Immunotherapy in triple-negative breast cancer: A literature review and new advances

Table 1 Randomized phase II/III immunotherapy trials en triple-negative breast cancer

Scenario	Trial	Phase	n	Intervention	Recruitment Status	Magnitude of clinical benefit
						PFS (mo)	OS (mo)	Additional information
Neoadjuvant	NCT03639948	II	100	Carboplatin + Docetaxel + Pembrolizumab	Recruiting
	NCT03289819	II	50	Pembrolizumab + Nab-paclitaxel → Pembrolizumab + Epirubicin and Cyclophosphamide	Recruiting
	NCT03356860 (B-IMMUNE)	II	57	Paclitaxel + Epirubicin + Cyclophosphamide + Durvalumab	Recruiting
	NCT02685059 (GeparNuevo) (June 2018)	II	174	Epirubicin + Nab-paclitaxel + Cyclophosphamide + Durvalumab	Active, no recruiting	-	-
				Population: Early TNBC				pCR was increased to 53.4% with Durvalumab vs 44.2% with chemotherapy alone, not being statistically significant (P = 0.048)
								In the PD-L1 (+) subgroup: pCR 58% vs 50.7% (P = 0.363)
								pCR was increased in patients with high levels of TILs y TMB-H (P < 0.01)
								3-yr iDFS was 84.9% with durvalumab vs 76.9% with placebo (HR: 0.54, 0.27-1.09, P = 0.0559); 3-yr DDFS 91.4% vs 79.5% (HR: 0.37, 0.15-0.87, P = 0.0148); 3-yr OS: 95.1% vs 83.1% (HR: 0.26, 0.09-0.79, P = 0.0076)
Neoadjuvant/Adjuvant	NCT03036488 (KEYNOTE-522) (August 2020)	III	1174	Carboplatin + Paclitaxel + AC (anthracycline + cyclophosphamide) +/- Pembrolizumab → Adjuvant Pembrolizumab	Active, no recruiting	-	-	Co-primary endpoints were pCR and EFS
				Population: Early TNBC				pCR: 64.8% in Pembro group vs 51.2% with placebo (P < 0.001)
								The benefit of Pembro in pCR was consistent in all subgroups, including PD-L1 (+): pCR 68.9% vs 54.9% (P < 0.001)
								A statistically benefit was observed in EFS (HR: 0.63, 0.48-0.82)
								Pembro showed a favorable trend in OS (HR: 0.72, 0.52-1.02)
	NCT02620280 (NeoTRIPaPDL1) (December 2019)	III	280	Carboplatin/nab-paclitaxel +/- Atezolizumab → anthracycline (AC/EC)	Active, no recruiting	-	-	Primary endpoint was pCR
				Population: Early TNBC				The pCR rates were not statistically significant between both groups: 43.5% with atezolizumab vs 40.8% with chemotherapy alone
								A multivariate analysis showed that the only variable associated with pCR was the PD-L1 (+) status: pCR 51.9% vs 48% (P < 0.0001)
								These results differ from KEYNOTE-522, where pembrolizumab achieved significant rates of pCR in a similar population
	NCT03281954	III	1520	Doxorubicin + Cyclophosphamide + Paclitaxel + Carboplatin +/- Atezolizumab → Atezolizumab	Recruiting
	NCT03197935 (IMpassion031) (September 2020)	III	204	AC (doxorubicin + cyclophosphamide) + Nab-paclitaxel +/- Atezolizumab → Adjuvant Atezolizumab	Active, no recruiting			pCR was 58% in Atezolizumab group vs 41% in placebo group (P = 0.0044)
				Population: Early TNBC				In the PD-L1 (+) population, pCR was 68.8% in the Atezolizumab group vs 49.3% in the placebo group (P = 0.021)
								A favorable trend was obtained in EFS (immature data) (HR: 0.76, 0.40 -1.44)
								In patients with early TNBC, neoadjuvant treatment of Atezolizumab + nab-paclitaxel and an anthracycline-based regimen achieve higher rates of pCR, with an acceptable safety profile
Adjuvant (for patients with residual disease after neoadjuvant chemotherapy)	NCT02954874	III	1000	Pembrolizumab vs observation	Recruiting
	NCT03756298	II	284	Capecitabine +/- Atezolizumab	Recruiting
Adjuvant	NCT03498716 (IMpassion030)	III	2300	Paclitaxel → dd Doxorubicin/Epirubicin + Cyclophosphamide +/- Atezolizumab	Recruiting			Primary endpoint was iDFS
								Secondary endpoints were iDFS according to PD-L1 status and nodal affectation, OS, safety, y health related to a QoL
	NCT02926196 (A-Brave)	III	335	Avelumab vs observation	Recruiting			This trial evaluates patients in two groups: (1) Primary TNBC patients who completed surgery followed by adjuvant therapy; and (2) Primary TNBC patients with residual disease after neoadjuvant chemotherapy (did not achieve pCR)
