Rugo Surveys Peers on Treatment After Metastatic Relapse of HR+, HER2– Breast Cancer

Hope S. Rugo, MD, FASCO

MODERATOR

Professor of Medicine

Winterhof Family Professor of Breast Cancer

Director, Breast Oncology and Clinical Trials Education

Medical Director, Cancer Infusion Services

University of California, San Francisco

Helen Diller Family Comprehensive Cancer Center

San Francisco, CA

EVENT REGION Arizona

PARTICIPANT LIST Waqas Arslan, MD | Manpreet Chadha, MD | Robert Yoo, DO | Manisha Chandar, DO | Christopher Chen, MD | Jason Salganick, MD

ARSLAN: I [chose] AI plus ribociclib [Kisqali] because in the new data abemaciclib [Verzenio] did not show overall survival benefit.¹ At this time, ribociclib is the only one which has shown overall survival [OS] benefit.² That’s why probably I would choose that.

RUGO: The CDK4/6 inhibitors have shown variable results across the board, and I think a lot of it has to do with the population that’s been selected in the different trials. Abemaciclib had very similar OS [to ribociclib but it was not statistically significant due to] the way the statistics were done.¹ And then in the PARSIFAL trial [NCT02491983], that looked at fulvestrant with palbociclib [Ibrance] or an AI with palbociclib, the OS was identical to that in these other trials.³ It’s very complicated, but I think a lot of us have migrated to ribociclib instead of abemaciclib because of the diarrhea and instead of palbociclib because of the OS data. AI would be the treatment of choice because the patient is 3 years out from the last AI. Within 1 year, we recommend fulvestrant because those patients have primary or secondary endocrine resistance.

CHADHA: That’s what I’ve done, [but] once or twice some insurances had me go back with their preferred CDK4/6 inhibitor. Like you said, if they’re more than a year out, I try to go with an AI. Otherwise, I save it for if they progress. If they have an ESR1 mutation, I feel that this will be a good [opportunity] to give [a CDK4/6 inhibitor with] fulvestrant.

RUGO: Or with a PIK3CA mutation, I agree. And who wants to get an injection every month if you can get a pill? I’ve tried to change a patient [from ribociclib] to palbociclib recently because the patient had very limited de novo metastatic disease, excellent response, with normal laboratory results at 1 month. At 2 months, the liver enzymes were in the 600 U/L range, so we held the ribociclib, and 1 month off treatment, her bilirubin was rapidly raising and peaked, so I admitted her. It peaked at 10.2 mg/dL and her liver enzymes peaked at 1700 U/L. They’re not normal yet, but abemaciclib can also cause some liver enzyme abnormality, so I only felt comfortable giving her palbociclib. Insurance [said] I had to try abemaciclib first, but we did a peer-to-peer [consultation] and easily got palbociclib approved in that setting. Insurance can play a role, and individual patients obviously play a big role too. Keeping in mind the adverse events of the different drugs is always important. I do wait on fulvestrant in this situation.

CASE UPDATE

AI therapy with letrozole (Femara) plus ribociclib was initiated. The patient required 1 dose reduction to 400-mg ribociclib due to anemia. Twenty months after she started therapy, routine staging scans showed new FDG avid sclerotic and lytic bone lesions. She noted a mild increase in lower back pain, although results from laboratory studies were normal.

RUGO: [In fact, 57.5%] of patients in the MONALEESA-2 trial [NCT01958021] had dose-reduced ribociclib,⁴ so that’s why they used 400 mg in the NATALEE trial [NCT03701334] in early-stage disease. The efficacy was similar, regardless of whether…you were getting 400 mg or 600 mg, so I think we should feel very comfortable dose reducing if we need to. A few days doesn’t matter, but if there are big delays, it makes a difference. I found that fatigue is much better if you use the lower dose. Some patients have bad fatigue and they do better at 400 mg.

DISCUSSION QUESTIONS

• Do you routinely rebiopsy or order circulating tumor DNA (ctDNA) testing at each progression? For how many lines of therapy?
  • Which test is preferable?
• Is there a situation where you would not obtain next-generation sequencing (NGS) with disease progression on endocrine therapy (ET) plus a CDK4/6 inhibitor?

