O’Shaughnessy Spotlights Key Updates in Triple-Negative Breast Cancer

Joyce A. O’Shaughnessy, MD

The treatment landscape of triple-negative breast cancer (TNBC) has undergone substantial growth in 2020, said Joyce A. O’Shaughnessy, MD, who noted that updates in the metastatic and neoadjuvant settings have added to the utilization of new standards of care.

During a 2020 Institutional Perspectives in Cancer webinar on breast cancer, O’Shaughnessy, cochair of Breast Cancer Research and chair of breast cancer prevention research at Baylor-Sammons Cancer Center of Texas Oncology, as well as the 2016 Giant of Cancer Care^® winner in Community Outreach, highlighted some of the most exciting updates in TNBC that emerged in 2020.

Frontline Immunotherapy

At the European Society for Medical Oncology (ESMO) Virtual Congress 2020, the final overall survival (OS) data from the phase 3 IMpassion130 trial (NCT02425891) demonstrated a clinically meaningful benefit for patients with PD-L1– positive metastatic TNBC who received first-line atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) versus placebo plus nab-paclitaxel.¹ Although OS was not statistically significant in the intention-to-treat (ITT) population, patients with PD-L1–positive TNBC by immunohistochemistry had a median OS of 25.4 months (95% CI, 19.6-30.7) with the addition of atezolizumab compared with 17.9 months (95% CI, 13.6-20.3) with placebo, translating to 3-year OS rates of 36% and 22%, respectively (stratified HR, 0.67; 95% CI, 0.53-0.86).

“Survival in IMpassion130 has really held up and has become the standard of care in the PD-L1[–positive] population,” said O’Shaughnessy. “We have to know PD-L1 status when our patients recur with metastatic [TNBC].”

Conversely, the phase 3 IMpassion131 trial (NCT03125902) failed to show a survival advantage with paclitaxel plus atezolizumab versus paclitaxel plus placebo in the ITT or PD-L1–positive population.² In September 2020, the FDA issued an alert that practitioners should not substitute paclitaxel protein-bound with paclitaxel in clinical practice.³

Additionally, the phase 3 KEYNOTE-355 trial (NCT02819518) showed a progression-free survival (PFS) advantage with pembrolizumab (Keytruda) plus several chemotherapy partners in the ITT population of patients with TNBC, as well as in PD-L1–positive (combined positive score [CPS] ≥1) patients.4 Moreover, the addition of pembrolizumab translated to a PFS benefit for patients with a PD-L1 CPS score of 10 or greater compared with chemotherapy alone (9.7 vs 5.6 months, respectively; HR, 0.65; 95% CI, 0.49- 0.86; P = .0012).

During the 2020 San Antonio Breast Cancer Symposium (SABCS), findings from subgroup analyses of the KEYNOTE355 trial showed that frontline pembrolizumab plus chemotherapy induced clinical benefit across patient subgroups, including those with PD-L1 expression by combined positive score compared with chemotherapy alone.⁵

In November 2020, the FDA granted an accelerated approval to pembrolizumab in combination with chemotherapy for the treatment of patients with locally recurrent, unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥ 10), based on findings from the KEYNOTE-355 trial.

Neoadjuvant Therapy

In the preoperative setting, results of the randomized phase 3 IMpassion031 trial (NCT03197935) showed improvements in pathologic complete response (pCR) rates with atezolizumab plus nab-paclitaxel, followed by atezolizumab plus doxorubicin Adriamycin and cyclophosphamide (AC), with subsequent surgery and atezolizumab, versus nab-paclitaxel plus placebo, followed by AC plus placebo, prior to surgery and observation in patients with TNBC whose primary tumor measured larger than 2 cm.⁶

Notably, the benefit was observed in the ITT population (pCR, 57.6% vs 41.1%, respectively) and was seen irrespective of PD-L1 status (positive, 68.8% vs 49.3%, respectively; negative, 47.7% vs 34.4%, respectively).

These findings were corroborated by results of the KEYNOTE-522 trial (NCT03036488), which evaluated a similar schema with pembrolizumab. In KEYNOTE-522, the pCR rates were 64.8% with pembrolizumab plus chemotherapy versus 51.2% with placebo plus chemotherapy in the ITT population; 68.9% versus 54.9%, respectively, in the PD-L1–positive population; and 45.3% versus 30.3%, respectively, in the PD-L1–negative population.⁷ Notably, patients with positive nodes achieved an absolute benefit of 20.6% with the addition of pembrolizumab (64.8% vs 44.1%, respectively; node negative, 64.9% vs 58.6%, respectively).

