Joyce A. O’Shaughnessy, MD, co-chair, Breast Cancer Research, chair, Breast Cancer Prevention Research, Baylor-Sammons Cancer Center, The US Oncology Network; member, Scientific Advisory Board, US Oncology Research Network, discusses key results from the phase 3 EMERALD trial (NCT03778931) of elacestrant, and the potential effects of the agent’s approval on the use of oral selective estrogen receptor degraders (SERDs) for hormone receptor (HR)–positive, HER2-negative breast cancer.

The oral SERD elacestrant was previously granted priority review status by the FDA based on findings from the EMERALD trial, which compared the efficacy and safety of elacestrant withstandard-of-care (SOC) fulvestrant (Faslodex) or an aromatase inhibitor in patients who had progressed on prior endocrine therapy. Results from the trial showed that elacestrant elicited a statistically significant improvement in progression-free survival (PFS) in the intent-to-treat (ITT) and 

-mutant populations compared with SOC agents, O’Shaughnessy states. Moreover, a longer duration of prior CDK4/6 inhibitor treatment was associated with better survival outcomes with elacestrant. This indicates that patients with 

 mutations who are endocrine sensitive will benefit most from treatment with this agent, O’Shaughnessy explains.

As the first oral SERD to demonstrate an improvement in PFS for HR-positive, HER2-negative breast cancer, the approval of elacestrant could change the current treatment paradigm, O’Shaughnessy says. The FDA is slated to decide on the drug’s application by February 17, 2023. Although elacestrant is currently the only oral SERD with positive, phase 3 clinical data, research with other oral SERDs is forthcoming, O’Shaughnessy continues. For example, a randomized phase 2 trial showed that the oral SERD camizestrant showed positive results in both the ITT and 

-mutant population compared with fulvestrant.

The approval of elacestrant would provide an oral alternative to fulvestrant for patients with endocrine-sensitive metastatic breast cancer, regardless of 

 mutation status, O’Shaughnessy says. This benefits patients in the second line who have done well on previous treatment with CDK4/6 inhibitors and are progressing with bone-only disease. The approval would also provide a much-needed single-agent endocrine therapy for patients who develop an 

 mutation after treatment with aromatase inhibitors, O’Shaughnessy notes. 

Current research with elacestrant, such as the phase 1b/2 ELEVATE trial (NCT05563220), aims to investigate its use in combination with agents such as alpelisib (Piqray), everolimus (Afinitor), palbociclib (Ibrance), and ribociclib (Kisqali). Efforts to move this agent into the adjuvant setting are also ongoing, O’Shaughnessy concludes.

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Joyce A. O’Shaughnessy, MD, discusses key results from the phase 3 EMERALD trial of elacestrant, and the potential effects of the agent’s approval on the use of oral selective estrogen receptor degraders for hormone receptor–positive, HER2-negative breast cancer.
 

Dr. O'Shaughnessy on Key Results From the EMERALD Trial in HR+/HER2- Breast Cancer

 Let’s transition then to summarizing some take-home points that you think are some of the most important things people should take away from our discussion today. Mark, I’ll start with you.

 Thank you, Joyce. I would say remember the fundamentals, renewed focus on pulmonary review of systems, careful pulmonary physical examination using a stethoscope. There may be things that are subtle that you might be able to hear that may not yet be radiographically apparent fully. That said, it’s important to review the radiographic findings and do your restaging as scheduled on time and not delay them unnecessarily. Remember our pulmonary consultant colleagues and collaborate with them. They don’t want to get involved in a case that’s already in the ICU [intensive care unit] intubated. Early referral to pulmonology is key, especially for symptomatic patients or for patients, as Charles mentioned, for whom we’re considering a new form of treatment and they have underlying risk factors for ILD [interstitial lung disease].

Finally, inform patients and your allied health personnel what to look out for, when they should call, what demands an earlier clinic appointment and follow-up, earlier look on scans, etc. Then remember that drug-induced lung disease can be acute, but it can also be insidious, and it can have rather long latencies like we see in the case of sometimes with immune checkpoint inhibition. With trastuzumab deruxtecan it could happen months into the treatment course, and pulmonary fibrosis with bleomycin or carmustine could happen years or even a decade after exposure. Those are my key summary points from today’s discussion. Thank you.

