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Spotlight

A 39-year-old premenopausal woman underwent bilateral mastectomy with reconstruction for ypT1b, ypN2a, grade 2 invasive ductal carcinoma (IDC), hormone receptor (HR) positive, HER2 positive (immunohistochemistry [IHC] 3+)

Germline testing results showed no actionable/pathogenic alterations​.

She received adjuvant TCHP (docetaxel, carboplatin, trastuzumab [Herceptin], and pertuzumab [Perjeta]) for 6 cycles, with trastuzumab/pertuzumab for 1 year; leuprolide plus aromatase inhibitor (AI) was initiated​.

Three years later: metastatic recurrence in the vertebral spine​

Bone biopsy confirms relapse, HR+, HER2+ (IHC 3+) IDC​

Next-generation sequencing: no actionable mutations identified ​

She received first-line THP (docetaxel, trastuzumab, and pertuzumab) for 6 cycles plus denosumab​.

Transitions to HP (trastuzumab plus pertuzumab)

What is your preferred frontline therapy for HR-positive, HER2-positive metastatic breast cancer (mBC)? ​

Are you using endocrine therapy for patients with HR-positive, HER2-positive mBC? ​

: This is a pretty straightforward case. What do people think? What's your usual practice for a patient who now has metastatic HER2-positive, HR-positive disease and have not received any other treatment for the metastatic setting?

I usually start out with THP in the first-line setting, and after finishing paclitaxel with HP, add something like ovarian suppression plus AI. If they have progressed on an AI, I consider fulvestrant.

Does anybody do anything different? Does anyone use a different chemotherapy? Does everyone use paclitaxel?

Both are very reasonable. The original study with HP [CLEOPATRA; NCT00567190] used docetaxel. Some of us have switched to use paclitaxel instead because, in some patients, it's a little better tolerated, but it does require more visits. But both are appropriate.

Does anybody not use chemotherapy up front? There are some data using endocrine therapy alone with HP with some good outcomes, but that hasn't been compared with chemotherapy.

 Given the fairly substantial survival benefit seen with THP for most patients, most physicians are using chemotherapy, at least as an induction.

Dr Madadi already talked about using endocrine therapy once you drop the chemotherapy. Does everybody tend to do that for an ER-positive, HER2-positive patient once you've stopped the chemotherapy?

The problem in this case is that the patient was already on AI. It doesn't hurt to add it if you want to stop or hold the chemotherapy, so to speak. But that's the only thing here. She was on AI, and she experienced progression. That's what makes me think, “Would there be any benefit here?” But it doesn't hurt. The downside is pretty low here in this case.

Yes, and as was brought up, you could use fulvestrant. If you wanted to do endocrine therapy, you could use fulvestrant if you were worried. It's a good point. This [disease] developed on AI. Are you going to get much mileage out of putting her back on an AI vs giving her fulvestrant? I think that's very reasonable. Unfortunately, this hasn't been tested in a definitive way, because the original CLEOPATRA trial did not allow any endocrine therapy. All the data we have on THP, at least right now, were in the absence of endocrine therapy. But for all the reasons you've all mentioned, it seems pretty reasonable. I think most of us end up doing it, whether it's an AI or fulvestrant, depending on the situation.

How do site(s) of progression and tumor burden factor into your decision making at this point?​ For example:

Progression limited to 1 or 2 small sites?​

What’s important to you? What sites would change your thinking on using trastuzumab deruxtecan [Enhertu; T-DXd] vs something else?

[It would be] concern about brain metastases because if there are extensive brain metastases, we have some data on the tucatinib [Tukysa] and capecitabine combination being more effective.

 Otherwise, systemically, I would say a majority of the time [I would use] T-DXd.

: Fair enough. What about the people who said doesn't matter? Why doesn't it matter? I am one of the people who says doesn't matter, and until recently, I would have said it does matter for the same reason that Dr Madadi just said. But some of the data that have come in more recently suggest that maybe it's not so important to use presence or absence of brain metastases in your treatment decision.