Additionally, the negative findings of the phase 3 NeoTRIP trial (NCT02620280) of nab-paclitaxel and carboplatin with or without atezolizumab shed light on the potential need to include doxorubicin in neoadjuvant strategies.⁸

“[The NeoTRIP] regimen lacked doxorubicin, which can favorably impact the immune microenvironment and make the tumor cells more immunogenic. It is thought that that may explain why NeoTRIP was negative but [IMpassion031 and KEYNOTE-522] were positive,” O’Shaughnessy said.

PARP Inhibitors

The PARP inhibitors olaparib (Lynparza) and talazoparib (Talzenna) have been welcome additions to the treatment armamentarium for patients with deleterious or suspected deleterious germline BRCA-mutant, HER2-negative, metastatic breast cancer, explained O’Shaughnessy. In TNBC, findings from the phase 3 OlympiAD (NCT02000622) and EMBRACA (NCT01945775) trials, evaluating the agents respectively, showed PFS benefits with the PARP inhibitors compared with physician’s choice of chemotherapy.^9,10

However, OS benefit was not found to be statistically significant in either trial.^11,12 Additionally, extended follow-up of the OlympiAD trial confirmed that the differences observed in the survival curves with olaparib versus chemotherapy were not statistically significant in the overall population.¹³ No benefit was observed irrespective of tissue receptor subtype, prior chemotherapy, or prior exposure to platinum-based chemotherapy regimens.

“We do want to be using the PARP inhibitors as soon as we can in the metastatic, germline BRCA[-mutant], HER2-negative population, whether [tumors are] triple negative or [estrogen receptor] positive,” explained O’Shaughnessy. “We want to get germline BRCA analyses on all our patients, regardless of age and family history, if they have HER2-negative breast cancer.”

Regarding safety, patients on olaparib had more anemia, vomiting, nausea, fatigue, headache, and cough compared with patients on chemotherapy. Mainly hematologic toxicities were observed with talazoparib in the EMBRACA trial, including anemia, neutropenia, and thrombocytopenia.

Additionally, findings from the randomized phase 3 BROCADE3 trial (NCT02163694) showed that veliparib, coadministered with carboplatin and paclitaxel, increased PFS in women with hormone receptor–positive breast cancer and TNBC who harbored a germline BRCA1/2 mutation.¹⁴

Patients who stopped chemotherapy after a mean of 11 cycles and continued on veliparib as monotherapy had a 36-month PFS rate of 26% compared with 11% of patients who remained on the control regimen (HR, 0.705; 95% CI, 0.566-0.877; P = .002). As such, the results suggest that maintenance veliparib confers a PFS benefit for patients versus chemotherapy, said O’Shaughnessy.

Sacituzumab Govitecan

In April 2020, the FDA granted an accelerated approval to sacituzumab govitecan-hziy (Trodelvy), a novel Trop-2– directed antibody-drug conjugate (ADC), for the treatment of patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease.

The approval was based on findings from a phase 1/2 trial that demonstrated an objective response rate of 33.3% by local assessment and a median duration of response of 7.7 months with the agent.¹⁵

Trop-2 is ubiquitously expressed on TNBC cells, which allows sacituzumab govitecan to be used more widely, O’Shaughnessy explained.

Results of the confirmatory phase 3 ASCENT trial (NCT02574455), which were presented virtually during the ESMO Virtual Congress 2020, revealed that sacituzumab govitecan induced an absolute PFS benefit of 3.9 months compared with physician’s choice of treatment (5.6 vs 1.7 months; HR, 0.41; 95% CI, 0.32-0.52; P < .0001).¹⁶ Additionally, the ADC led to an absolute OS benefit of 5.4 months versus physician’s choice of treatment (12.1 vs 6.7 months; HR, 0.48; 95% CI, 0.38-0.59; P < .0001).

Regarding safety, 4.7% of patients on sacituzumab govitecan experienced an adverse event that led to treatment discontinuation. Moreover, no severe cardiotoxicity, grade 3 or greater neuropathy, or grade 4 or greater interstitial lung disease events were observed.

