Results from the phase 2 clinical trial DESTINY-Breast01 showed that the investigational human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate [Fam-] trastuzumab deruxtecan (T-DXd) has durable objective responses in patients with HER2-positive breast cancer who were heavily pretreated. Although T-DXd had a generally manageable safety profile, interstitial lung disease (ILD) was identified as a risk warranting proactive awareness and management. Physician’s Weekly interviews Charles Powell, MD, MBA, director of the Mount Sinai-National Jewish Health Respiratory Institute, to discuss the pooled risk analysis of ILD in patients with HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan.


The updated analysis from DESTINY-Breast01 was presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, which was held virtually 4-10 June, 2021, and demonstrated an objective response rate of 61.4%, and median progression-free survival of 19.4 months [1].  Although not a common adverse effect of fam-trastuzumab deruxtecan-nxki (T-DXd) in patients with HER2-positive metastatic breast cancer, preventing high-grade interstitial lung disease (ILD) can be achieved by effective early detection and optimal management. In the initial report, it was noteworthy that ILD of any grade occurred in 13.6% of patients; 2.7% of cases was grade 1, 8.2% was grade 2, 0.3% was grade 3, 0% was grade 4, and 2.2% was grade 5. Of these total 25 events, the mean time to investigator-reported onset was 193 days (range 43-535 days); 7 patients recovered, 2 were recovering, 12 were either outcome unknown or not followed until resolution, and 4 patients died. Of these 4 fatal cases, onset of ILD was from 63-148 days, 3 patients received steroids as part of the treatment, and death occurred 9-60 days after diagnosis of ILD. Researchers recommend to monitor patients for symptoms, hold T-DXd, and start steroids as soon as ILD is suspected [2-4].

Pooling data from August 2015 to June 2020 (61 patients participated in phase 1 studies DS8201-A-J101 [NCT02564900], and DS8201-A-A104 [NCT03383692], and 184 patients were in the phase 2 DESTINY-Breast01 study [NCT03248492]), including this update from ASCO, indicated that ILD occurred in 15.5% of patients with HER2-positive metastatic breast cancer following treatment with trastuzumab deruxtecan (T-DXd) at the approved dose (5.4 mg/kg) for a median 9.7 months (range, 0.7 to 40.3 months) [5]. Imaging and clinical data from baseline through the time of potential ILD case were retrospectively reviewed by an independent adjudication committee.

The data showed that majority of ILD cases were Grade 1 or 2 (79%) and occurred in the first 12 months. They added that the risk decreased after 12 months from the start of treatment, suggesting no cumulative toxicity. Six (2.4%) patients died due to a Grade 5 ILD event.

The median time to first ILD event was 5.6 (range, 1.1 to 20.8) months, with 97% of patients experiencing the first onset of ILD prior to 12 months. In total, 42% of patients were treated for ≥12 months.

The investigators concluded that when T-DXd was administered at the approved dose (5.4mg/kg), most ILD events were low grade and occurred in the first 12 months. They added that the risk decreased after 12 months from the start of treatment, suggesting no cumulative toxicity.

Physician’s Weekly asked Dr Charles Powell for some insight:

How to distinguish ILD from lung fibrosis?

 

“Lung fibrosis really represents an end stage of what can occur in interstitial lung disease. When we talk about fibrosis, we are talking about scar tissue and scar tissue that can be permanent. Interstitial disease represents a spectrum. The early phases of that spectrum are treatable and reversible and can avoid fibrosis and avoid scarring. Thus, the types of fibrotic lung disease that we think about typically will start as an interstitial lung disease, but most of the cases of interstitial lung disease that occur do not progress to fibrosis.”

How does trastuzumab deruxtecan trigger ILD in a subset of patients?

“The specific mechanism is not known. It is fair to say for the hundreds, if not thousands of drugs that can cause interstitial lung disease. Lung toxicity is a common event that can occur from multiple different treatments for multiple different conditions. Also, the lung is a very sensitive organ and is subject to inflammation and toxicity from a variety of drugs. So what is special or different, if you will, about trastuzumab deruxtecan? For background purposes, trastuzumab deruxtecan is an antibody drug conjugate and the antibody drug conjugate has a targeting antibody and a payload intended to increase specific toxicity to the tumor cells.