Are there any other site issues? It sounds like most of the importance was because of brain metastases. Are there any other factors, like comorbidities or safety issues; to whom would you not give T-DXd to in the second line?

 I would be concerned about someone who already has interstitial lung disease.

Yes, in somebody who already had pneumonitis. Would you think about trying something different [based on] performance status? This patient was doing well, but [what about] for somebody who was debilitated, with a lot of comorbidities? [What if they had], not necessarily lung issues, but were someone who's pretty limited.

I think that for somebody with a limited performance status, maybe we would be thinking something gentle, like vinorelbine plus trastuzumab, and neither the [tucatinib] nor T-DXd. But for me, somebody has to have pretty limited performance status to not want to at least try T-DXd, especially if I think their performance status is limited because of their disease burden.

Fair enough, and you also don't have to use full dose in that patient if you're concerned.

1. Arpino G, de la Haba Rodríguez J, Ferrero JM, et al. Pertuzumab, trastuzumab, and an aromatase inhibitor for HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer: PERTAIN final analysis. 

. 2023;29(8):1468-1476. doi:10.1158/1078-0432.CCR-22-1092

2. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. 

 2020;38(23):2610-2619. doi:10.1200/JCO.20.00775

3. Hurvitz SA, Modi S, Li W, et al. 377O A pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) with brain metastases (BMs) from DESTINY-Breast (DB) -01, -02, and -03. 

. 2023;34(suppl 2):S335-S336. doi:10.1016/j.annonc.2023.09.554

During a Case-Based Roundtable® event, Ian Krop, MD, and participants discussed considerations affecting first- and second-line treatment of metastatic HER2-positive breast cancer in the first article of a 2-part series.



Therapy Type and Site of Metastases Factor into HR+, HER2+ mBC Treatment

Samer A. Al’Hadidi, MD, discusses the follow-up data for ciltacabtagene autoleucel in patients with multiple myeloma.

Considering 3-Year Follow-Up Data of Cilta-Cel in Multiple Myeloma

Samer A. Al’Hadidi, MD, assistant professor in the Department of Internal Medicine — Division of Hematology and Oncology at UAMS Winthrop P. Rockefeller Cancer Institute in Little Rock, Arkansas, discusses the follow-up data for ciltacabtagene autoleucel (cilta-cel; Carvykti) in patients with multiple myeloma.

During a Case-Based Roundtable event, Al’Hadidi reviewed the 3-year follow-up data of CARTITUDE-4 trial (NCT04181827). Patients on the trial experienced superior progression-free survival (PFS), overall survival (OS), and duration of response with cilta-cel vs standard of care (SOC). Al’Hadidi also notes that there are still two-thirds of patients responding to cilta-cel compared with one-third with SOC.

The longer-term toxicities observed in the trial included higher risk of developing secondary malignances with cilta-cel, which is something oncologists tend to focus on, according to Al’Hadidi. Additionally, he discussed the real-world data showing that the 1-year PFS rate with cilta-cel was almost 70%.

 We discussed cilta-cel use and updated data that came from CARTITUDE-4 that [were] presented in the IMS [International Myeloma Society] meeting. [These] updated data [were] with the follow-up of almost 3 years. That showed 30-month PFS of 60% in cases of cilta-cel and around 26% in the SOC arm. Also, OS seemed to be better with the early use of cilta-cel with a 30-month OS of 76% compared [with] 64% in the SOC arm. With the longer follow-up, we also see longer data on response, and we have deeper responses with stringent CR being better with longer follow-up in cases of cilta-cel, as well as the 30-month duration of response, where two-thirds of patients who got cilta-cel are still responding, compared [with] around one-third of patients in the SOC arm.

