Chemoimmunotherapy Anchors Frontline Treatment in Metastatic TNBC


Patients with newly diagnosed metastatic triple-negative breast cancer should undergo PD-L1 expression testing on tumors to determine whether they are candidates for frontline chemoimmunotherapy.

Kevin Kalinsky, MD, MS

Kevin Kalinsky, MD, MS

Patients with newly diagnosed metastatic triple-negative breast cancer (TNBC) should undergo PD-L1 expression testing on tumors to determine whether they are candidates for frontline chemoimmunotherapy, which has become the preferred standard in eligible patients, according to Kevin Kalinsky, MD, MS.

The emergence of immune checkpoint inhibitor (ICI) therapy for patients with PD-L1–positive TNBC is among the advancements in the past several years that are shaping the treatment landscape for this breast cancer subtype. Other milestones include the approval of sacituzumab govitecan-hziy (Trodelvy) for patients with previously treated metastatic TNBC and PARP inhibitors for those with germline BRCA1/2 (gBRCA1/2) mutations, Kalinsky said.

Kalinsky will discuss key facets of integrating these therapies into the paradigm for metastatic TNBC during a presentation focused on treatment sequencing strategies on Friday, March 4, at the 39th Annual Miami Breast Cancer Conference®. He is the Louisa and Rand Glenn Family Chair in Breast Cancer Research and director of both the Glenn Family Breast Center and breast medical oncology at Winship Cancer Institute of Emory University in Atlanta, Georgia.

In an interview in advance of his presentation, Kalinsky stressed the importance of biomarker evaluation. “When patients are newly diagnosed with metastatic disease, they should have testing,” he said. “It is standard of care to check for PD-L1 status. If they’re PD-L1 positive, they should get immunotherapy in the front line.”

Furthermore, patients should receive genetic testing to assess whether they are candidates for PARP inhibitor therapy or for a treatment approach associated with germline aberrations. “They should be checked for the presence or absence of hereditary mutations, including BRCA,” Kalinsky said.

Frontline Immunotherapy

In July 2021, the FDA granted regular approval to pembrolizumab (Keytruda), a PD-1 inhibitor, in combination with chemotherapy for patients with unresectable or metastatic TNBC with PD-L1 positivity, defined as a combined positive score (CPS) of 10 or greater via an FDA-approved test.1 The PD-L1 IHC 22C3 pharmDx assay, an immunohistochemistry test, has been designated as the companion diagnostic for the indication.2 At the same time, the FDA approved pembrolizumab for patients with high-risk, early-stage TNBC in combination with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery.1

In the metastatic setting, the phase 3 KEYNOTE-355 (NCT02819518) trial evaluated pembrolizumab plus chemotherapy in patients with locally recurrent unresectable or metastatic TNBC who had not previously received chemotherapy in the metastatic setting, regardless of PD-L1 expression status. A total of 847 patients were randomized 2:1 to receive pembrolizumab at 200 mg (n = 566) or placebo (n = 281) every 3 weeks in combination with nab-paclitaxel (Abraxane), paclitaxel, or gemcitabine plus carboplatin. The primary end points were progression-free survival (PFS) and overall survival (OS) for participants with PD-L1–positive tumors (CPS ≥ 10 and CPS ≥ 1) and in the intention-to-treat (ITT) population.3

After a median follow-up of 44.1 months, the median OS in patients with a CPS of 10 or greater was 23.0 months (95% CI, 19.0-26.3) in the pembrolizumab arm compared with 16.1 months (95% CI, 12.6-18.8) with placebo (HR, 0.73; 95% CI, 0.55-0.95; 1-sided P = .0093), according to findings from the final analysis presented at the 2021 European Society for Medical Oncology Congress. Median PFS for this population was 9.7 months (95% CI, 7.6-11.3) with pembrolizumab compared with 5.6 months (95% CI, 5.3-7.5) with placebo (HR, 0.66; 95% CI, 0.50-0.88). Pembrolizumab therapy also resulted in a 52.7% objective response rate ([ORR] 95% CI, 45.9%-59.5%) in patients with a CPS of 10 or greater compared with 40.8% (95% CI, 31.2%-50.9%) with placebo.4

Although median OS was higher among patients with a CPS of 1 or greater and in the ITT population, the results did not reach the thresholds for statistical significance (HR, 0.86 and 0.89, respectively). In the subgroup of participants with a CPS of less than 10, the pembrolizumab-containing regimen was not superior to the placebo arm (HR, 1.04).4

