Enhertu in HER2-Mutant Lung Cancer: The First Year, Side Effects and Sequencing

Dr. Julia Rotow, a thoracic medical oncologist at Dana-Farber Cancer Institute and global co-lead investigator of DESTINY-Lung04, discussed how the trial could change treatment sequencing for patients with newly diagnosed advanced or metastatic HER2-mutant lung cancer.

DESTINY-Lung04 compared Enhertu (trastuzumab deruxtecan) with chemotherapy plus immunotherapy and met its primary end point. Median progression-free survival was 14.3 months with Enhertu versus 8.3 months with chemoimmunotherapy, an improvement of about six months. Based on these results, Rotow said she would prioritize Enhertu before chemoimmunotherapy.

Treatment sequencing has become more complex with HER2-targeted tyrosine kinase inhibitors (TKIs), including zongertinib and sevabertinib. Rotow said efficacy has appeared similar across these approaches, with response rates around 70% and progression-free survival around 14 months. Because TKIs are oral and may offer favorable side effect profiles, she expects them to be used frequently in the frontline setting. However, she emphasized that patients who receive a TKI first should receive Enhertu next, before chemoimmunotherapy.

Interstitial lung disease (ILD), or pneumonitis, remained an important side effect of Enhertu, occurring in just over 20% of patients. Most cases were asymptomatic or mild, and Rotow emphasized early recognition and treatment. Other side effects she watches for include nausea, fatigue and low blood counts.Questions also remain about brain metastases and overall survival. CNS outcomes were not reported, although preliminary progression-free survival results favored Enhertu among patients with brain metastases. The interim analysis also did not show an overall survival improvement, which Rotow said may partly reflect differences in the treatments patients received after leaving the trial.One result that surprised Rotow was how well the chemoimmunotherapy control arm performed despite low or negative PD-L1 expression and limited tobacco use among many patients. She said the findings suggest immunotherapy may still have a role in HER2-mutant lung cancer, but she would currently reserve it for later-line treatment rather than use it first or second.

0:05 — Who led the DESTINY-Lung04 trial?

"I'm Dr. Julia Rotow. I'm a thoracic medical oncologist at the Dana-Farber Cancer Institute, where I'm clinical director and research director for our thoracic oncology program. My work and research focuses on the treatment of oncogene-driven lung cancer, including HER2-mutant lung cancer, which is of course very relevant to the DESTINY-Lung04 trial. [I am] also the co-lead investigator globally on the DESTINY-Lung04 study."

0:25 — What did the DESTINY-Lung04 trial compare?

"DESTINY-Lung04 was evaluating what to use in the front-line setting, or first newly diagnosed setting, for people who have metastatic or advanced lung cancer with a HER2 mutation. The study was comparing what has previously often been the standard of care globally for these patients at diagnosis, which is chemotherapy plus immunotherapy. So it tests the idea of a HER2-directed therapy versus standard chemoimmunotherapy for people with a new diagnosis with a HER2 mutation."

0:55 — What did DESTINY-Lung04 find?

"What the study showed was that if you treat people with [Enhertu] instead of chemoimmunotherapy, we saw better progression-free survival. This was the primary end point of the study, so it's the key outcome measure for the study, and this improved by about six months, so from 8.3 months if you got chemo plus immunotherapy to 14.3 months if you got Enhertu first."

1:20 — What do the DESTINY-Lung04 results change for patients starting treatment?

"It means for patients, when thinking about sequencing therapy, that until now our national guidelines have really listed either Enhertu or chemoimmunotherapy as reasonable options currently in the previously treated setting. And it now means that instead of this, I would really advocate that people should be getting Enhertu before they get chemoimmunotherapy, based on these kinds of efficacy outcomes."

1:43 — What are the side effects of Enhertu in HER2-mutant lung cancer?

"One key side effect that did come out was risk of something called ILD, or pneumonitis, so lung inflammation. This is a known side effect of Enhertu, and it did occur in a sizable fraction of patients on the trial, just over 20%. Most was asymptomatic or mild. Most resolved with appropriate management, and certainly patients who got aggressive and proactive management did better than those patients who, for example, had delayed or less aggressive management for this side effect."

2:08 — How does a patient choose between an oral pill and an infusion for HER2-mutant lung cancer?

"My takeaway is that on the efficacy side, we've seen very similar efficacy outcomes with these regimens, and it's striking looking at an ADC versus TKI. We saw response rates in the 70% range, and progression-free survival sitting around 14 months as well for these different classes of drugs. I do think that the tyrosine kinase inhibitors, [zongertinib] and [sevabertinib], do have a favorable side effect profile, and of course the convenience of an oral targeted therapy. So I think in practice we're going to see a lot of that being given in the frontline setting.

"There is a randomized phase 3 study very similar to what I just presented, looking at zongertinib versus chemoimmunotherapy, which is not yet read out, but we're waiting for that data, and that will hopefully confirm the sort of efficacy profile we've seen thus far being reported in the frontline setting. And of course, there's a similar study ongoing for sevabertinib as well, which also has very similar efficacy data. I think a little more challenging toxicity profile, with some of the risk of diarrhea or skin rash. That's a little lower on my list, but certainly an available and reasonable option as well.

"In the early-line setting, I think the other key point here is that patients who do get a TKI first, if they do receive one, should get Enhertu next. I think that's really critical, before chemoimmunotherapy. And in the many regions of the world where chemoimmunotherapy has still been our frontline treatment, patients should be getting Enhertu first, again based on the DESTINY-Lung04 data. So I do think with these recent approvals and recent data, we're seeing some reshuffling of how we're sequencing these therapies in practice."