								The first and second co-primary endpoints are DFS in all patients and DFS in B group
Locally advanced or mTNBC	NCT02768701	II	40	Cyclophosphamide + Pembrolizumab	Active, no recruiting
	NCT03121352	II	30	Carboplatin, Nab-paclitaxel y Pembrolizumab	Recruiting
	NCT02499367 (TONIC)	II	67	Control or irradiation 3 x 8 Gy or oral cyclophosphamide or Cisplatin or Doxorubicin → anti-PD-1 (Nivolumab)	Active, no recruiting			Five cohorts were included in the randomization, all followed by nivolumab
								Overall, the ORR was 20%
								Most responses were observed with cisplatin (ORR: 23%) and doxorubicin (ORR: 35%)
	NCT02819518 (KEYNOTE-355) (December 2020)	III	858	Nab-paclitaxel or Paclitaxel or Carboplatin/Gemcitabine +/- Pembrolizumab	Active, no recruiting	9.7 vs 5.6 (HR: 0.82) in CPS ≥ 10	-	Co-primary endpoints were PFS and OS (this latter is pending outcome)
				Population: First-line mTNBC				Pembro treatment was statistically significant only for patients with high levels of PD-L1 (expressed in CPS ≥ 10)
								Pembro + chemotherapy showed a significant increase in PFS among mTNBC patients
								A recent update showed that KEYNOTE-355 trial met primary endpoint of OS in patients with mTNBC whose tumors expressed PD-L1 (CPS ≥ 10)
	NCT02555657 (KEYNOTE-119) (September 2019)	III	600	Capecitabine, Eribulin, Gemcitabine, or Vinorelbine vs Pembrolizumab	Active, no recruiting	2.1 vs 2.1 (HR: 1.14)	12.7 vs 10.7 (HR: 0.78)	Pembro did not show improvement in OS or PFS as 2L/3L of treatment for mTNBC vs chemotherapy (OS: 9.9 mo vs 10.8 mo, HR: 0.97, 0.82- 1.15)
				Population: Second and third-line mTNBC				OS in tumors with CPS > 10: 12.7 mo vs 11.6 mo (HR: 0.78, 0.57-1.06)
								A greater benefit was obtained in OS/PFS in tumors with high levels of PD-L1 (expressed in the CPS score)
								Pembro was well tolerated and had less adverse events compared with chemotherapy
	NCT02447003 (KEYNOTE-086) (March 2019)	II	285	Pembrolizumab monotherapy	Active, no recruiting	-	-	Primary endpoint: ORR in the total population and PD-L1 (+)
								ORR was 5.3% in the total population, and 5.7% in the PD-L1 (+) population
								Pembro demonstrated antitumor activity in patients previously treated with mTNBC (≥ 1 systemic treatments)
	NCT02425891 (IMpassion130) (November 2018)	III	902	Atezolizumab + Nab-paclitaxel (comparator: placebo + Nab-paclitaxel)	Active, no recruiting	7.5 vs 5.5 (HR: 0.62, P < 0.001)	25.0 vs 15.5 (HR: 0.62)	In the analysis of the ITT population, the median PFS was 7.2 mo vs 5.5 mo (HR: 0.80, P = 0.002). In PD-L1 (+) patients, the median PFS was 7.5 mo vs 5.5 mo (HR: 0.62, P < 0.001)
				Population: First-line mTNBC				In the analysis of the ITT population, the median OS was 21.3 mo vs 17.6 mo (HR: 0.84, P = 0.08). In PD-L1 (+) patients, the median OS was 25.0 mo vs 15.5 mo (HR: 0.62)
								Final analysis showed that OS benefit with atezolizumab + nab-paclitaxel in the ITT population was not statistically significant, but a clinically meaningful OS benefit was observed in PD-L1 IC-(+) patients
	NCT03125902 (IMpassion131) (September 2020)	III	600	Paclitaxel +/- Atezolizumab (comparator: placebo + paclitaxel)	Active, no recruiting	5.7 vs 6.0 (HR: 0.82, P = .20) in PD-L1 (+) population	22.1 vs 28.3 (HR: 1.12) in PD-L1 (+) population	Primary endpoint was PFS
				Population: First-line mTNBC				In the ITT population, the median PFS was 5.7 mo in atezolizumab group vs 5.6 mo in placebo group (HR: 0.86)
								OS: 19.2 mo vs 22.8 mo (HR: 1.11, 0.87-1.42)
								The 2-yr OS rates were 51% and 49% in placebo and atezolizumab groups, respectively
	NCT03371017 (IMpassion132) (early recurrence)	III	350	Carboplatin + Gemcitabine or Capecitabine +/- Atezolizumab	Recruiting			Primary endpoint was OS
								Estimated completion date: July 2023