 We also discussed data on adverse events to watch for with longer follow-up, including secondary malignancies. We focus in general in secondary hematologic malignancies, because we worry most about those sorts of cancers, and there was around 3.5% risk of developing secondary hematologic malignancies in cases of cilta-cel, compared [with] 0.5% in the SOC arm. We also discussed data on real-world use of cilta-cel now since it’s being used more often in daily practice. There were data on the 1-year PFS close to 70% in those patients treated in the real world.

Luis E. Raez, MD, discusses the current liquid biopsy options for patients with lung cancer through assessing circulating tumor DNA.

Liquid Biopsy Techniques Test Lung Cancer MRD Level

Luis E. Raez, MD, medical director and chief scientific officer at Memorial Cancer Institute in Pembroke Pines, Florida, discusses the current liquid biopsy options for patients with lung cancer through assessing circulating tumor DNA (ctDNA).

These choices include identifying tumor-specific clones with tumor genotype-informed tests, such as Signatera, or detecting ctDNA in the blood with tumor genotype-uninformed tests. Raez highlights the debate between these 2 approaches, noting that tumor-informed biopsies are personalized and follow the tumor's evolution, while tumor-uninformed ctDNA detection only indicates cancer recurrence and is not patient specific.

Currently, Signatera is awaiting approval from the FDA as a molecular residual disease (MRD) test generally, but there are many ongoing studies using Signatera, emphasizing the potential benefits for patients. However, there is frustration for both patients and physicians when unable to determine if a patient will need additional systemic therapy post-surgery, according to Raez, underscoring the importance of accurate posttreatment assessments.

 We have 2 options now in liquid biopsies. One is to do tumor informed, meaning Signatera; we go to the tissue, and we identify among 16 different clones, which one or which ones the patient has, and we look for these tumor-specific clones. That's what we call them tumor informed. The other option, the other technologies that we use now, is only ctDNA. If we find ctDNA in your blood, it's because there is a recurrence. If there is no ctDNA in your blood, you are doing well, but that's tumor uninformed. So now we have the debate between which one of these technologies is better. Signatera looks very rational because you want to follow what your tumor has, and it's personalized because we do it patient by patient. So that's why—we will see, I guess. For lung cancer, that's what we do.

 We are waiting for FDA approval for MRD. To be fair, there are other MRD options, but this is something [where]...there is more than 80 or 90 studies ongoing with Signatera. That is why we're very excited that we may get some indications and validation and benefit for the patients. That's the most important thing because, as I said, if you have 100 patients with lung cancer, breast cancer, [etc], and after surgery, not knowing who is cured and who is not is something very frustrating—not only for the patients, but also for the doctors because we have to put them on treatment that they may not need.

Petros Grivas MD, PhD, discusses immunotherapy trials in muscle-invasive and metastatic bladder cancer.

IO Trials Change Practice in Localized and Metastatic Bladder Cancer

Petros Grivas, MD, PhD, clinical director of the genitourinary cancers program at University of Washington Medicine and professor at Fred Hutchinson Cancer Center in Seattle, Washington, discusses the key trials of bladder cancer using immunotherapy (IO) he highlighted during a Case-Based Roundtable event.

Grivas said that in the localized bladder cancer setting, he examined data from the CheckMate 274 trial (NCT02632409) supporting adjuvant nivolumab (Opdivo), the AMBASSADOR trial (NCT03244384) of adjuvant pembrolizumab (Keytruda), and the NIAGARA trial (NCT03732677) of neoadjuvant and adjuvant durvalumab (Imfinzi). The NIAGARA trial combined durvalumab with gemcitabine/cisplatin before surgery and continued durvalumab afterward. The trial showed event-free survival and overall survival benefit 

leading to the FDA granting priority review

 in early December, and Grivas said the participants discussed the practice-changing potential of these data.

