Huppert Discusses Later-Line Therapy Decisions in HR+, HER2– Metastatic Breast Cancer

Laura Huppert, MD

MODERATOR

Assistant Professor

University of California, San Francisco School of Medicine

San Francisco, CA

EVENT REGION Pacific region

PARTICIPANT LIST Vikramsinh Dabhi, MD | Navanshu Arora, MD | Merin Stephen, MD | Weiqiang Gao, MD | Sherry Hsu, MD | Bin Xie, MD | Gigi Chen, MD

CASE SUMMARY

A 62-year-old woman presented with a 6-cm right breast mass that had been slowly growing for 1 year with palpable axillary nodes. Liver function tests (LFTs) were normal. A CT scan shows 2 liver nodules, the largest being 2 cm. Bone scan shows extensive disease in thoracic spine and ribs. Breast biopsy confirms grade 2 invasive ductal carcinoma, estrogen receptor positive, progesterone receptor positive, HER2 0 by immunohistochemistry, and BRCA1/2 negative. Liver biopsy confirms metastatic disease with similar markers. Disease staging was T3N1M1, and she had an ECOG performance status of 0.

The patient received treatment with letrozole (Femara) plus ribociclib (Kisqali), with denosumab (Prolia) to address bone metastasis. A best response of partial response was achieved.

Thirty months after treatment initiation, follow-up imaging showed enlarging liver nodules and 2 new lung nodules (largest measuring 1.2 cm). Her ECOG performance status was 1, LFTs were normal, and glycated hemoglobin A1c was normal.

DISCUSSION QUESTION

• What would your next step in treating this patient be?
  

HUPPERT: If you saw this patient today, what would you do next? Would you do a biopsy? Would you get genomic testing? Would you switch therapy?

DABHI: Is liquid biopsy an option?

HUPPERT: Yes; why would you go to liquid biopsy?

DABHI: If it’s a site that’s very amenable to a tissue biopsy, I would get the tissue biopsy. Otherwise, to spare them an invasive procedure, I wouldn’t mind going forward with a liquid biopsy, because it’s fairly innocuous and you can get some good information to see [whether] there have been any mutational changes that might guide your next decision step.

HUPPERT: Agreed. What mutations are you looking for here?

DABHI: The PIK3CA mutation [and] the ESR1 mutation may be helpful because we have at least some targeted therapies available in those situations.

HUPPERT: I totally agree. Getting a liquid biopsy makes sense, particularly looking for those 2 mutations, [as] we do have targeted therapy options there. The ESR1 mutation in particular, with the approval of elacestrant [Orserdu], is now an option.¹

DABHI: Were there notable symptoms, or was it just imaging changes?

HUPPERT: [Just] imaging changes.

DABHI: There is not an urgency to change therapy. It affords you a little bit of time to review what the results are. If there was an urgency, I might then take steps in the interim. But I think you could wait 2 or 3 weeks, then make your decision more thoughtfully.

ARORA: Did we already do germline testing?

HUPPERT: Good question. We know the patient was BRCA1/2 negative. If we hadn’t done that, we should definitely do that now. But I believe we got negative testing.

CASE UPDATE

Tissue is sent for genomic testing but does not show PIK3CA, ESR1, or other actionable mutations.

DISCUSSION QUESTIONS

• What are the unmet needs in the post-CDK4/6 inhibitor setting and for hormone receptor (HR)-positive/HER2-negative metastatic breast cancer?
• What are some recent developments that aim to address these needs?

HUPPERT: After the discussion of this case, would any of you change your recommendations?

DABHI: I wouldn’t; it confirmed what we were talking about. I do see the counterpoint that was made by one of my colleagues, which is whether it would be beneficial—and there’s no study I know—to alter the mechanism substantially so you maintain some, or potentially might gain, greater future hormonal durable response. If you stack different hormonal manipulations back-to-back, maybe if you did chemotherapy for a while and then came back to it a year or so later, maybe you resensitize to the hormonal manipulation. I don’t know [whether] that’s true.