CPS: Combined positive score; dd: Dense dose; DDFS: Distant-disease free survival; DFS: Disease-free survival; EFS: Event-free survival; HR: Hazard ratio; IC: immune cells; iDFS: Invasive disease-free survival; ITT: Intention to treat; mTNBC: Metastatic triple-negative breast cancer; pCR: Pathological complete response; PFS: Progression-free survival; ORR: Objective response rate; OS: Overall survival; QoL: Quality of life; TNBC: Triple-negative breast cancer.

Table 2 Common commercially monoclonal programmed death ligand 1 antibodies for immunohistochemical analysis to assess the expression of programmed death ligand 1 (considering Food and Drug Administration approvals)

PD-L1 antibody	Immunotherapy	IHC assay	Cut-off	Line
22C3	Pembrolizumab	DAKO	TPS ≥ 1%	1L
			TC ≥ 1%	2L
28-8	Nivolumab	DAKO	TC ≥ 1%	2L
SP142	Atezolizumab	Ventana	TC ≥ 50% and/or IC ≥ 10%	1L
			TC ≥ 1% and/or IC ≥ 1%	2L
SP263	Durvalumab	Ventana	TC ≥ 1%	1L maintenance, in unresectable stage III after chemoradiation therapy
	Nivolumab		TC ≥ 1%	2L
	Pembrolizumab		TC ≥ 50%	1L
73-10	Avelumab	DAKO	TC ≥ 1%	2L (not approved)

Notes: (1) Atezolizumab in combination with nab-paclitaxel is approved as 1L of treatment for patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) whose tumors express programmed death ligand 1 (PD-L1) immune cells (IC) (PD-L1 stained tumor-infiltrating IC of any intensity covering ≥ 1% of the tumor area), as determined by a Food and Drug Administration (FDA) approved test (Ventana SP142); and (2) Pembrolizumab with chemotherapy is approved as 1L of treatment for patients with locally recurrent unresectable or mTNBC whose tumors express PD-L1 CPS ≥ 10, as determined by an FDA approved test (PD-L1 IHC 22C3 PharmDx). CPS: Combined positive score; IC: Immune cell; IHC: Immunohistochemistry; TC: Tumor cell; TPS: Tumor proportion score; 1L: First-line; 2L: Second-line; PD-L1: Programmed death ligand 1.