Part 1: Sacituzumab Shows Efficacy in Second-Line Metastatic TNBC

Sara Tolaney, MD, MPH

Chief of Breast Oncology and Associate Director

Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute

Associate Professor, Harvard Medical School

CASE SUMMARY:

• A 48-year-old woman with T1N1 triple-negative breast cancer (TNBC) received adjuvant dose-dense doxorubicin, dose-dense cyclophosphamide, and paclitaxel, which she tolerated well. Eight months after completion of adjuvant therapy, she reports worsening fatigue. ​
• Labratory results: alanine aminotransferase 1.5x upper limit of normal, aspartate transaminase 1.5x upper limit of normal
• CT showed 1 liver and 2 left lung lesions​.
• Biopsy of the liver lesion confirmed recurrent metastatic TNBC ​(mTNBC).
• Brain MRI: negative for brain metastasis ​
• Genetic panel testing: negative for detectable mutations​
• PD-L1 on immune cells (IHC 22C3 pharmDx): 0%​
• No significant comorbidities; otherwise healthy​
• ECOG performance status: 0​

TARGETED ONCOLOGY^TM: What was the FDA indication for sacituzumab govitecan-hziy (Trodelvy) leading to its approval for use in patients with breast cancer?

SARA TOLANEY, MD: For patients with mTNBC, they must have received 2 or more prior systemic therapies, and at least 1 of the therapies [must have been] for metastatic disease.¹ Patients can be on second-line treatment, had 1 in the metastatic setting, and the second one could have been in the adjuvant setting.

It’s tricky because I would love to give this particular patient sacituzumab up front. Technically that’s not really the way the indication is from the FDA label because you must have had at least 1 line of therapy in the metastatic setting. Although, I think that many people may argue that, if someone is recurring so soon after capecitabine, they probably had metastatic disease while receiving the capecitabine. But that’s not the way the label is written. If you decided to use sacituzumab in that particular case, you would have to see if insurance would approve it, and how savvy they would be about the nuances of the label.

Initially sacituzumab got an accelerated approval based on their phase 1 basket data.² They got the full indication once they had the full ASCENT trial [NCT02574455] data. Initially, they had an indication for the third line and beyond, and then more recently, they were given an indication where patients just had to have 2 treatments and at least 1 of which was from metastatic disease so [the approval] in fact moved it up to the second-line setting.

Could you describe the study design of the phase 3 ASCENT trial?

The ASCENT trial took patients who had metastatic disease. Patients had to have had 2 chemotherapies for advanced disease, but they counted as 1 chemotherapy if patients had an early relapse. There were some patients who were second line because they had an early relapse, but the rest were third line and beyond. They were randomized to get sacituzumab or treatment of physician’s choice therapy. The trial’s primary end point was progression-free survival [PFS], and secondary end points included overall survival [OS], overall response rate [ORR], duration of response [DOR], and time to response [TTR].

What were the characteristics of the patient population of the ASCENT study of sacituzumab?

[Reflecting the real-world population], only about 7% of patients had known germline BRCA mutations. There were about 30% of patients who had estrogen receptor [ER]–positive disease at the time of their initial diagnosis, but when they recurred in the metastatic setting, they were triple negative. We certainly do see this clinically but they did have that mix of patients.

This is a population with predominantly visceral metastases. About 70% of patients had received 2 or 3 lines of prior systemic chemotherapy, and all had received prior taxane. Most patients had prior anthracycline, platinum, and capecitabine. There were 7% of patients who had a prior PARP inhibitor, who were the patients with the BRCA mutations. There were about 30% of patients who had had prior [PD-1/PD-L1] checkpoint inhibitors.³ So, [this population was] not unlike our modern-day population.

What were the survival outcomes observed in the study?

What I think is remarkable is that the PFS for sacituzumab is just under 6 months [95% CI, 4.3-6.3].³ But when you look at the control arm, you see that the PFS for treatment of physician’s choice is [1.7] months [(95% CI, 1.5-2.6) HR, 0.41; 95% CI, 0.32-0.52; P < .001]. This is really telling because it shows you how poorly we do with standard chemotherapy for mTNBC, that the PFS is very short.

If you look at the OS, you see it almost doubles with sacituzumab, going from 6.7 months [95% CI, 5.8-7.7] to [12.1] months [(95% CI, 10.7-14.0) HR, 0.48; 95% CI, 0.38-0.59; P < .001]. So [sacituzumab was associated with] very dramatic improvement, not just in PFS, but also in OS.

What were the outcomes for different treatment options given as treatment of physician’s choice in the control arm?

The choices were, eribulin [Halaven], vinorelbine [Navelbine], capecitabine, and gemcitabine. The PFS and OS were similar across all the different agents. Numerically, gemcitabine had the highest PFS compared with eribulin, vinorelbine, or capecitabine. But it was 2.7 months compared with around 2 months and all of them do not do well.³

Did the survival outcomes observed vary by different subgroups?

If you look at the subgroups, every subgroup benefits [from sacituzumab]. Whether or not patients had ER–positive disease at their initial diagnosis, prior to recurring, whether they had liver metastases, whether or not they had prior checkpoint inhibition, the benefit is remarkably similar.

[The study reported] outcomes by BRCA mutation status. Sacituzumab does better than treatment of physician’s choice therapy in the patients with germline BRCA mutations as well. So, [that is] not a reason to choose or not choose sacituzumab based on mutation.

What was the response rate seen in the study?

There was a 35% response rate for sacituzumab, compared with just 5% for chemotherapy.³ I think this is very important when having discussions with patients about the benefits of chemotherapy in pre-treated mTNBC because it tells us that, to be honest with our patients, we have to tell them that the average response rate is only 5% and the average PFS for chemotherapy is just under 2 months. So, again, patients do not do very well with standard chemotherapy outside the first-line setting.

What was the significance of the outcomes of patients with and without brain metastases in the study?

The trial was designed in an interesting way, where [the investigators] took the PFS in the patients who did not have brain metastases as baseline. So PFS in patients without brain metastases was the primary end point. However, they did an analysis of the full population, which included patients who had a history of brain metastases. What that means is, people could have had stable brain metastases and go on the study. In fact, when you add in those patients, you still see the same hazard ratio, so in this case it was 1.7 months versus 4.8 months, for the overall population.³ So, benefits were seen in the whole population as well.

What adverse events were reported in the study?

This is important, because I think the safety data have a lot of implications for what we do in clinics. The rate of grade 3 and 4 neutropenia is above 50%.³ Diarrhea is an issue, but it’s mostly low-grade diarrhea. Only 10% of patients had grade 3 diarrhea, and none [had] grade 4. There was nausea, but, again, it is low-grade nausea.

_References:

_{1. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. FDA. Published April 7, 2021. Accessed February 4, 2022. https://bit.ly/3Gzg1FC}

_{2. FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer. FDA. Published April 22, 2020. Accessed February 4, 2022. https://bit.ly/3uvckOD1.}

_{3. 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}