Clinical Commentary: Sharma Shows How Sacituzumab Impacts Treatment for Patients With TNBC

Priyanka Sharma, MD

Assistant Director of Clinical Research

Co-Program Leader, Drug Discovery, Delivery and Experimental

Therapeutics Program

University of Kansas Medical Center

Kansas City, KS

Treatment Options in TNBC

In this case, the patient received first-line gemcitabine and carboplatin and had a partial response for 6 months, which in this situation is robust. A progression-free survival of 6 months with this rapid recurrence is quite nice. You don’t see that in many trials, but after 6 months, she has progression in the liver, which is now enlarging, and her performance status has declined a bit.

I don’t use doublet [regimens] a whole lot and there isn’t any survival advantage for those. Often, in our registration for phase 3 trials that are comparing first-line therapy…taxane [will be] the control arm for these patients. Patients who have rapid recurrence, especially in this era, if they’ve had anthracycline, taxane, platinum, and capecitabine given to them during that initial period, then the decisions are a bit more challenging in terms of what to give these patients in the firstline setting that is likely to provide benefit.

In terms of then thinking about treatment options for this patient with rapid recurrence, the underlying comorbidities [of the patient are]…one of the first 2 things we think about as we’re making treatment decisions, with patients’ wishes and treatment goals being important [as well].

However, these patients with [TNBC who] have these rapid recurrences within the first 12 months have quite poor outcomes, especially in this era where most of them received all our good drugs in [the] frontline setting. [For example,] if a patient has a tumor that had a short time of response to the drugs that they were exposed to, probably, you’re not going to get much response reexposing the cancer to the same drugs if it’s within the short time period.

The Role of Sacituzumab Govitecan in TNBC

Some of these patients must consider what they got in the curative setting as a line of therapy for metastatic disease. Assuming this person had platinum[-based] and taxanebased chemotherapy, in the first line my choice would be agents that are not those, and out of the regular chemotherapy options, I would be left with eribulin [Halaven].

However, in the ASCENT study [NCT02574455], sacituzumab was superior to eribulin,¹ so ideally, I would like for the patient to have access to sacituzumab with rapid progression out of what is available right now, as you want to target HER2 positive, and sacituzumab is the most robust option. Of course, at times we are restricted by what the label of the drug is, and what we can get our patients access to.

Sacituzumab was approved by the FDA for patients with unresectable, locally advanced, or metastatic TNBC who received 2 or more prior systemic therapies, with at least one of them for metastatic disease.² The 1 prior therapy in the neoadjuvant or adjuvant setting counts as 1 line, and then 1 line of metastatic therapy, and in a case [like this] it sometimes makes even more sense to introduce it in the first line, because you’re kind of out of options from good agents, unless there is a trial that’s available.

Assessing Subgroups [A question clinicians ask themselves when sequencing treatment is whether] we should save the best for last as some patients just won’t get there, and the other thing that I have noted is for patients where this is working, I don’t run into cumulative toxicity. For other treatments, like taxanes or even vinorelbine, even when it’s working, often after a certain number of cycles, you run into neuropathy or other adverse events [AEs] where you now must stop the drug because of them. So, if you can get through managing the cytopenias and diarrhea, then if it’s working, then somebody can stay on it for a year to a year and a half without worrying about neuropathy.

But I do have to say that when this was our first antibody drug conjugate [ADC] for patients with breast cancer beyond trastuzumab [Herceptin] and in HER2-positive patients, the general thought process, or what we expected, was, it’s going to be like T-DM1 with no neutropenia and we won’t have issues with it. When you’re [treating] patients in clinic, it is kind of like [treating] somebody on chemotherapy in terms of some of the AEs, so even though it is an ADC and has more robust activity for the cancer itself, the other AEs do mimic chemotherapy, so it requires that management for the patients.

If we look at the ASCENT data by the germline BRCA status, what we see is the presence or absence of germline mutation [in the disease] doesn’t impact the efficacy of sacituzumab [Table³ ]. Of course, it plays an important role for a patient to have access to a PARP inhibitor, probably before they got to needing sacituzumab, and the TROP2 expression was also assessed in ASCENT with more than 80% of patients [having] a high or medium expression [whereas] only 20% have low expression. There wasn’t enough power to compare the low vs the high to medium expression subgroups but given [that] most patients have high to medium expression, TROP2 expression isn’t considered a biomarker for the efficacy of sacituzumab.

So at least to date…we don’t have any valid clinically available biomarkers that help us select and say that this population is going to benefit the most or, on converse, [that] this population is unlikely to benefit from sacituzumab. The survival after this point is poor for these patients; if you look at overall survival, it’ll be under 6 months for many of these patients, and clearly, an area of unmet need, and we need better treatment options for these patients; [having] access to look for a trial, obviously, is important.

Toxicity Management With Sacituzumab

It does come up sometimes in terms of whether we can deliver these ADCs to our older patients. I don’t want to say patients greater than 65 years are necessarily older patients, but certainly older than our average patients with TNBC, and we see [whether] the efficacy was maintained regardless of the age. Sacituzumab was not any less effective in older patients, and the physician’s choice was also, by the same comparison, not any more effective in older patients.

As expected, the dose reductions were more frequent in older patients, but they were similar overall between both arms, and the treatment discontinuation due to treatmentrelated AEs was, again, a very small proportion of patients, and, equally, just seen in both arms.4 So, if older patients have trouble tolerating the standard chemotherapy drug, they will have similar trouble tolerating sacituzumab, but this is not particularly any harsher for older patients.

Now, if I’m kind of worried about [patients experiencing] diarrhea I will start at a lower dose, because I think it’s easier to manage low-grade diarrhea, get a good system in place, and then build the dose up, as opposed to the patient getting into severe trouble with that diarrhea or with something else like kidney dysfunction or hospitalization. I’ve been starting to do that, especially in women who are over 70 years…I start one dose [level] lower and I will let them get through per the cycle, and figure out what we’re going to do, and then with the second cycle, if we feel comfortable, we go back up on the full dose.

_References:

_{1. Bardia A, Tolaney SM, Loirat D, et al. Sacituzumab govitecan (SG) versus
treatment of physician’s choice (TPC) in patients (pts) with previously treated, metastatic triple-negative breast cancer (mTNBC):final results from the phase3 ASCENT study.J Clin Oncol. 2022;40(suppl16):1071.
doi:10.1200/JCO.2022.40.16_suppl.1071}

_{2.FDA grants regular approval to sacituzumab govitecan for triple-negative
breast cancer. FDA. April 8,2021. Accessed November 10, 2022.
https://bit.ly/3TmLaSN}

<sub>3. Bardia A, Tolaney SM, Punie K, et al. Biomarker analyses in the phase III
ASCENT study of sacituzumab govitecan versus chemotherapy in patients
with metastatic triple-negative breast cancer.Ann Oncol. 2021;32(9):1148-
1156. doi:10.1016/j.annonc.2021.06.002</sub>

_{4. Bardia A, Hurvitz SA, Tolaney SM, et al; ASCENT Clinical Trial Investigators.
Sacituzumabgovitecan inmetastatictriple-negativebreastcancer.N Engl J
Med. 2021;384(16):1529-1541.doi:10.1056/NEJMoa2028485}