Where are the opportunities for toxicity? One is with the antibody, because we know that already can occur with trastuzumab by itself. Two is the off-target effect of the warhead where the chemotherapy drug, let’s say the antibody binds the cells that are not cancer cells. Let’s say the enzyme laces and releases the chemotherapy drug before it is solely internalized by the cells. Let’s say the cells that are affected by the chemotherapy drug die, which can happen, and then the chemotherapy gets released. Off-target effects of the chemotherapy, the antibody toxicity by itself and an activation of the immune and inflammatory systems that can be associated with drugs such as this can also contribute to the toxicity. The ILD could be a collection of different mechanisms in different patients, or there may be a sole mechanism, but that has not yet been identified. The key message here is that, although interstitial lung disease can occur, when detected early and managed appropriately, it is a manageable toxicity. And so that brings up and reinforces the importance of early detection.”

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Early symptoms?

“In the context of trastuzumab deruxtecan, in the early stages during clinical trials, patients would be seen in the clinical trial setting every 3 weeks or so, and they would get imaging every 6 weeks. The toxicity, if it was present, it could be detected on the imaging studies.

The first symptom to keep in mind would be shortened breath, during activities that normally did not cause shortness of breath. The second one would be a cough. Acquiring a new cough and a new shortness of breath would be the earliest symptoms, and patients should seek medical help right away in those circumstances.

We can think about the use of more sophisticated tools to identify early onset of interstitial lung disease, such as monitoring oxygen. So many people more comfortable now with wearable pulse-oximeters. Now we would not expect that reading to be low during rest in patients who have mild or moderate interstitial lung disease, but we would expect that number to change and go down with exercise in somebody who might have mild or moderate interstitial lung disease.”

What are the interventions that are possible to ameliorate the disease onset and progression?

“For very mild interstitial lung disease -very mild is most commonly referred to asymptomatic- that would be picked up on an imaging study. For trastuzumab deruxtecan, we would halt the drug in the context of the clinical trials, and follow the patient is followed. When the ILD resolves, if it resolves within a month or a month and a half, then the drug can be restarted again and the patients will be monitored with or without a change of the dose. For patients who have symptoms, the drug again is held and then the clinician will potentially use steroids for treating the condition. And again, following it up and in the case of trastuzumab deruxtecan, it is not recommended to continue the drug after recovery from a symptomatic episode of interstitial lung disease.

The concepts of treatment interruption in asymptomatic patients and treating symptomatic patients with steroids are very effective approaches here.”

What are the next challenges?

“Firstly, we need to better understand the mechanisms that are associated with the development of interstitial lung disease. There are animal models. The best animal model is a monkey and there has been some recent work from Daiichi and AstraZeneca to develop and validate this model and to understand the toxicity and the mechanisms, potentially there will be molecular biomarkers that can emerge from this research tool and this line of research.

Secondly, we need  is to identify who is at risk. We have some signals on different risk factors for ILD that come from the single arm studies that we have presented thus far. For example, some of these risk factors include patients living in Japan having a higher risk of developing ILD and patients who have pre-existing kidney disease having an increased risk of ILD, both of which are very interesting and require a bit more exploration.

The third area for really further development is to develop strategies to better monitor patients. To enable identifying early onset disease.”

Could the kidney disease association have something to do with having an existing fibrotic disease?

“We do not know the answer to that question. I think that is a great question because since this drug is not cleared by the kidneys, it is potentially very likely that the finding of the association with kidney disease is an indicator that there is some other condition that patient may have in addition to the kidney disease that may signify a risk for having ILD. ”

 

References

  1. Jerusalem G et al. J Clin Oncol 39, 2021 (suppl 15; abstr 526) DOI10.1200/JCO.2021.39.15_suppl.526
  2. Krop IA, et al. GS1-03. SABCS 2019.
  3. Tamura K, et al. Lancet Oncol. 2019;20(6);816-826.
  4. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510
  5. Powell CA, et al. Analysis of study drug–related interstitial lung disease (ILD) in patients (pts) with HER2+ metastatic breast cancer (mBC) treated with trastuzumab deruxtecan (T-DXd). ESMO Breast Cancer Virtual Congress 2021 (5-8 May, 2021), abstract 92O.