The regular approval for pembrolizumab in metastatic TNBC converted an accelerated approval that the FDA had granted for the agent in November 2020 and solidified a place for ICI therapy in the treatment paradigm for this breast cancer subtype.1 In August 2021, Genentech voluntarily withdrew an accelerated approval indication for atezolizumab (Tecentriq), a PD-L1 inhibitor, in combination with nab-paclitaxel for patients with metastatic TNBC with tumors expressing PD-L1 after the agent did not reach its primary PFS end point in a confirmatory trial.5

Sacituzumab Govitecan

In the recurrent setting, sacituzumab govitecan has been introduced into the TNBC paradigm as a later-line therapy for patients with previously treated metastatic disease, but its robust single-agent activity shows its potential to have a much broader effect on breast cancer treatment as clinical trials continue to report out.6

“It is the first antibody-drug conjugate [ADC] that has been approved in the metastatic setting for patients with TNBC,” said Kalinsky, who was an investigator involved in the development of the agent. “There is an OS advantage. It’s an important agent in this subtype of breast cancer.”

Sacituzumab govitecan demonstrated an improvement in PFS and OS compared with single-agent chemotherapy among patients with relapsed or refractory metastatic TNBC in the phase 3 ASCENT trial (NCT02574455).7,8 Based on the study findings, the FDA granted regular approval to sacituzumab govitecan in April 2021 as monotherapy for patients with unresectable locally advanced or metastatic TNBC who have received 2 or more prior systemic therapies, including at least 1 for metastatic disease. That decision converted a 2020 accelerated approval in the same indication to full approval.7

In ASCENT, 529 patients with TNBC were randomized 1:1 to receive sacituzumab govitecan at 10 mg/kg (n = 267) or physician’s choice of chemotherapy (n = 262), with investigators prespecifying single-agent eribulin, capecitabine, gemcitabine, or vinorelbine. The primary end point was PFS by blinded independent central review in patients without known brain metastases. Findings were reported after a median follow-up of 17.7 months.

Among 468 patients in this population, sacituzumab govitecan therapy resulted in a median PFS of 5.6 months (95% CI, 4.3-6.3) compared with 1.7 months (95% CI, 1.5-2.6) for those who received chemotherapy (HR, 0.41; 95% CI, 0.32-0.52; P < .001). Sacituzumab govitecan also demonstrated improvement in median OS, a secondary end point. In patients without brain metastases, the median OS was 12.1 months (95% CI, 10.7-14.0) in the sacituzumab govitecan arm vs 6.7 months (95% CI, 5.8-7.7) in the chemotherapy group (HR, 0.48; 95% CI, 0.38-0.59; P < .001).8

Sacituzumab govitecan also improved median PFS and OS in the full population, which included 61 patients with brain metastases. In the full population, the median PFS was 4.8 months (95% CI, 4.1-5.8) with sacituzumab govitecan and 1.7 months (95% CI, 1.5-2.5) with chemotherapy (HR, 0.43; 95% CI, 0.35-0.54; P < .0001). The median OS, respectively, was 11.8 months (95% CI, 10.5-13.8) and 6.9 months (95% CI, 5.9-7.7), which translated into an HR for death of 0.51 (95% CI, 0.41-0.62; P < .0001).8,9

Like other ADCs, sacituzumab govitecan has 3 main components: an antibody coupled with a cytotoxic payload joined by a linker. The agent is comprised of a humanized monoclonal antibody directed at Trop-2, an antigen expressed on the surface of tumor cells in more than 90% of breast cancers; SN-38, the active metabolite of irinotecan and a topoisomerase I inhibitor; and a hydrolysable linker.8,9

Although sacituzumab govitecan is directed at Trop-2, the ASCENT trial did not require that patients’ tumors exhibit a certain expression level for inclusion. In a biomarker analysis of Trop-2 expression among 290 evaluable ASCENT participants, investigators found sacituzumab govitecan was more effective than chemotherapy among patients with metastatic TNBC with a high histochemical score ([H-score]> 200-300) and medium H-score (100-200) via IHC testing in terms of median PFS, OS, and ORR. Efficacy outcomes also were numerically higher for patients with low Trop-2 levels (H-score, 0 to < 100) who received sacituzumab govitecan (n = 27) than for those who had chemotherapy (n = 32), but the number of participants in the subgroup was too small to reach definitive conclusions, investigators said.10

The potential for broader applications for sacituzumab govitecan in breast cancer is being explored in numerous clinical trials. These include the phase 3 TROPiCS-02 trial (NCT03901339), which is ongoing but no longer recruiting participants, comparing sacituzumab govitecan with physician’s choice of single-agent chemotherapy in patients with hormone receptor–positive, HER2-negative metastatic breast cancer with disease progression after at least 2 prior chemotherapy regimens. The German Breast Group is conducting the phase 3 SASCIA trial (NCT04595565) testing sacituzumab govitecan with physician’s choice of capecitabine or platinum-based chemotherapy as postneoadjuvant treatment for patients with HER2-negative breast cancer, including TNBC and hormone receptor–positive disease.6

