Therapy Progression in TNBC Leads to Important Second-Line Decision

AS INVESTIGATORS CONTINUE to focus on targeted therapies, some cancers present a separate challenge from most cases. This is where triple-negative breast cancer (TNBC) sits in comparison with other subtypes of the disease.

Although targets like HER2, estrogen receptor (ER), and progesterone receptor (PR) have received attention, there are patients with TNBC don’t have either ER or PR and don’t make much of the HER2 protein. Patients with this disease tend to be younger, and the disease is more aggressive and usually spreads faster by the time it’s diagnosed in patients. According to the National Cancer Institute Surveillance, Epidemiology, and End Results Program database, patients with localized TNBC had a high 5-year relative survival rate of 91%.¹ However, the likelihood of a 5-year relative survival lessens to 66% if the cancer spreads to nearby structures in the body and just 12% if they have distant metastases. Treatment options for these patients are not as robust as other disease types or even different types of breast cancers, which means disease progression is not uncommon.

With patients who have metastatic TNBC, understanding the treatment methods and options as they progress is paramount, but not every physician may take their patient down the same treatment path from the frontline to later lines of treatment. This is due in part to the continuing call for more individualized treatment and finding ways to move beyond the tough toxicities presented by chemotherapy, and the advent of novel therapies that have shown their potential for wider use in this patient population, such as sacituzumab govitecan-hziy (Trodelvy).

This antibody-drug conjugate (ADC) was approved by the FDA in 2021 for patients with unresectable locally advanced or metastatic TNBC who received 2 or more systemic therapies prior to the use of sacituzumab govitecan.² This drug was initially given an accelerated approval in 2020 with the same indication, highlighting the lack of treatment options for patients with TNBC whose disease has recurred. Moreover, this approval provided physicians with a stronger step in their treatment algorithm after the failure of first-line treatment. Still, the choices from the first line to the second line of treatment for patients with TNBC differ among physicians.

In 2 separate, live virtual Case- Based Roundtable events, physicians from across the country discussed the treatment path from frontline therapy to second-line sacituzumab govitecan for patients with metastatic TNBC.

ANALYZING DIFFERENT APPROACHES IN THE FRONTLINE SETTING OF TNBC

The physicians in each group looked at the hypothetical patient case of a 45-year-old woman with T2N+ TNBC who received 200 mg of neoadjuvant pembrolizumab (Keytruda) every 3 weeks for 4 cycles, in addition to paclitaxel/carboplatin chemotherapy, followed by an additional 4 cycles of pembrolizumab plus doxorubicin/cyclophosphamide. The patient then underwent a lumpectomy with axillary lymph node dissection and adjuvant therapy of pembrolizumab given every 3 weeks for 9 cycles, in addition to capecitabine. Eight months after the completion of her adjuvant therapy, the patient reported worsening fatigue and was confirmed to have metastatic disease after a CT scan showed 3 hepatic lesions and regional lymph node involvement and a liver biopsy confirmed her diagnosis, as she was ER/PR negative and her immunohistochemistry for the HER2 protein was 0.

Hope S. Rugo, MD, the moderator for one of the events, pointed out that a patient like this who is already relapsing at 8 months after treatment will have a short immediate survival window, but physicians must balance toxicities and look to another treatment soon after the patient’s adjuvant therapy fails. Rugo then asked the participants to answer a poll on what they would give a patient like this who recurred 8 months after adjuvant capecitabine. The results were nearly evenly split between physicians who wanted to find a clinical trial for this patient and those who wanted to continue either single-agent or combination chemotherapy.

Rugo mentioned that she generally does not use combination chemotherapy in a patient case like this, but when she does decide on using combination chemotherapy in the frontline setting, it would be with gemcitabine and carboplatin. Although chemotherapy, and particularly combination therapy, is still a cornerstone of treatment for these patients, it can lead to high rates of toxicity and have been found to lead to worse quality-of-life outcomes.³ This is because the patients who do not achieve a pathologic complete response to neoadjuvant chemotherapy are much more likely to then relapse and show resistance to chemotherapy.

According to a literature review published in Cells, one of the most common developments of chemoresistance comes from transporter-mediated drug efflux, such as ATP-binding cassette (ABC) transporters that use ATP to efflux compounds from anticancer drugs.³ These ABC transporters have been associated with MRP1 and MRP8, which are expressed more frequently in patients with TNBC than other patients with different cancer subtypes. Further, findings have shown that the expression of these proteins are increased in patients with TNBC receiving neoadjuvant chemotherapy. Still, the lack of frontline treatment options means physicians will have to work with the options available to them and balance toxicities while looking for responses.

