Roundtable Discussion: Rao Looks At Multiple Scenarios That Highlight Single-Agent Treatment in Metastatic TNBC

Ruta D. Rao, MD

Medical Director

Rush University Cancer Center

Associate Professor

Department of Internal Medicine, Division of Hematology, Oncology and Cell Therapy, Rush Medical College

Rush University Medical Center

RAO: Does anyone want to chime in and say which intravenous [IV] chemotherapy they would use at this point?

RAJA: I was thinking of paclitaxel [Abraxane] for this patient while another option would be docetaxel [Taxotere], but I like paclitaxel because of the better toxicity profile.

RAO: Would you hesitate to use a taxane 8 months after her adjuvant taxane, or to you that’s a good [choice]? We know that there’s no absolute right or wrong answer here.

RAJA: I think patients who fail paclitaxel can still [have a taxane in] 8 months; that’s reasonable. I think a 6-month treatment-free interval may still be reasonably good; it’s just taxane sensitivity.

RAO: Did anybody else have any other thoughts on which IV single-agent chemotherapy they used?

ZOGHBI: I was thinking about carboplatin and a gemcitabine chemotherapy agent. I think after the dose there’s paclitaxel followed by docetaxel, and I think she progressed relatively quickly. I think evaluation for clinical trial [is also appropriate], it’s not a bad option to have it done at the same time while I’m initiating my therapy.

RAO: Right, I think you bring up a great point. We always should be considering if we have a clinical trial available for these patients.

BHAMIDIPATI: I’m thinking more of eribulin, because there were some phase 2 data where patients who have relapsed within under 12 months from the neoadjuvant or adjuvant therapy could be a good option, too.¹

GUPTA: IV chemotherapy seems like the logical choice here, but [the patient is] recurring too quickly here. We can talk about it as more than 6 months, but how about going to sacituzumab [Trodelvy]? I know that’s not the label indication, but that is a reasonable thing to consider here. I know the response rate is higher, plus it will be a slightly different approach, so to speak.

RAO: Again, that’s an off-label use for sacituzumab,² but I think we would all consider it because of her short, less than 1-year recurrence from her adjuvant therapy. To the previous comment, I think eribulin is also one of the top choices for single-agent IV chemotherapy in these situations. It looks like nobody chose oral single-agent chemotherapy. Does that mean that no one would give this patient capecitabine? I’m reading it as that. Any other comments on what chemotherapy you would choose for this patient?

SUMOZA: Despite this [patient having] a rapid progression of disease, they did the liver biopsy. Any change of the receptors?

RAO: That’s a great question and that’s always one of the reasons that we would do a re-biopsy. In this case, we’re saying no, there’s no change in receptors. The liver biopsy still came back with TNBC, but that’s where the PD-L1 testing was done and found to be [a score of] zero.

ZOGHBI: I think, then, sacituzumab is not a bad idea if we get it approved. In my own mind [at least it’s a good idea], since it’s a different mechanism of action, especially if the clinical trial proved to be a good choice in those patients who are RCA negative and who have PD-L1 negative at least.

RAO: I think what I’m hearing from a few of you at least is that we need something that works a little bit differently than our standard chemotherapies for this patient who’s progressed quickly after some of our strongest breast cancer therapy.

ZOGHBI: Exactly.

RAO: So let’s do an alternative scenario here. It’s our same patient, but now let’s say what frontline therapy would you recommend for this patient with metastatic recurrence [24 months after adjuvant ddAC-paclitaxel]? Again, she presents in the same way but now the time interval is 24 months. [So would] anybody change what they would give as their first-line therapy? If so, what were you thinking before and what did you change it to now?

MATTAR: I would change from gemcitabine/carboplatin to paclitaxel. I feel there’s enough time spent between the prior taxane with the paclitaxel and now I feel more comfortable with it. Earlier on, I would have felt it was too close to be giving back-to-back. I would have liked platinum-based therapy because this lady is aggressively progressing at a fairly young age.

DORIUS: I would also change my answer because on the previous question I would have answered clinical trial for both, so if there’s a good trial for this patient, especially in the prior case, but also in this one, I would have chosen that. But I agree, and I would have been more likely to use a taxane as my first-line metastatic treatment in this second case than I would have been in the first one.

ZOGHBI: I also chose IV chemotherapy and it just came to my mind this is a young lady and sometimes oral chemotherapy in that setting might be an option for patients who don’t want to come to the office, for patients who maybe have a lifestyle that includes traveling. It just may be a few patients who may elect oral chemotherapy vs IV just more for lifestyle modification, or they maybe have something going on [that it fits their situation better]. I sometimes reserve it for those indications if patients cannot or don’t want to get IV chemotherapy. In fact, I had a patient case with TNBC who didn’t want to come in, so I gave her capecitabine. She stayed for 3 years with TNBC, and in fact, on a half-dose of capecitabine. To be honest, when she progressed, she didn’t want anything as she just went to hospice after that. I just keep that capecitabine maybe for people like this lady, who didn’t want to be on a chair, or patients who don’t want to make it to the office for IV treatment for certain reasons.