In the metastatic setting, he discussed the JAVELIN Bladder 100 (NCT02603432), CheckMate 901 (NCT03036098), and EV-302 (NCT04223856) trials which each have had practice-changing impact over the past several years using IO. In particular, updated data from the CheckMate 901 trial of gemcitabine/cisplatin plus nivolumab vs gemcitabine/cisplatin showed its improvement in efficacy with consistent tolerability. The EV-302 trial added enfortumab vedotin (Padcev) to pembrolizumab and showed significantly better outcomes vs platinum-based chemotherapy in patients who were not previously treated in the locally advanced/metastatic setting. Their discussion of these trials showed how the trial data is quickly being adopted in community and academic practices and also shed light on barriers and opportunities for implementing these treatments.

 We talked about localized bladder cancer, muscle invasive disease, and the adjuvant therapy data with checkpoint inhibition. We covered the data from the CheckMate 274 trial with adjuvant nivolumab vs placebo and the corresponding FDA and EMA approval a few years ago. We also covered the AMBASSADOR trial that was recently presented at [the 2024 European Society of Medical Oncology Annual Congress] with a corresponding 

 publication by Dr Apolo in our group. And we discussed the nuances, details, efficacy data in terms of disease-free survival, overall survival, and toxicity data as well.

We also covered the NIAGARA trial, this perioperative trial using neoadjuvant and adjuvant durvalumab, a checkpoint inhibitor against PD-L1 in patients who have localized muscle-invasive bladder cancer. The neoadjuvant durvalumab was given together with gemcitabine/cisplatin neoadjuvantly, then adjuvant durvalumab alone and the comparator arm was neoadjuvant gemcitabine/cisplatin alone. The trial showed significant event-free survival and overall survival benefit. We're waiting to see the regulatory agency's decision about the efficacy and safety data, and we had the chance to discuss the potential practice-changing nature of this data, how the group feels about it and how they will plan in the future to possibly implement changes in their clinical practice, taking into account, as I mentioned, the totality of the efficacy and safety data from those trials.

We also discussed metastatic disease. We focused mainly in the frontline setting of metastatic urothelial carcinoma from bladder or other parts of the urinary tract. We discussed the data from the 3 practice-changing trials, Javelin Bladder 100, CheckMate 901, and EV 302. We focused a little bit more on the last 2 trials that were more recent as of ESMO 2023 and later, and we covered, again, efficacy and toxicity data from CheckMate 901, with gemcitabine/cisplatin nivolumab vs gemcitabine/cisplatin, as well as EV 302 with pembrolizumab/enfortumab vs platinum-based chemotherapy. And it was a great discussion, again, illustrating how quickly the field is moving forward, and what the reaction is by colleagues in the community and academic practices in terms of the adoption of the data sets and, of course, barriers and opportunities for further improvement.

Petros Grivas, MD, PhD, discusses the key trials of bladder cancer using immunotherapy he highlighted during a Case-Based Roundtable event.

Are you familiar with step-up dosing used for bispecific antibodies approved to treat relapsed/refractory multiple myeloma (R/R MM)?​

How comfortable are you managing toxicities associated with GPRC5D-directed therapy?

What's the quality of life like for patients on [talquetamab (Talvey)] in terms of toxicity while on treatment, beyond the step-up dosing and cytokine release syndrome [CRS] or neurologic [toxicity]?

: To give you a short answer, it's a mixed bag. How many of you have used selinexor [Xpovio]? That’s a pretty tough drug in some patients, especially if you give it at a high dose. The approval came at an 80-mg, twice-a-week dosing schedule, which was [difficult], and then we started giving it weekly with a lot of antiemetic support and all that.

Talquetamab [does not] require so much supportive care, but it has very unique toxicities, particularly the dysgeusia that leads to weight loss.

 Sometimes you see some skin toxicities. Many of those patients have an incredible response to this agent, so we do have time to hold the therapy and do some of the supportive care…. Some patients don't have any of that. As they get further into this, we get a better sense as to what their experience has been. Dose modifications and dose holds are critical, especially for people who are in response, and then being more preventative about some of these known toxicities of this target is important to try to get people through it.