HUPPERT: As you said, we don’t have perfect data there. We know from the RIGHT Choice [NCT03839823] trial, which was presented at [San Antonio Breast Cancer Symposium, that] we used to sometimes do chemotherapy up front and then switch to endocrine therapy. It was thought [to be] beneficial.² The RIGHT Choice trial proved that strategy isn’t beneficial, so we haven’t definitively looked at that in the second and third lines like was suggested. But generally, our strategy is to exhaust endocrine therapies as much as possible, then switch to chemotherapies. On occasion, I have gone back to endocrine therapies after chemotherapy, but usually not. It hasn’t been evaluated, but that’s generally been our approach.

DABHI: It’s hard to do such a study, [as] it would require full cooperation from everybody involved.

HUPPERT: What are some of the unmet needs in the post-CDK4/6 era in terms of endocrine therapies? What are the challenges you face in this setting? …Fulvestrant [Faslodex] monotherapy doesn’t help much. Especially in these patients who don’t have mutations, what we can do that gives us bang for our buck is one challenge.

ARORA: You don’t have very many choices after that. You don’t get durable responses.

HUPPERT: That’s definitely a challenge. Some patients respond to some of these agents, but many of them are not durable, so [it’s] an issue.

STEPHEN: Most of the next-line options are more toxic. Because these drugs are so well tolerated, patients are used to that tolerance.

HUPPERT: Yes…[it’s] hard to go toward chemotherapy. We want to try to use these drugs, but some of these drugs also have a lot of toxicities. There are pluses and minuses.

CASE UPDATE

The patient progressed after endocrine and CDK4/6 inhibitor therapy. She received fulvestrant/everolimus for progressive disease. Initial follow-up imaging post treatment showed stable disease. Six-month posttreatment imaging showed liver and lung nodules enlarged from initial posttreatment scan. She was treated with capecitabine (Xeloda) and paclitaxel until progression of disease. Following progression, she was treated with sacituzumab govitecan (Trodelvy).

DISCUSSION QUESTION

• What is your reaction to the TROPiCS-02 study (NCT03901339) of sacituzumab govitecan for HR-positive, HER2- negative locally recurrent inoperable or metastatic breast cancer?

HUPPERT: Thinking about the TROPiCS-02 and the sacituzumab govitecan data, what’s your general take on it?

DABHI: The initial progression-free survival [PFS] number is not impressive at a 6-week difference [5.5 vs 4.0 months; HR, 0.66; 95% CI, 0.53- 0.83; P = .0003].³ It seems that if you are witnessing a notable response in your patient, then they may turn out to be in that [21.3% of patients who had] 12-month PFS, so you may want to adhere to that. [However], if you’re not seeing that response pretty quickly, then I would say the toxicity outweighs the very small difference you see in the overall group. I would be more likely to switch relatively quickly.

HUPPERT: What toxicity is most problematic for your patients, Dr Dabhi?

DABHI: I only have 1 patient on this drug, and I will say the day 1/day 8 [schedule] is not feasible for that patient. I had to switch to every 2 weeks, with a little bit of G-CSF [granulocyte colony-stimulating factor] support. The primary toxicity has been GI [gastrointestinal]. It’s not just diarrhea; it was… less predictable changes in the GI symptoms for the first 3 to 5 days, and then fatigue lasting probably closer to 7 days.

HUPPERT: Thanks so much. Are there other thoughts on the TROPiCS-02 data?

GAO: Do the TROPiCS-02 data include those patients with brain metastases?

HUPPERT: Yes, there were patients with stable brain metastases in the TROPiCS-02 trial. The trial excluded active brain metastases.

There’s a lot of interest in the CNS [central nervous system] activity of these drugs. We have more and more data that there potentially is CNS activity of ADCs [antibody-drug conjugates]. Trastuzumab deruxtecan [T-DXd; Enhertu] [demonstrated] CNS response in multiple trials.^4,5 I think there’s some also for sacituzumab for CNS response. In patients with [leptomeningeal disease], there is some response in small cohorts.⁶ I’m interested in CNS metastases as an area of interest, and a high area of unmet need is patients with especially active brain metastases and how these drugs work in them.

GAO: The reason I’m asking is it looks like T-DXd did show activity on the brain metastases. It’s hard to say which medications are better, and [whether] it will let me choose. I probably will put my patients with brain metastases on T-DXd. With stable or no brain metastases, I would probably use sacituzumab.

HUPPERT: Yes, it’s a good point. Understanding the CNS efficacy of these agents is paramount.

