. Joshua Sabari, Alfredo Addeo, Julia Rotow, and Helena Yu discuss findings from DESTINY-Lung04, which evaluated trastuzumab deruxtecan (T-DXd) against chemotherapy plus immunotherapy in the frontline treatment of HER2-mutant non-small cell lung cancer (NSCLC). They discuss the progression-free survival benefit of 14.3 versus 8.3 months and higher response rates with T-DXd, while exploring why these improvements did not translate into a statistically significant overall survival benefit. The panel also compares T-DXd with emerging HER2-directed TKIs, including zongertinib and sevabertinib, focusing on treatment selection and tolerability. Particular attention is given to interstitial lung disease (ILD), including early detection, corticosteroid management, treatment interruption, and considerations for rechallenge or permanent discontinuation based on severity.

Transcript:

Dr. Sabari:  Julia, you presented the DESTINY-Lung04 data, and congratulations on that data disclosure at WCLC. Positive for progression-free survival versus chemotherapy and immunotherapy, but negative for overall survival. Dissect those data for me, and how do you think that then enters the frontline? Or are you still going to be using a TKI, zongertinib or sevabertinib, in the frontline setting?

Dr. Rotow: Yeah, so really happy to be part of sharing these data, of course. This was the DESTINY-Lung04 trial comparing T-DXd first line for HER2-mutant lung cancer, really exon 19 and 20 mutations, versus chemoimmunotherapy, so platinum, pemetrexed, and pembrolizumab as the control arm.

And you’re right that the key takeaway here, I would say, is that doing the HER2-directed therapy upfront improved progression-free survival by about six months.

So you got a PFS of 14.3 months instead of 8.3 months with chemoimmunotherapy and showed a better response rate. So a response rate of 70% with T-DXd compared to 45% with chemoimmunotherapy.

So I think that upfront efficacy was very much there using a HER2-directed treatment. We’ve long wanted to have something like this in the frontline setting for our patients.

So it’s good to see it demonstrated against what is still the standard of care in many places globally, which is to do chemotherapy or chemoimmunotherapy for this patient population.

Now you’re right, of course, OS was not improved in this study compared to chemo-IO. And I think that may reflect, in part, significant changes we’ve seen in standard of care during the course of the trial.

HER2 has changed very quickly, which has been very rewarding to see, right? We’ve gone from identifying it as an actionable alteration with no effective therapies to variable availability of things like T-DXd or HER2 ADCs in the previously treated setting, to the availability of ADCs off-label in the frontline setting, to TKIs being used in the previously treated patient population, and then very quickly in the frontline as well in many places around the world.

And we see these kinds of changes in standard of care, and there were differences in access to subsequent therapy that had an impact on outcomes in the OS finding in this study.

And in fact, if we do sensitivity analyses trying to correct for access to HER2-directed therapies, we do see that the OS hazard ratio drops below one into the 0.9 range.

That’s statistical modeling, but I think it tries to help account for what we see in real life, which is that patients have access to many effective lines of treatment that impact survival even beyond what you get in the frontline setting.

Dr. Sabari: Yeah, I think crossover is real.

Dr. Addeo: I was just going to add that one of the issues, at least as an oncologist, when we use this drug is that we alluded to the similarity with breast cancer. But one of the things we have seen more in lung cancer is toxicity. ILD seems to be slightly higher than what our colleagues treating patients with breast cancer have seen.

And so I think, at least in Europe, the data were not perceived as a huge success, even if, of course, PFS was positive. The fact that OS was not there was not the only main difficulty, but it was also a significant negative aspect.

Also, ILD is a concern, not only in how to treat it, but how to detect it. What do you do if you have a grade one? Should you stop it? Should you continue? Therefore, it’s quite obvious that having a TKI option, not only because it’s oral but also because toxicity seems to be more manageable by oncologists, would be beneficial.

Perhaps it would be more troublesome for the patient because having diarrhea is, of course, quite problematic. But for us, at least for me, it’s easier to deal with than ILD, where it’s always difficult. We don’t know what to do or how to handle all that.

Dr. Yu: Well, ILD affects second- and third-line therapy. Can you give them immunotherapy after? I think it really does, let alone making sure that symptoms resolve. So I think that’s a big challenge.

Dr. Sabari: Yeah, so we know that interstitial lung disease occurs in upwards of 20%, one in five patients, and I think this is real. Julia, how do you monitor for it? How do you manage it? Are you stopping with a grade one? Are you retreating? Give us some insight. You have a lot of experience here.

Dr. Rotow: Yeah, and that’s a great question. ILD is indeed a real toxicity on T-DXd, and as you mentioned, about one in five patients in the study had some grade of ILD. That was mostly grade one or grade two, and of those, most were asymptomatic, so radiographic findings being treated appropriately for pneumonitis or ILD.

In clinical practice, the advice right now is for grade one, that’s asymptomatic findings on scan only, to hold treatment, consider steroids, and if things resolve quickly, you can consider a rechallenge with therapy. Patients who have symptomatic ILD, that’s grade two or higher, anything symptomatic, should discontinue therapy.

It does mean that being aggressive in grade one can be helpful to hopefully help this resolve and allow patients to resume treatment. That’s what happened in the trial. A lot of the investigators, when they found asymptomatic ILD, were treating it with steroids. That made it grade two, but also, I hope, gave patients a better chance for good outcomes and recovery and to go on to subsequent therapies.

I think that in clinical practice, I’ve gotten more and more aggressive with any form of ILD on these types of therapies, even asymptomatic, with a very low threshold to initiate a course of steroids and to monitor very closely. And of course, as we’re starting patients on treatment, it’s critical that patients are aware of the signs and symptoms, that their families are aware of the signs and symptoms, and that the clinic infrastructure is aware as well, so you can initiate appropriate triage, intervention, and evaluation if symptoms do develop.

Dr. Sabari: Yeah, really important to identify it early and treat with high-dose steroids. And I agree with you, holding the drug, and once you see resolution radiographically, I feel comfortable resuming in a grade one patient. In a grade two or grade three, I really don’t feel comfortable rechallenging that patient.