I've had some patients who had pretty significant dysgeusia who we had to hold therapy for and then give it to them at a very reduced schedule, and they're able to eventually tolerate it. I think the more experience we get with this, we are going to get better clarity. So far in my experience, at least, it doesn't seem to be disease burden–related.

 Because this is an antibody, I would think if you held the dose, you don't expect things to improve quickly.

[It can take] a couple of weeks, sometimes even longer. Because this binds the target and continues to deliver the T cell response to those areas, which then leads to the inflammation and persistent symptoms, it can linger for patients who have had severe toxicity, and then sometimes you have to revisit the step-up dosing in those patients that you ended up holding for.

The other question is, do the adverse events [AEs] correlate with response?

In my experience so far, yes, patients who have had the most profound AEs have been in a complete response, many times with undetectable light chains.

Are you rigid about that cutoff for re-hospitalizing them and giving the induction doses? Do you have any flexibility there if you're a few days over and you think they're going to get in trouble with toxicity if you re-treat them after 33 days instead of 29 days?

I don't personally think so. In other settings, particularly in some of the clinical trials that I've been a part of for a while now, some people have been getting it even every 3 months for various reasons, and we have not repeated step-up dosing. We can't endorse that because we don't have the data yet to support it, but I have done delays that are a week or beyond the standard schedule that [have not been an issue].

Sometimes I would redo the premedications for those patients. The premedications are for the step-up dosing and the first full dose for a lot of these bispecific antibodies, and it does include steroid medicines. You can think about doing that if you wanted to make sure they don't get recurrent CRS, but many times, especially if they're in a response, it doesn't trigger the same T cell expansion as it did at the onset. That’s what this is all about. Some of that hinges on their response. Patients who have experienced progression because we've held so long are the ones I worry more about, because they're most likely going to then have that expansion again, if it’s going to work, and then those you have to be mindful of. But prophylactic tocilizumab [Actemra] and dexamethasone are being studied, and the use of that, if it makes it to the clinical practice, will eliminate a lot of this issue.

1. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. 

. 2022;387(24):2232-2244. doi:10.1056/NEJMoa2204591

During a Case-Based Roundtable® event, Omar Nadeem, MD, and participants discussed managing toxicities of talquetamab in the second article of a 2-part series.

Talquetamab Tolerability and Dose Interruption Considered in R/R MM

Targeted Oncology: What data support the use of teclistamab (Tecvayli) in patients with relapsed/refractory (R/R) multiple myeloma?

The MajesTEC-1 trial [NCT03145181, NCT04557098] was the first-in-human phase 1/2 open-label, multicohort, multicenter, dose escalation study that looked at teclistamab in patients with R/R multiple myeloma who previously received more than 3 lines and were triple class exposed. These patients were B-cell maturation antigen [BCMA] naive. The treatment was using the step-up dose of teclistamab at 0.06 and 0.3 mg…then the treatment dose was 1.5 mg/kg on a weekly basis. They continued with the treatment until progression, and they followed all patients 2 years after.

The primary end point was looking at overall response rate [ORR]. The key secondary end point was looking at the duration of response and the depth of response as well as minimal residual disease [MRD] status. It’s very important to evaluate MRD status when patients with multiple myeloma, especially after induction, after stem cell transplant, and as we are doing these BCMA-targeted therapies, because we're learning MRD negativity correlates very well with prolonged progression-free survival [PFS] and overall survival [OS].

How do you evaluate MRD in patients with multiple myeloma?

That's still the problem with multiple myeloma. It's different from acute lymphoblastic leukemia, where it's flow cytometry. Here, when you look at clinical trials, every clinical trial looked at MRD negativity in a different assay, some next-generation sequencing [NGS], some polymerase chain reaction, and some flow cytometry. The one I prefer is the Mayo Clinic NGS, and it's available, and that's what we use right now in the practice.

During a Case-Based Roundtable® event, Hana Safah, MD, discussed updated data and adverse event management related to teclistamab in patients with multiple myeloma in the second article of a 2-part series.

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