Traina Discusses Components of the ASCENT Trial in Patients With TNBC

Tiffany A. Traina, MD

Associate Attending Physician Vice Chair, Oncology; Department of Medicine Section Head

Triple Negative Breast Cancer Clinical Research Program Memorial Sloan Kettering Cancer Center

Associate Professor of Medicine, Weill Cornell Medicine New York, NY

Targeted Oncology^TM: What are the National Comprehensive Cancer Network (NCCN) guidelines for sacituzumab govitecan-hziy (Trodelvy) in TNBC?

TRAINA: The NCCN guidelines were updated, and sacituzumab is on there as a preferred regimen, specifically for [patients with] TNBC.¹ Though it is not a category 1 recommendation, we expect we’ll probably be seeing data to come. But it’s for patients who’ve had at least 2 prior therapies, one of those in the metastatic setting. [Editor's note: This event occurred before the latest update to the NCCN guidelines. In the June 2022 update of the NCCN guidelines, sacituzumab govitecan received a category 1 recommendation based on final results from the ASCENT trial (NCT02574455).^1,2]

What were the data that led NCCN to recommend an antibody-drug conjugate like sacituzumab govitecan in patients with TNBC?

This is based on the randomized phase 3...ASCENT study, which recruited patients who had metastatic TNBC and had received 2 or more prior chemotherapy regimens for advanced disease, with no upper limit.²

There were some heavily pretreated patients in this trial. More than 500 patients with a 1:1 randomization of sacituzumab vs treatment of physician’s choice [TPC]. TPC on the study essentially covered many of the agents in the guidelines: eribulin [mesylate (Halaven)], vinorelbine [Navelbine], capecitabine [Xeloda], gemcitabine—often the agents we most commonly reach for in the second- and third-line setting.

The primary end point was progression-free survival [PFS], and [they looked at] all the usual secondary end points [overall survival (OS), overall response rate (ORR), duration of response (DOR), and safety]. Generally, [the study population was] young women, early 50s, good performance status to be able to be on a clinical trial, some with germline BRCA1 or BRCA2 mutations, accounting for about 8% of the population.²

About 70% of these patients had triple-negative disease from the beginning, as opposed to someone who had an estrogen receptor [ER]–positive primary disease and then a triple-negative metastasis. The median time from diagnosis of metastatic disease to coming on study was just over a year, speaking to that rapid tempo of progression, knowing that these folks were largely in the third line of treatment and later. Sixty-one patients had had brain metastases at baseline [that were] treated.

For the baseline characteristics in the primary efficacy population, burden of disease [was] largely visceral lung and liver disease.² Patients had a median of 3 prior lines of chemotherapy, but upward of 16 prior regimens of therapy for advanced disease. It’s remarkable to think of 16 regimens for use. The prespecified stratification factors for prior chemotherapy regimens was 2 or 3 prior or more than 3. So about 70% of patients were exposed to 2 or 3 prior chemotherapy regimens, and 100% of these patients had prior treatment with a taxane. But most had seen prior anthracycline, cyclophosphamide, and even platinum and capecitabine before coming on study. Fortunately, there’s alignment between the percentage of folks who had germline BRCA mutations and the percentage of folks that got prior PARP inhibitors, about 8%.

Please describe the efficacy on this trial for patients with TNBC.

As [I mentioned], the primary end point was PFS.² Sacituzumab was superior, with about a 60% improvement in PFS [HR, 0.41; 95% CI, 0.32-0.52; P<.0001]. The patients getting TPC did poorly here, with a 1.7-month median PFS [95% CI, 1.5-2.6]. Sacituzumab was associated with almost a 6-month median PFS [95% CI, 4.3-6.3]. So clearly, both a statistically significant and clinically meaningful improvement in PFS. But I think also what was incredibly encouraging [were] the OS data, [and OS] was a secondary end point. There was about a 50% improvement in OS, which was statistically significant [HR, 0.48; 95% CI, 0.38-0.59; P<.0001]. A doubling from about 6.5 months [with TPC] to 12 months with sacituzumab. So this was exciting and practice changing for our patients.

If you look at the prespecified subgroups, pretty much every category was favoring sacituzumab over TPC.² That was regardless of age, prior regimens, sites of visceral disease or sites of metastases, and whether [the] initial tumor was triple negative or ER positive. When we look at ORR, the waterfall plots look terrific. We’re getting a bit spoiled seeing these with antibody-drug conjugates. So nearly all patients that were treated with sacituzumab derived some degree of benefit, a complete response, definitely clinical benefit overall of 45%...compared with 9% with TPC. Median DOR was double at 6 months...compared with about 3 months. Pretty much by all metrics evaluated, sacituzumab was superior to TPC.

How did patients with brain metastases do on the ASCENT trial? The primary end point [we’ve reviewed so far] was efficacy in a specified population that excluded those patients with brain metastases.² [Now let’s discuss] the primary end point of PFS in the full intention-to-treat [ITT] population, including those patients who had stable, treated brain metastases. The benefit is maintained in the ITT population as well, with sacituzumab appearing superior to TPC and the hazard ratio, again, consistent with about a 60% improvement in PFS [HR, 0.43; 95% CI, 0.35-0.54; P<.001].

What was the safety profile for sacituzumab govitecan?