HSU: You stressed that the point is if you look at the 12-month data, the PFS looks pretty impressive. I had 2 patients on this drug who had no major adverse events whatsoever. [When] you treat a patient and it’s a third-line or fourth-line therapy, you expect only 6 months of PFS. [If] they’re still responding after 12 months, it will convert you to a believer right away.

XIE: The overall survival [OS] benefit is a big deal for…sacituzumab [From the Data⁶]. I use it for patients, but I would echo Dr Dabhi’s comments. It’s not an easy drug to give, with cytopenia and GI toxicity. I also have to do dose reductions, but the benefit is a little better than with eribulin [Halaven]. From that standpoint, OS benefit would be very important.

HUPPERT: Yes, thank you for that point. [It is] definitively compelling to have that OS data now…[for] both ADCs, in fact.

DISCUSSION QUESTIONS

• Have you treated patients with both approved ADCs? In what order?
• If a patient’s disease progresses after receiving both ADCs, what do you treat with next?

HUPPERT: When treating metastatic breast cancer with a TROP-2 inhibitor, including sacituzumab as a TROP-2– directed ADC, have you treated with both approved ADCs? [It appears] not many of us [have] yet, which is why… this is an area of eager interest. These ADCs were just approved in the past year or so, and so we’re all starting to use them, and use them one after another in certain patients. Dr Chen, what was your experience using one and then the other?

CHEN: There was a patient [who] I first treated with sacituzumab. This was before the T-DXd was approved. It was for triple-negative breast cancer. I treated her with sacituzumab first, and she did have a fairly good response. I did give her every-other-week treatment with G-CSF in between, and I did do a dose reduction. When she progressed, that’s when the T-DXd was approved. We went back and she did have the [HER2] 1+ status, so she was able to get the T-DXd. She’s still on it [and has been for] quite a few months.

HUPPERT: That is really good to hear. Anecdotally, I have also seen responses of one after the other. But it’s good to know you’ve seen a success story, and it’s good for others to be aware of that area of interest. Hopefully we’ll have more data soon.

If a patient’s disease progresses after receiving 1 or both ADCs, what do you reach toward next? I know there are not definitive data here.

DABHI: Patient preference drives the chemotherapy options. I’ll take a step back. If the duration of time between the last hormonal manipulation and now is substantial, one could even consider reverting back. Otherwise, I generally go with the chemotherapy drug. If they prefer oral, then it’s going to be capecitabine [Xeloda], otherwise it’s a taxane.

HUPPERT: I agree; taxanes are great. If they haven’t received capecitabine, that’s great. I use it a lot. We have lots of options there.

I tend to not go back to endocrine therapy after they’ve exhausted it, unless they have limited disease and there’s a compelling reason where they need to be on an oral [therapy] and they haven’t seen an agent before. It’s always an option in theory, too.

_REFERENCES

_{1. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. News release. FDA. January 27, 2023. Accessed August 21, 2023. https:// tinyurl.com/yfdwjtc5}

_{2. Lu YS, Mahidin EIBM, Azim H, et al. Primary results from the randomized phase II RIGHT Choice trial of premenopausal patients with aggressive HR+/HER2− advanced breast cancer treated with ribociclib + endocrine therapy vs physician’s choice combination chemotherapy. Cancer Res. 2023;83(suppl 5):GS1-10. doi:10.1158/1538-7445.SABCS22-GS1-10}

_{3. Rugo HS, Bardia A, Marmé F, et al. Sacituzumab govitecan in hormone receptor-positive/ human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2022;40(29):3365-3376. doi:10.1200/ JCO.22.01002}

_{4. Jerusalem GHM, Park YH, Yamashita T, et al. Trastuzumab deruxtecan (T-DXd) in patients with HER2+ metastatic breast cancer with brain metastases: a subgroup analysis of the DESTINY-Breast01 trial. J Clin Oncol. 2021;39(suppl 15):526. doi:10.1200/JCO.2021.39.15_suppl.526}

_{5. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2- low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690}

_{6. Rugo HS, Bardia A, Marmé F, et al. Overall survival (OS) results from the phase III TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with HR+/HER2- metastatic breast cancer (mBC). Ann Oncol. 2022;33(suppl 7):S1386. doi:10.1016/j. annonc.2022.08.012}