YOO: If there is any new site of metastatic disease, I will definitely rebiopsy unless it’s bone-only disease, [for instance] a new lymph node or visceral disease, especially since trastuzumab deruxtecan [T-DXd; Enhertu] is approved for HER2-low [disease]. If the initial biopsy was HER2 0, I always try to do a biopsy to see if I get 1+ or 2+. If it’s bone-only disease, it’s sometimes a tough case. If there’s not much bulky vertebral body disease, then I don’t biopsy every time. For ctDNA, I tend to repeat it at each progression in case I find anything new, although it has a pretty low yield.

RUGO: Would you keep doing that through multiple lines of therapy or do you stop at some point?

YOO: I think at least once, if I want to find anything new. Usually I do have a tissue sequencing unless the patient has bone-only metastatic disease, but after once or twice, if there isn’t anything new, I stop doing it.

CHANDAR: At the initial diagnosis of metastatic disease, I would obtain tissue testing. At each progression, I would favor a liquid biopsy…. I hear the point about HER2 low. If we’re looking to use T-DXd, it’s reasonable to pursue a repeat biopsy. But…if we’re looking for ESR1 or PIK3CA, liquid biopsy is probably appropriate.

CHEN: When it is the first new diagnosis of metastatic disease, I always get a biopsy to confirm that it is breast cancer because sometimes it could be something else. With each subsequent progression, I will do a liquid biopsy.

RUGO: Yes, we’ve all had a patient turn out to have lung cancer…. I’ve had 2 of those, where it looked like breast cancer but it wasn’t. It’s always good to do a biopsy to make sure what your tissue site is, but ctDNA can be one way to look for additional mutations over time. One mutation that can be hard to find unless you do serial testing is an ESR1 mutation that develops under the pressure of estrogen therapy [ET].

ARSLAN: If the ctDNA is positive for HER2, can we use anti-HER2 treatment in that patient or does it have to be positive by FISH [fluorescent in situ hybridization] or IHC?

RUGO: HER2 has been defined as either having protein on the surface of the cell and…having gene amplification by FISH. But when you do ctDNA [testing], you’re looking for [ERBB2] mutations. What you can find in ctDNA are so-called somatic mutations in HER2, and there have been data that have correlated with response particularly to oral tyrosine kinase inhibitors [TKIs] in patients who have somatic mutations of HER2, in combination with ET. Neratinib [Nerlynx] has been studied, although [it leads to] a lot of diarrhea.⁵ But tucatinib [Tukysa] is currently being studied in these patients with somatic DNA mutations. I think it’s worthwhile because sometimes patients respond. I had 1 patient who had responded to trastuzumab emtansine [Kadcyla] before there was any T-DXd with that situation.

SALGANICK: In the real world, we would not be able to get a drug approved based on NGS. That’s a specific carve out in the insurances. They won’t allow it.

RUGO: We’ve run into that too, and sometimes I’ll get expanded access or compassionate use. We have the ability to do it, so I’m not suggesting that everybody can do that, but we’ll send them the papers that have shown that there’s efficacy in that setting. Sometimes we’re able to get the drugs in that situation. This is kind of a unique situation where you see that mutation testing. Interestingly, most insurers just approve it. The same is true with somatic BRCA mutations. I’m always surprised that the insurers approve. It may be that they’re not really understanding what they’re seeing; that may be part of it.

SALGANICK: I think it’s [available] to you but [not all oncologists].

RUGO: I don’t think so. I’ve argued with some insurers and eventually got compassionate-use drugs. They do stay with their rules a lot, but there are also clinical trials. Clinical trials may not be in your area but [researchers] are studying olaparib [Lynparza] and talazoparib [Talzenna] in patients who have somatic BRCA1 and BRCA2 mutations and also in patients who have germline PALB2 mutations, and those results seem to be quite good. For HER2 somatic mutations, there’s a lot of interest in replacing the neratinib with tucatinib to try to have it be better tolerated. There are always issues [concerning] when you can get drugs approved [by insurance].

CASE UPDATE

Blood-based ctDNA analysis showed an ESR1 mutation.

CHADHA: I think 20 months is a decent time, and I have seen some success with switching to fulvestrant with a different CDK4/6 inhibitor. [This was] when I was starting with palbociclib, and there are data for ribociclib in the second line with fulvestrant showing benefit.⁶

RUGO: That is the MAINTAIN trial [NCT02632045]. It was a small phase 2 trial with 120 patients, and all the patients had received palbociclib. If they had mutations including ESR1, they had no benefit, although the numbers are small so it’s very hard to say. The only data we have on using the same CDK4/6 inhibitor after it, palbociclib followed by palbociclib in the PACE trial [NCT03147287], showed no benefit.⁷

CHADHA: I just don’t have much faith in elacestrant [Orserdu]. I know the data are there, but I haven’t yet seen a good success story.