RAO: I think it’s just important, like you said, to talk about how you give the treatment, what it requires in terms of coming to the office, and even [discuss] some of the toxicities. We know that capecitabine does not cause hair loss and a taxane will, which to some patients is very important.

HADDADIN: [This patient] progressed on 2 lines of treatment, so I think sacituzumab is appropriate. The clinical trial is also appropriate, so I think these are probably the 2 main choices that I will look at.

BHAMIDIPATI: I would choose sacituzumab. I mean it’s per the label, at least in first-line treatment with at least 1 treatment in the metastatic setting. This is a second line technically. For [patients who are] PD-L1 negative, this is one of the problems as the only option we have is essentially IV chemotherapy or sacituzumab, and that’s about it. Anything after sacituzumab is almost nothing, 1 thing I would do is next-generation sequencing [NGS]. It mentioned about BRCA, but maybe the [homologous recombination] deficiency could be something I would leverage in this case because she’s young.

RAO: Now [in our alternate scenario], a patient who recurs 24 months after their adjuvant therapy, but the same situation, gets first-line therapy that gives her a partial response for 6 months. We can say that that was the gemcitabine plus carboplatin combination again. Now she’s progressing and you have to pick her second-line therapy. What would you give her this time?

RAJA: I would use sacituzumab. Again, the time of whether it’s 8 months or 24 months would not make any difference.

RAO: So you’re looking more at the fact that this is a second-line treatment, not thinking now about the amount of time between her disease recurrence?

RAJA: That’s correct.

MATTAR: The 8 months has value for not using the same class of drug, but at each level I’m already using a different class of drug, so it doesn’t matter, 8 months or 2 years.

RAO: Sure, I think that’s probably how most of us are thinking about this. But what are the therapeutic options for patients with rapid recurrence? I guess 1 thing I’ll ask all of you: Is this a situation where you would consider a single agent or when you have this rapid recurrence—remember our patient was somewhat symptomatic with fatigue—would you consider combination chemotherapy for someone like that? Her liver function tests [LFTs] were 1.5 x the upper limit of normal at her initial presentation. The age is important, a patient in their 40s or 50s is different than somebody in their 70s or 80s. Patients in their 70s or 80s will be different and you will start talking about 1 more line and then comfort care. Somebody in their 40s you cannot stop at second line. That’s why I tend to use doublet in a younger lady like this and single agent in an older lady [who is] kind of preparing for hospice. The older patients should also be defined more by physiological age than chronological age.

ZOGHBI: I think disease burden also plays a role, along with the rapid progression, and symptomatic, too. So I also chose on the first answer combination chemotherapy.

RAO: Were you thinking that because you were worried about her disease burden, because she had enough to cause abnormal LFTs?

ZOGHBI: Exactly. Again, she is young and has increased LFTs. I mean the liver is different than bones, like with no certain site of metastasis, tends to be more aggressive, a clinical presentation vs another site. We know in general TNBC tends to be a more aggressive disease vs other types of breast cancer.

RAJA: I had 1 patient who did well and the other 2 did not [on sacituzumab]. Tolerability? Significant nausea and vomiting in patients. That was worse than the diarrhea. Again, everybody has different toxicities. I do use granulocyte colony-stimulating factor [G-CSF] to take care of the neutropenia.

RAO: How are you giving the G-CSF?

RAJA: I gave it on day number 8, and I gave them pegfilgrastim [Neulasta], so that should take care of it.

RAO: Did you have any trouble with the patient being neutropenic on day 8 after the first day of the cycle?

RAJA: Yes. That happens every so often and I have to dose reduce in that situation.

MATTAR: I use it as well. Neutropenia has been the main issue for us and sometimes we have trouble with the insurance claim to get any of the pegfilgrastim or the G-CSF if they have febrile neutropenia. That had been some of the problem, that they don’t approve it, or they approve it 72 hours later where you’re already close to day 8. That has been honestly challenging, but it’s well tolerated, other than neutropenia, and we’re all familiar with that. We just have to adjust.

RAO: Do you see the diarrhea and nausea in your patients?

MATTAR: [I do, and its] less problematic. I have had some diarrhea, but it was more the neutropenia that was a problem.

RAO: [What about] fatigue? How does it compare in terms of fatigue to when you give other chemotherapies to these patients?

MATTAR: Those poor ladies, they are on their third line [of treatment]. They’re already exhausted. I don’t think that I can blame it on this drug vs the next drug.

DORIUS: I had a patient who I gave this to, and she had severe diarrhea, such that I had to reduce her dose because it wasn’t controlled. She was fit going into [treatment], too, so I was a little surprised at that, but she’s done fine on a reduced dose.

RAO: The reduced dose was effective in controlling her diarrhea, right? What about efficacy for your patient? Have you determined that yet?