3:35 — What does the first year on Enhertu look and feel like?

"Patients often want to know what it is actually like to be on these treatments, and what they can expect early on, right after they start. What can they expect a few weeks or months or a year into therapy? The duration of effect was real for this agent. People had a progression-free survival over a year. They've been on treatment for a while, so managing side effects matters.

"We are familiar with the side effects of this class of drugs. Most commonly we're watching for some of the side effects we've seen with chemotherapy, like GI side effects, which oncologists are good at managing, like nausea. Watching for fatigue, since that requires dose modification or dose holds or dose delays to make it manageable for patients over time. We're watching for low blood counts. That's often an asymptomatic side effect, or something that can lead to fatigue or risk of infection. That's a lab finding that doctors are checking regularly on therapy.

"So when I think of my patients on Enhertu, I think about managing nausea properly, managing fatigue properly and keeping an eye on their blood counts. Of course, being really vigilant for any symptoms of lung inflammation, like a new cough, new trouble breathing, new fever. This really requires physicians to be aware, physicians' offices to be aware, and patients and families to be aware, so they can raise the alarm and be seen and be appropriately evaluated if these symptoms develop."

5:05 — What does DESTINY-Lung04 show about brain metastases?

"CNS mets are a real risk in HER2-mutant lung cancer and lung cancer as a whole. They are a real therapeutic challenge. We know that our list of agents that have known and established activity against brain metastases, in terms of shrinking or controlling brain mets, is shorter than our list of options we have more broadly for lung cancer. That does mean we really keep an eye on CNS outcomes data for any new agent that we see enter the possible treatment landscape.

"Now, DESTINY-Lung04 did not report the CNS outcomes. It's a really critical analysis and can be done separately and reported. I hope in a future conference or future meeting we can delve into that data in more detail. At least so far, preliminarily, progression-free survival also trended toward favoring Enhertu in patients with brain metastases. So the initial look at least looked promising. We have a reasonable body of data for Enhertu and other ADCs in this drug class showing that they do seem to cross the blood-brain barrier, and we do see responses in the CNS to these agents. So that's reassuring. And similarly for the TKIs, it's really important to also note that the HER2-targeted TKIs do indeed also have reported evidence of CNS activity."

6:20 — How long do patients stay on treatment for HER2-mutant lung cancer?

"Both regimens in this case have an indefinite duration of therapy. Enhertu was every three weeks until disease progression or side effects. Same thing with the chemoimmunotherapy. It's platinum-pemetrexed, so a chemotherapy doublet plus [Keytruda], a triplet regimen for the first four cycles, and then, as per KEYNOTE-189, patients got pemetrexed and Keytruda maintenance. But for indefinite therapy, as long as disease was controlled, and again, as per side effects. So it does mean that side effect management is really critical. Patients can be on treatment for a while, as we saw, and we need to be vigilant about managing these for folks on treatment."

7:00 — What surprised the investigators in DESTINY-Lung04?

"The surprise to me, in some sense, was how well the control arm did. We know that this was a positive study. Enhertu beat the control, and it beat a control that I think performed better than I might have predicted chemoimmunotherapy would perform in HER2-mutant lung cancer. There's long been controversy in the field over whether immunotherapy offers benefit in HER2-mutant disease. It often strikes younger patients, patients without a history of tobacco use, a little more like EGFR-mutant lung cancer. We have known that traditional checkpoint inhibitor immunotherapy has not offered a lot of activity.

"Here it was included because we didn't want to leave out an agent that might offer benefit to these patients in the control arm. I think it was appropriate to include it, but I was surprised to see that the median progression-free survival in the control arm really matched the median in the control arm for KEYNOTE-189, which was chemoimmunotherapy broadly in lung cancer, not oncogene-specific. The study had a lot of patients with minimal tobacco use history and low or negative PD-L1 scores. That's consistent with the HER2-mutant patient population, but often trends toward worse immunotherapy sensitivity.

"So it's good to see it beat a difficult control arm, and it makes the outcome of the study more definitive. But it does raise some really interesting questions about whether we should be reassessing the role of immunotherapy in HER2-mutant lung cancer. There's a tail in the survival curve as well in the control arm, and that would be very good news for our patients. There is some signal for immunotherapy activity. It shouldn't be frontline. It shouldn't be second line right now. It's probably a third-line agent with chemotherapy. But it does encourage me to think about still including immunotherapy among my patients' future treatment options until we have more data, because it shows some really tantalizing signals of activity there."

8:55 — What did DESTINY-Lung04 show about overall survival?

"One thing we haven't talked about yet is the overall survival outcomes from the study, and it's necessary to point out that at least in this interim analysis, we did not see improved overall survival. So we saw better progression-free survival, but not long-term survival. This speaks to the way things are changing in oncology, again in a good way, as we have more and more effective lines of treatment and more variability in what patients receive next after a given line of therapy. It's harder and harder to detect overall survival.

"We saw within this study that there was a lot of variability in what people got next after this clinical trial, what they got second line, and there was a lot of difference in how much people had access to things like immunotherapy or other HER2 therapies or HER2-targeted pills between the control arm and the treatment arm. I think that did impact what we saw for survival and made it harder to detect survival advantages. But net, I think it was a positive that we saw patients doing really well, with the overall survival starting to cross 30 months in HER2-mutant lung cancer. That's quite a bit longer than we've seen historically, in the days before personalized or HER2-directed treatments. I think it speaks to progress in the field, and I hope that we keep that momentum going and keep moving those numbers further and further down the line for all our patients."

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