RUGO: The trouble when we get some of these new drugs is that the patients have all been more heavily pretreated. They all had fulvestrant and then they had elacestrant. They had fulvestrant and another drug. They’ve even had a chemotherapy drug and received elacestrant. I don’t think we expect fulvestrant to work in that setting, and elacestrant doesn’t work well either, but it does work across mutations.⁸ I think when you’re giving this in the second-line setting, you’re going to see a very different response from when you give the drug in a later line, which is how we all start using drugs when they get approved. [When] we’re running out of options…it doesn’t work well. Because this patient received ribociclib up front, we don’t have any data that you need to add another CDK4/6 inhibitor. Fulvestrant has just performed abysmally as a control arm recently, which has been disappointing.

After a CDK4/6 inhibitor, subsequent endocrine therapies don’t work quite as well, but that’s why we looked at it. I wasn’t even an investigator in the EMERALD trial [NCT03778931], but I… suggested that they looked based on CDK4/6 inhibitor duration because…it defined an endocrine-sensitive population. But you could define a group of patients who have poorer response to subsequent therapies because we’ve seen that before.

ARSLAN: If this patient were PIK3CA mutation positive, would you have given elacestrant or anti-PIK3CA treatment like alpelisib [Piqray]?

RUGO: It’s a great question. The issue is that, in general, it’s a little easier to take single-agent elacestrant, and data suggested that in a small number of patients, elacestrant worked just as well as fulvestrant alone, even if you had a PIK3CA mutation [From the Data⁸]. What we’ve been thinking is we would give elacestrant first and then we would give fulvestrant and capivasertib [Truqap] or something, now that capivasertib is available. What order we give it in remains to be seen. There will be capivasertib data with [another] oral SERD [selective estrogen receptor degrader], camizestrant, that are still pending. There have been a lot of drug-drug interaction issues with the SERDs combining them with different targeted agents that are being worked through…. It will be a while…before we’re going to be combining them with these targeted agents.

You might decide [what to give based] on how much disease the patient had. If a patient had primary visceral disease, a lot of rapid progression, and very short response to the CDK4/6 inhibitor and letrozole, progressing within 6 months, I don’t think any of us would think that single-agent elacestrant would work well. But in a patient like this, I think you may get some mileage out of it based on the data that we have.

REFERENCES:

1. Toi M, Huober J, Sohn JH, et al. MONARCH 3: final overall survival results of abemaciclib plus a nonsteroidal aromatase inhibitor as first-line therapy for HR+, HER2– advanced breast cancer. Presented at: San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract GS01-12.

2. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med. 2022;386(10):942-950. doi:10.1056/NEJMoa2114663
3. Llombart-Cussac A, Pérez-García JM, Bellet M, et al; PARSIFAL Committee and Trial Investigators. Fulvestrant-palbociclib vs letrozole-palbociclib as initial therapy for endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer: a randomized clinical trial. JAMA Oncol. 2021;7(12):1791-1799. doi:10.1001/jamaoncol.2021.4301

4. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29(7):1541-1547. doi:10.1093/annonc/mdy155

5. Jhaveri K, Eli LD, Wildiers H, et al. Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial. Ann Oncol. 2023;34(10):885-898. doi:10.1016/j.annonc.2023.08.003

6. Kalinsky K, Accordino MK, Chiuzan C, et al. A randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition (CDK 4/6i) in patients (pts) with unresectable or hormone receptor–positive (HR+), HER2-negative metastatic breast cancer (MBC): MAINTAIN trial. J Clin Oncol. 2022;40(suppl 17):LBA1004. doi:10.1200/JCO.2022.40.17_suppl.LBA1004

7. Mayer EL, Ren Y, Wagle N, et al. GS3-06 palbociclib after CDK4/6i and endocrine therapy (PACE): a randomized phase II study of fulvestrant, palbociclib, and avelumab for endocrine pretreated ER+/HER2– metastatic breast cancer. Cancer Res. 2023;83(suppl 5):GS3-06. doi:10.1158/1538-7445.SABCS22-GS3-06

8. Bardia A, O’Shaughnessy J, Bidard F-C, et al. Elacestrant vs standard-of-care in ER+/HER2- advanced or metastatic breast cancer (mBC) with ESR1 mutation: key biomarkers and clinical subgroup analyses from the phase 3 EMERALD trial. Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract PS17-02.