DORIUS: Not yet. She just had about 3 cycles of it, so I think scans are coming up soon. We’ll see.

HADDADIN: My patient was being heavily pretreated, and think she was on the fourth line. She had lots of pain issues, so she was on opioids as well. I started her on pegfilgrastim from the beginning because she had history of neutropenic fevers and she was taking it with the previous regimen. I never had any issues with neutropenia. She was on narcotics, and she was a bit constipated, but she never had any diarrhea with this treatment, however, she was annoyed by the hair loss. As for efficacy, she did not actually respond to treatment with this regimen, but she was heavily pretreated.

BHAMIDIPATI: I have a few patients that had sacituzumab, a couple of patients with brain metastases on third line of therapy or something after PD-L1 when atezolizumab [Tecentriq] was approved. After failing on the therapy, they had treated brain metastases, but I did not see much response because the patient did progress with new brain metastases. Then I would say in 2 out of 3 of my patients I could see some response with the sacituzumab, relatively longer time to progression, but again, the nausea was more of a problem than the diarrhea that I have seen. The G-CSF, I agree with others that it is what I would use. Sometimes I would have done the days after the first day of sacituzumab, but usually that is more with eribulin than with the sacituzumab that I have seen that kind of using the G-CSF. But pegfilgrastim on day 8 is what I have used in the past.

HUESER: The comment about not being able to get the G-CSF up front is becoming more and more of an issue before the insurance will pay for it. I try to be proactive as it’s getting much more difficult, because neutropenia is the usual AE [in many patients].

RAO: Anybody else have something that they say to the patient about how its mechanism of action is working? What do you tell your patients about the toxicities of this drug in particular?

HADDADIN: I tell my patients it’s kind of like a Trojan horse, where you have the drug-antibody conjugate, and it does deliver the drug to the cancer cell. [When it comes to the toxicity], I go through everything, but again, main concern is neutropenia and diarrhea, so these are the main 2 things I discuss with my patients.

RAO: So, the outcomes of the phase 3 ASCENT trial [were analyzed] in context of other therapies that have been most used in the setting of relapsed or refractory metastatic TNBC.³ Were you all surprised to see how the treatment of physician’s choice arm did in this trial or do you think of it in the context of other trials in the metastatic triple-negative setting [From the Data³]? Has anyone used it in the second-line setting or have most of you used it in the third-line setting or did you only start using it after the full approval, which allows us to use it in the second line?

HUESER: After the full approval.

RAO: After the full approval? So more so in the second line.

RAJA: Yes, at the first opportunity, use this drug. In the second line, if they only receive the adjuvant, only adjuvant therapy. And if they’re not, then it’s going to be third line.

RAO: Somebody had brought this up earlier. What is your overall approach to molecular testing at the time a patient has a relapse or progression?

HADDADIN: I test everybody.

MATTAR: At any time we have to change therapy, we have seen that. Maybe not as much in the breast cancer landscape, but we see it more [in other patients with] cancers. They can acquire new mutations. I have seen even 1 case of microsatellite instability [MSI] become significantly changed from the beginning and I was able to give him new therapy later [when his colon cancer progressed]. I don’t know how that case happened, honestly, but the patient did end up having MSI-high disease and I treated them with immunotherapy. After, I sent him to hospice and then I called him back and I said, “I have that.” Honestly, this was a case after third line for months and I don’t know how he did acquire, if the first one did miss it. Honestly, I checked again because in my mind it could have been missed before, but it wasn’t missed before. New lesion, new spot, new Guardant360, and I find out that they have that.

HUESER: I think more often longitudinal genomic profiling is the way to go. I mean you just never know what’s going to pop up positive, what new target is going to be there. To your point, some of the NGS companies will tell you as they go back, as their technology gets better and they rerun old samples, they will find druggable mutations. I think sending it off, there’s no harm in it.

RAO: Right. I think especially for these patients where we’re really looking for additional treatment options, if you find that 1 patient who has something, it can be helpful.

BHAMIDIPATI: One thing that I’m excited about is that the HER2 low is something that I kept looking for, kept on noticing in my charts, like looking at initial samples and saying 1+ expression that I put in brackets these days, hoping 1 day I will have a drug. NTRK is another one I keep hunting for. I found only 1 tumor that had NTRK, not the breast cancer, but I keep looking for it.

_References

_{1. Pellegrino B, Cavanna L, Boggiani D, et al. Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). ESMO Open. 2021;6(1):100019. doi:10.1016/j.esmoop.2020.100019}

_{2. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. FDA. April 8, 2021. Accessed May 17, 2022. https://bit.ly/3lk8bay}

_{3. O’Shaughnessy J, Punie K, Oliveira M, et al. Assessment of sacituzumab govitecan versus treatment of physician’s choice cohort by agent in the phase 3 ASCENT study of patients with metastatic triple-negative breast cancer. J Clin Oncol. 2021;39(15):1077. doi:10.1200/JCO.2021.39.15_suppl.1077}