Genetic Biomarkers

All patients diagnosed with recurrent or metastatic breast cancer should undergo tumor testing for gBRCA1/2 mutations to determine if they are candidates for PARP inhibitor therapy, according to National Comprehensive Cancer Network (NCCN) breast cancer treatment guidelines. The FDA has approved 2 PARP inhibitors, olaparib (Lynparza) and talazoparib (Talzenna), in HER2-negative breast cancer settings, but the NCCN panel believes these agents could be considered for use in patients with any breast cancer subtype with a gBRCA1/2 mutation.11

Specifically, olaparib is approved for the treatment of adult patients with deleterious or suspected deleterious gBRCA, HER2-negative metastatic breast cancer who have received chemotherapy in the neoadjuvant, adjuvant, or metastatic setting.12 Talazoparib is indicated for patients with gBRCA-mutated HER2-negative locally advanced or metastatic breast cancer.13

The FDA approved olaparib based on data from the phase 3 OlympiAD trial (NCT02000622), in which patients with previously treated gBRCA-mutated HER2-negative metastatic breast cancer were randomized 2:1 to receive olaparib tablets (300 mg twice daily) or standard single-agent chemotherapy (capecitabine, eribulin, or vinorelbine). Of the 302 patients treated during the study, approximately 50% had TNBC at baseline.12

For the overall study population, median PFS with olaparib was 7.0 months compared with 4.2 months with chemotherapy (HR, 0.58; 95% CI, 0.43-0.80; P < .001). A subgroup analysis showed that patients with TNBC derived a greater benefit from olaparib therapy (HR, 0.43; 95% CI, 0.29-0.63) compared with participants with hormone receptor–positive disease (HR, 0.82; 95% CI, 0.55-1.26).14

The indication for talazoparib is based on findings from the phase 3 EMBRACA study (NCT01945775), in which patients were randomized 2:1 to receive talazoparib capsules (1 mg once daily) or physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). Approximately 44% of the 431 patients randomized during the study had TNBC at baseline.

In the full population, the median PFS for patients in the talazoparib arm was 8.6 months (95% CI, 7.2-9.3) vs 5.6 months (95% CI, 4.2-6.7) in the chemotherapy arm (HR, 0.54; 95% CI, 0.41-0.71; P < .001). Results from a subgroup analysis suggested patients with hormone receptor–positive disease received a greater benefit from talazoparib (HR, 0.47; 95% CI, 0.32-0.71) than those with TNBC (0.60; 95% CI, 0.41-0.87).13,15


  1. FDA approves pembrolizumab for high-risk early-stage triple-negative breast cancer. FDA. Updated July 27, 2021. Accessed February 15, 2022.
  2. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). FDA. Updated December 1, 2021. Accessed February 15, 2022.
  3. Keytruda. Prescribing information. Merck & Co Inc; 2022. Accessed February 15, 2022.
  4. Cortés J, Cescom DW, Rugo HS, et al. KEYNOTE-355: final results from a randomized, double-blind phase III study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC. Ann Oncol. 2021;32(suppl 5):S1289-S1290. doi:10.1016/annonc.2021.08.2089
  5. Genentech provides update on Tecentriq U.S. indication for PD-L1-positive, metastatic triple-negative breast cancer. News release. Genentech. August 27, 2021. Accessed February 15, 2022.
  6. Adams E, Wildiers H, Neven P, Punie K. Sacituzumab govitecan and trastuzumab deruxtecan: two new antibody-drug conjugates in the breast cancer treatment landscape. ESMO Open. 2021;6(4):100204. doi:10.1016/j.esmoop.2021.100204
  7. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. FDA. Updated April 8, 2021. Accessed February 16, 2022.
  8. 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
  9. Trodelvy. Prescribing information. Immunomedics Inc; 2021. Accessed February 17, 2022.
  10. 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
  11. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 2.2022. Accessed February 17, 2022.
  12. Lynparza. Prescribing information. AstraZeneca Pharmaceuticals LP; 2022. Accessed February 17, 2022.
  13. Talzenna. Prescribing information. Pfizer Inc; 2021. Accessed February 17, 2022.
  14. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523-533. doi:10.1056/NEJMoa1706450
  15. Litton JK, Rugo HS, Ettl, J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753-763. doi:10.1056/NEJMoa1802905
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