 Thank you, awesome. How about you, Charles? What would you add?

 My 2 takeaways are first, drug-induced ILD or drug-related pneumonitis is a diagnosis of exclusion. It’s important to embark upon that diagnostic pathway to exclude other causes of the radiographic or symptomatic findings, and we outlined the process for that. The second takeaway is that when detected early, drug-related pneumonitis is manageable and treatable, and it’s important to keep that in mind, and it’s important to be aggressive with our educational efforts, so that patients and treating physicians are aware. We’re talking about new cancer agents that are incredibly powerful, offering patients opportunities for response and survival benefits after they’ve progressed through multiple other prior regimens. These drugs have potential to be incredibly effective and yes, some are associated with an increased risk of drug-related pneumonitis. Using this type of multidisciplinary approach that we’ve been talking about, where there’s a partnership between patient, the treating oncologist, and the pulmonologist, and emphasis on early detection, then really the therapeutic benefits can be realized with mitigation of the toxicity.

 Super. It’s been great talking to you, highly educational for me. I learned a great deal, and this is going to be a really useful program for people. I thank you so much for your time. I think we covered the waterfront of the key topics. I hope this has been useful to you and will help you taking care of your patients in your practice. Thanks very much for listening.

Experts highlight key messages regarding optimal identification and management of interstitial lung disease. 

Optimizing the Management of ILD: Take-Home Messages

Data from the following clinical trials are discussed:

LBA1 - Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase 3 DESTINY-Breast03 study (DESTINY-Breast03)

279P - Trastuzumab deruxtecan (T-DXd) in patients with HER2-positive metastatic breast cancer (MBC): Updated survival results from a phase 2 trial (DESTINY-Breast01)

280P - Intracranial activity of trastuzumab-deruxtecan (T-DXd) in HER2-positive breast cancer patients with active brain metastases: Results from the first stage of the phase 2 TUXEDO-1 trial (TUXEDO-1)

HER2CLIMB-04: Phase 2 open label trial of tucatinib plus trastuzumab deruxtecan in patients with HER2+ unresectable locally advanced or metastatic breast cancer with and without brain metastases (trial in progress)

Expert oncologists discuss data from several phase 2 and phase 3 trials presented at ESMO 2021 on the use of trastuzumab deruxtecan for HER2-positive breast cancer and how it impacts their practices.

Updates in HER2+ Breast Cancer from ESMO 2021

: With that in mind, we have a long list of agents, some higher risk than others, but they’re valuable to us. Mark, when you’re approaching a patient, whether it’s HER2-positive disease, ER-positive disease, PD-L1–positive disease, how do you think about managing and balancing the benefits, the potential benefits, and the risk? Does the risk for ILD [interstitial lung disease] make you concerned and put the treatment off a bit for the patient? How do you think through that risk and benefit discussion?

: Great question. Unfortunately, in oncology we rarely have the consideration to not treat. Some of the agents we’ve been talking about have very important efficacy data, including survival benefits and the like. We can’t put off the likes of say CDK4/6 inhibitors in ER-positive metastatic breast cancer. The key is patient education so they’re aware of what to look out for at home, when to call the office, when to insist on an early follow-up clinic visit, for example. We have a 24-hour hotline for oncology patients at my center, so training those staff so that it’s on their Rolodex of when they’re going to triage patients, page the physician on call and send them over to the emergency department vs having them come in the next day or two for clinic follow-up. That’s very important training.

All of us make use of allied health personnel in the form of nurse practitioners and physician assistants. Educating those folks is critical because they sometimes do independent visits, independent from the attending physician at academic centers at least They need to be very aware and adept at management of ILD, drug-induced ILD in particular. These are the things I would be talking about with patients. The fact is the risk of drug-induced ILD is usually lower than the risk of disease progression in the case of many patients with metastatic breast cancer. The equation falls out on the side of treatment rather than watchful waiting for most patients with breast cancer. That may not be the case for other diseases like melanoma. Sometimes you can have a watch and wait attitude there based on a solitary lung nodule that’s been resected, for example, that sort of thing. I’m thinking about patient education and staff education at all times for this condition for the drugs that frequently are associated.