“Of course, clinical trials [also work for a] patient such as this, but otherwise, I would do single-agent chemotherapy. Drugs such as gemcitabine are attractive or for these patients, [as they are] tolerable,” Ian DeRoock, MD, a medical oncologist at the Ironwood Cancer and Research Centers in Casa Grande, Arizona, said during the discussion of frontline therapy in the virtual event led by Rugo. “I have given carboplatin and gemcitabine for similar reasons, and some of [my] patients were worried that were progressing fairly rapidly and [were then] concerned about getting a more immediate response [from their therapy].”

When asked the same question, 6 physicians from a different live virtual event discussing the same case agreed with DeRoock, responding that they would use single-agent chemotherapy, with 4 of them saying they would choose capecitabine in this case. Another 4 physicians responded that they would put a patient like this on a clinical trial after relapse 8 months from neoadjuvant therapy [Poll 1]. This group was led by Roberto A. Leon-Ferre, MD, and focused on the National Comprehensive Cancer Network guidelines that recommend the use of systemic chemotherapy in a patient with TNBC with a PD-L1 combined positive score of less than 10% and no germline BRCA1/2 mutation,⁴ much like the patient case in the roundtable discussions.

However, Rugo’s group of physicians asked the question: Why not introduce sacituzumab govitecan in this setting? According to Rugo, this patient could technically be considered in the second-line setting since their disease recurred within 12 months of their adjuvant therapy, but the FDA approval for sacituzumab govitecan requires the patient to have 2 prior lines of therapy. Although she cautioned not to use sacituzumab govitecan so soon, she sees this setting as one that’s good to try for patients with invasive breast cancers and highlighted the ongoing ASCENT-07 trial (NCT05840211).5 Although the study is currently looking at the use of sacituzumab govitecan for patients with HR-positive/HER2-negative metastatic breast cancer, it is looking at the use of the ADC in an earlier line of therapy, and these results could lead to more trials for patients with TNBC.

DISEASE-FREE SURVIVAL CONSIDERED IN FRONTLINE APPROACH

Disease recurrence in the frontline setting prior to the use of second-line therapy for patients with TNBC is not necessarily tied to a specific time frame but rather the first disease recurrence and the number of subsequent therapies. Thus, both groups were also presented with an alternate scenario, in which the patient had metastatic disease recurrence 24 months after their adjuvant combination with chemotherapy and then given a host of systemic therapies. In both virtual events, most physicians responded with either the continued use of capecitabine or single-agent chemotherapy in general. Seven physicians in Leon-Ferre’s group chose to stick with capecitabine compared with 5 in Rugo’s group [Poll 2].

“A lot of people are interested in looking at capecitabine again, or single-agent chemotherapy, and [those are] the 2 big choices [at this stage]— it’s interesting,” said Rugo, professor of medicine, Winterhof Family Professor of Breast Cancer, and director of breast oncology and clinical trials education at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center. “Having that longer disease-free interval makes us more interested in giving single-agent chemotherapy, or even retesting capecitabine.”

In a meta-analysis of available data on the efficacy and safety of the addition of capecitabine for patients with TNBC published in Frontiers in Oncology, investigators found that capecitabine provided a significant disease-free survival (DFS) and overall survival (OS) benefit across the board when added to treatment for patients with TNBC.⁶ Pooling the HRs from 11 randomized controlled trials, the investigators looked at available data from 2804 patients with TNBC who were given additional capecitabine and saw a DFS HR of 0.77 (95% CI, 0.68-0.86) and an OS HR of 0.73 (95% CI, 0.63-0.85). Although there is promise of a good DFS rate for patients on this treatment, the drug is associated with specific adverse events (AEs) that physicians must balance. In the meta-analysis, capecitabine was associated with a higher risk of diarrhea, with an odds ratio (OR) of 3.1 (95% CI 2.32-4.15); hand-foot syndrome (OR, 25.8; 95% CI, 15.32-43.42); and leukopenia (OR, 2.1; 95% CI, 1.13-3.84).⁶

“The way I think about it is that we’re more willing to recycle one of the early-stage drugs like a platinum [therapy]. Some may also argue to re-expose [the patient] to a taxane, because even though the patient was exposed to it, they didn’t technically progress on it. So, you may be able to recycle these drugs given the longer disease-free interval,” Leon-Ferre, a consultant in the Division of Medical Oncology and Department of Oncology and assistant professor of oncology at Mayo Clinic in Rochester, Minnesota, said while explaining his rationale for further chemotherapy in a patient case like this.