Safety is clearly something to discuss and to be aware of in the balance. Quality of life is important for our patients in making choices, and we need to keep adverse events [AEs] in mind. The most common AEs are cytopenias and gastrointestinal [GI] toxicities.²

Neutropenia was common, and grade 3 neutropenia accounted for about 34% with sacituzumab vs 20% with TPC. The component related to febrile neutropenia was, fortunately, much lower, with 5% grade 3 febrile neutropenia with sacituzumab as opposed to 2% with TPC.

In terms of GI events, diarrhea is the AE to be aware of. Knowing that the payload here is a metabolite of irinotecan [Camptosar], grade 3 diarrhea is quite common with irinotecan. But with sacituzumab, it was about 10% grade 3, and much less common with treatment of physician’s choice chemotherapy. But this is an AE that we can mitigate, we can educate around, and we can use supportive strategies to be able to manage.

Can you describe efficacy with the different TPC options used on this trial?

Joyce O’Shaughnessy, MD, presented data on this at the 2021 ASCO [American Society of Clinical Oncology] Annual Meeting. The majority of physicians reached for eribulin; half chose to prescribe eribulin in this setting. Very few chose vinorelbine, capecitabine, or gemcitabine. But regardless of TPC choice, sacituzumab was superior. Across the board, sacituzumab performed better than those TPC options. This feels consistent with what we would have done pre-sacituzumab, using eribulin as one of our most active drugs, particularly in TNBC. Although sacituzumab is looking like it’s superior, I don’t know that we could say much about the TPC arms in a head-tohead comparison here. I think this all looks pretty consistent with what physician practice would be in the drugs that we choose.³

How does germline BRCA status affect TPC vs sacituzumab govitecan?

Germline BRCA status was examined.⁴ So caveat here and caution: Very few patients, just 7% or 8% of the population, had known germline BRCA1 or BRCA2 mutations. I would say that the data are consistent, that sacituzumab has activity in those patients who carry germline BRCA mutations. Response rates were about 35% compared with 5%. The median PFS hazard ratio is about 0.40, favoring sacituzumab over TPC, and median OS [hazard ratio was 0.48] favoring sacituzumab over TPC—even in those with germline BRCA mutations. It had small numbers, but I think just consistent with the overall trial results.

Is TROP2 expression important when you are determining if patients with TNBC should receive sacituzumab govitecan?

This is a question that we hear a lot. Whether TROP2 expression is important, or do we need to test for TROP2 to know whether sacituzumab is an option. The FDA indication is regardless of a companion diagnostic, and this analysis looked at TROP2 expression divided by high, medium, and low scoring.^4,5 Across the board, regardless of TROP2 expression, sacituzumab appeared to perform better than TPC.⁴ Even if you’re looking at TROP2 low, sacituzumab is better. Now, the numbers are small and these are all unplanned analyses, but it is encouraging to see that there appears to be activity regardless. TROP2 is highly expressed across epithelial cancers, across even other breast cancers, triple negative as well as ER positive. So I think the takeaway here is that we do not need TROP2 as a biomarker for choice and activity in using sacituzumab.

Were the outcomes with sacituzumab govitecan different in patients 65 years and older?

Kevin Kalinsky, MD, MS, presented these data at ASCO, looking specifically at the subset of patients 65 years and older compared with those younger than 65 years.⁶ There were fewer than 100 patients who were [older than] 65 in the study. But in totality, the efficacy looked consistent with the overall study population. The ORR was quite high at 50% with sacituzumab vs 0% with TPC [in those 65 years and older]. Median PFS looked prolonged with a hazard ratio of 0.2 and it was statistically significant [95% CI, 0.12-0.40; P < .0001].

I don’t know that I would read so much into this as much as saying it appears to have consistent efficacy that looks like the overall ITT population. I think what’s reassuring is the safety piece of this. [Although] dose modifications were more frequent in patients that were older, the modifications were similar, whether you were getting sacituzumab or TCP chemotherapy.^5,6

There didn’t appear to be an impact on efficacy with dose modification. Treatment discontinuations were comparable and rare, 2% whether you were [older than 65 years or younger than 65 years]. Thankfully, there were no grade 5 events [related to treatment]. There were some patients studied that were older than 75 years, and rates of AEs were comparable if you were older than 75 vs older than 65.

I think it just gives us some comfort in knowing that the drug has activity, that it has a reasonable safety profile, and that we should not be discriminating based on age but being sensitive to performance status and comorbidities as our driver, not just chronologic age. Some of the most common treatment-related AEs were consistent with the overall population; neutropenia and cytopenias are common. But that is true for sacituzumab as well as TPC. About 10% grade 3 diarrhea with sacituzumab and rare with TPC.

REFERENCES

1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 4.2022. Accessed July 22, 2022. https://bit.ly/3MP4uF6

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

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

4. Bardia A, Tolaney SM, Loirat D, et al. LBA17 ASCENT: a randomized phase III study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triplenegative breast cancer (mTNBC). Ann Oncol. 2020;31(suppl 4):S1142- S1215. doi:10.1016/j.annonc.2020.08.2245

5. Trodelvy. Prescribing information. Gilead Sciences Inc; 2022. Accessed June 09, 2022. https://bit.ly/3MV45RD

6. Kalinsky K, Oliveira M, Traina T, et al. Outcomes in patients (pts) aged ≥65 years in the phase 3 ASCENT study of sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2021;39(suppl 15):1011. doi:10.1200/JCO.2021.39.15_suppl.1011