: Yes. What I’m hearing you say, Mark, is that you treat with the best treatment you have for the patients. We increasingly thankfully have moved a lot of these effective agents into the curative setting, such as now pembrolizumab in the preoperative triple-negative breast cancer setting. Thankfully, the risk of serious pneumonitis is very low, like in the 1% to 2% range. I’m sure as we get into patients with more robust immune systems, we’re going to see more lower grade, but we have to treat anyway because this is going to cure an extra percentage of patients.

That’s my approach, too. I’ve never not utilized an agent because of concern that someone might get ILD. That’s mostly come to the fore with trastuzumab deruxtecan. My experience has been so far that I certainly haven’t seen anything that I’ve been concerned about. I have had some patients who have developed some kind of small patchy infiltrates that are a change from their CT scan that have made me worry. If it’s a tiny, little thing, I must admit I’ve chosen to just continue to treat the patient and follow them closely. With a second change now I’m referring, etc. I haven’t been, unlike with some of the other immune-related adverse events where I have had heartburn and insomnia, that has not happened with the pulmonary effects so far, checkpoint inhibitors, nor with everolimus. I haven’t seen that much everolimus-related ILD or pneumonitis in recent years. With trastuzumab deruxtecan, I just haven’t had a lot of issues, but a little bit of the transient things coming and going. It’s right, we’re using now the CDK4/6 inhibitors in the adjuvant setting. What you were saying, Mark is just vigilance, heightened awareness on the part of the patient, the family, all of our staff, ourselves, etc.

Key opinion leaders share risk-benefit considerations when utilizing therapies that may increase a patient’s risk of developing ILD.

Understanding the Risk-Benefit Comparison of Agents That May Cause ILD

Joyce A. O’Shaughnessy, MD, co-chair of Breast Cancer Research, chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center, Texas Oncology, chair of The US Oncology Network, and 2016 Giant of Cancer Care

 in Community Outreach, discusses the clinical implications of the TEXT and SOFT trials in premenopausal women with hormone receptor-positive breast cancer.

Based on 8-year follow-up from the TEXT and SOFT trials, the most important practical point with regard to endocrine therapy for premenopausal women is that those who have very low-risk indolent disease who are not going to receive chemotherapy may do fine with tamoxifen alone provided that they are not too young, says O'Shaughnessy; these are women under the age of 35 or even 40. Women over the age of 40 with very indolent, low-risk disease are also appropriate to receive tamoxifen monotherapy.

Conversely, the more high-risk features younger women have, the greater the benefit of an aromatase inhibitor (AI) plus an LHRH agonist, says O’Shaughnessy. These features include progesterone receptor (PR) negativity, large grade 3 cancers, highly proliferative disease, and node-positive disease. These data provide invaluable insight into the use of endocrine therapy, which is critically significant as it is by far the most important therapy for premenopausal estrogen receptor (ER)-positive women, says O’Shaughnessy. For these patients with high-risk features, there is up to a 15% absolute benefit in distant disease-free survival with the use of an LHRH agonist in combination with an AI.

Joyce A. O’Shaughnessy, MD, co-chair of Breast Cancer Research, chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center, Texas Oncology, chair of The US Oncology Network, and 2016 Giant of Cancer Care® in Community Outreach, discusses the clinical implications of the TEXT and SOFT trials in premenopausal women with hormone receptor-positive breast cancer.

Joyce A. O'Shaughnessy

Articles

Dr. O'Shaughnessy on Key Results From the EMERALD Trial in HR+/HER2- Breast Cancer

Optimizing the Management of ILD: Take-Home Messages

Updates in HER2+ Breast Cancer from ESMO 2021

Understanding the Risk-Benefit Comparison of Agents That May Cause ILD

Dr. O'Shaughnessy on Clinical Implications of the TEXT and SOFT Trials in Breast Cancer