During Rugo’s event, the idea of introducing sacituzumab govitecan earlier into this patient’s treatment was brought up again, but she reiterated to hold it until the second line. Although she has seen patient cases where sacituzumab govitecan worked earlier, the second line is where it’s approved for now and further testing is needed to prove its efficacy in the front line for patients with metastatic TNBC.

SACITUZUMAB GOVITECAN SHOWS THE MOST IMPACT IN THE SECOND LINE

When asked what they would recommend for the second line of treatment for a patient like this, 11 physicians in Leon-Ferre’s group chose sacituzumab govitecan compared with 9 physicians in Rugo’s group; 2 physicians in Rugo’s group wanted to stick with capecitabine and 1 wanted to remain on a general taxane path [Poll 3]. Rugo responded to these chemotherapy responses by explaining that in her experience, capecitabine hasn’t worked well for patients with TNBC at this point of treatment, but it’s possible to try it if the physician monitors the patient frequently. However, the use of taxane therapy depends on the patient’s resistance to them when they are first given chemotherapy in the frontline setting.

In both groups, the physicians echoed each other on the ability to use sacituzumab govitecan early in this second line and giving the patient the most active agent possible. Their impressions of the ADC came from the results of the phase 3 ASCENT trial (NCT02574455), which looked at a total of 486 patients with TNBC without brain metastases who were randomly assigned to either 10 mg/kg of sacituzumab govitecan (n = 267) given intravenously on days 1 and 8 of a 21-day cycle compared with patients on the treatment of physician’s choice (n = 262).⁷

The study reached its primary end point of progression-free survival (PFS) with a significant difference in median PFS in the sacituzumab govitecan arm vs physician’s choice of therapy, at 5.6 months (95% CI, 4.3-6.3) vs 1.7 months (95% CI, 1.5-2.6), respectively (HR, 0.39; 95% CI, 0.31-0.49; P < .0001).⁷ Further, the secondary end point of OS favored the use of the ADC, with a median OS of 12 months (95% CI, 10.7-14.0) in the sacituzumab govitecan arm compared with 6.7 months (95% CI, 5.8-7.7) in the control arm (HR, 0.48; 95% CI, 0.39-0.59; P < .0001).

All subgroup results in this trial favored the use of sacituzumab govitecan, notably in patients with or without the previous use of PD-1 or PD-L1 inhibitors, with a median PFS of 4.2 months (95% CI, 3.2-5.6) vs 1.6 months (95% CI, 1.4-2.3) in the chemotherapy arm (HR, 0.37; 95% CI, 0.24-0.57) and 6.2 months (95% CI, 4.9-7.1) vs 2.1 months (95% CI, 1.5-2.7) in the control arm (HR, 0.42; 95% CI, 0.32-0.56).⁷

“When compared with all the options in the [treatment of physician’s] choice, none showed particularly encouraging results, emphasizing that, unfortunately, cytotoxic chemotherapy is incredibly limited in the second line for metastatic TNBC,” Leon-Ferre said.

_REFERENCES

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_{2. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. FDA. Updated April 8, 2021. Accessed October 9, 2023. https://bit.ly/46PRf1w}

_{3. Nedeljković M, Damjanović A. Mechanisms of chemotherapy resistance in triple-negative breast cancer-how we can rise to the challenge. Cells. 2019;8(9):957. doi:10.3390/cells8090957}

_{4. NCCN. Clinical Practice Guidelines in Oncology. Invasive breast cancer, version 4.2023. Accessed October 9, 2023. https://bit.ly/3Fd0Vau}

_{5. Study of sacituzumab govitecan versus treatment of physician’s choice in patients with hormone receptor-positive/ human epidermal growth factor receptor 2 negative (HR+/ HER2-) metastatic breast cancer who have received endocrine therapy (ASCENT-07). ClinicalTrials.gov. Updated September 15, 2023. Accessed October 9, 2023. https://bit.ly/48R1Fzs}

_{6. Xun X, Cao Q, Hong P, et al. Efficacy and safety of capecitabine for triple-negative breast cancer: a meta-analysis. Front Oncol. 2022;12:899423. doi:10.3389/fonc.2022.899423}

_{7. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485}