Furthermore, during the 2020 SABCS, data from a subgroup analysis of the ASCENT trial were presented virtually, showing that sacituzumab govitecan increased ORR and PFS compared with chemotherapy among patients with metastatic TNBC who had stable brain metastases.¹⁷ A biomarker analysis of the trial revealed that sacituzumab govitecan induced clinical benefit compared with physician’s choice of therapy for patients with metastatic TNBC, irrespective of Trop-2 expression.¹⁸ Patients with median or high Trop-2 scores derived greater efficacy from the ADC.

Currently, sacituzumab govitecan is being evaluated in the ongoing SASCIA trial (NCT04595565) for patients with HER2- negative early-stage breast cancer who have had at least 16 weeks of taxane-based neoadjuvant chemotherapy versus physician’s choice of treatment.¹⁹ Pending positive results, this trial could bring the novel ADC into the curative setting for patients, O’Shaughnessy concluded. 

References

1. Emens LA, Adams S, Barrios CH, et al. IMpassion130: final OS analysis from the pivotal phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. Ann Oncol. 2020;31(suppl 4):S1148. doi:10.1016/j.annonc.2020.08.2244
2. Miles DW, Gligorov J, André F, et al. Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2020;31(suppl 4):S1142-S1215. doi:10.1016/annonc/annonc325
3. FDA alerts health care professionals and oncology clinical investigators about efficacy and potential safety concerns with atezolizumab in combination with paclitaxel for treatment of breast cancer. News release. FDA. September 8, 2020. Accessed January 8, 2021. https://bit.ly/328EFvy.
4. Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol. 2020;38(suppl 15):1000. doi:10.1200/JCO.2020.38.15_suppl.1000
5. Rugo HS, Schmid P, Cescon DW, et al. Additional efficacy endpoints from the phase 3 KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract GS3-01.
6. Harbeck N, Zhang H, Barrios CH, et al. IMpassion031: results from a phase III study of neoadjuvant (neoadj) atezolizumab + chemotherapy in early triple-negative breast cancer (TNBC). Ann Oncol. 2020;31(suppl 4):S1142-S1215. doi:10.1016/annonc/annonc325
7. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549
8. Gianni L, Huang CS, Egle D, et al. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple negative, early high-risk and locally advanced breast cancer: NeoTRIPaPDL1 Michelangelo randomized study. Cancer Res. 2020;80(4). doi:10.1158/1538-7445.SABCS19-GS3-04
9. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Eng J Med. 2017;377(6):523-533. doi:10.1056/NEJMoa1706450
10. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Eng J Med. 2018;379(8):753-763. doi:10.1056/NEJMoa1802905
11. Robson ME, Tung N, Conte P, et al. OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol. 2019;30(4):558-566. doi:10.1093/annonc/mdz012
12. Litton JK, Hurvitz SA, Mina LA, et al. Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial. Ann Oncol. 2020;31(11):1526-1535. doi:10.1016/j.annoncc.2020.08.2098
13. Robson M, Im SA, Senkus E, et al. OlympiAD extended follow-up for overall survival and safety: olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Cancer Res. 2020;80(4). doi:10.1158/1538-7445.SABCS19-PD4-03
14. Ayoub JP, Friedlander ML, Dieras VC, et al. Veliparib plus carboplatin-paclitaxel in patients with HER2-negative advanced/metastatic gBRCA-associated breast cancer: results in hormone receptor-positive and triple-negative breast cancer subgroups from the phase III BROCADE3 trial. Ann Oncol. 2020;31(suppl 2):S62-S82. doi:10.1016/annonc/annonc122
15. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Eng J Med. 2019;380(8):741-751. doi:10.1056/NEJMoa1814213
16. Bardia A, Tolaney SM, Loirat D, et al. ASCENT: a randomized phase III study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2020;31(suppl 4):S1149-S1150. doi:10.1016/j.annonc.2020.08.2245
17. Diéras V, Weaver R, Tolaney SM, et al. Subgroup analysis of patients with brain metastases from the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in metastatic triple-negative breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract PD13-04.
18. Hurvitz SA, Tolaney SM, Punie K, et al. Biomarker evaluation in the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual.
19. Sacituzumab govitecan in primary HER2-negative breast cancer. ClinicalTrials.gov. Updated on December 14, 2020. Accessed on December 17, 2020. http://bit.ly/2LFHJJL.