The emerging role of immune checkpoint inhibitors for the treatment of breast cancer

Figures & data

Table 1. Randomized clinical trials of immune checkpoint inhibitors in advanced/metastatic breast cancer. Outcomes listed for immunotherapy containing arms vs. non-immunotherapy arms

Study	Patient Population	Sample Size	Treatment	ORR	Median PFS (months)	Median OS (months)	Comment
NCT02555657 KEYNOTE-119 Phase 3 Open-label	TNBC 2^nd or 3^rd line Prior anthracycline and taxane	n = 312 n = 310	Pembrolizumab Capecitabine, Eribulin, Gemcitabine, or Vinorelbine	9.6% 10.6%	2.1 3.3 (not formally tested)	9.9 10.8 (not formally tested)	No OS difference in ITT (not formally tested), CPS ≥ 1 (p = 0.073), and CPS ≥ 10 (p = 0.057) subgroups. Post-hoc analysis suggest OS benefit in CPS ≥ 20 (median 14.9 mo vs 12.5 mo)
NCT02425891 IMpassion130 Phase 3 Double-blind Placebo-controlled	TNBC 1^st line TFI ≥12 months	n = 451 n = 451	Atezolizumab + nab-paclitaxel Placebo + nab-paclitaxel	56% 46%	7.2 5.5 (p = 0.002)	21.0 18.7 (p = 0.08)	OS difference seen in PD-L1+ subgroup (median 25.4 mo vs 17.9 mo) but not statistically assessed due to hierarchical design.
NCT03125902 IMpassion131 Phase 3 Double-blind Placebo-controlled	TNBC 1^st line TFI ≥12 months	n = 431 n = 220	Atezolizumab + Paclitaxel Placebo + Paclitaxel	54% 47%	5.7 5.6 (not formally tested)	19.2 22.8 (not formally tested)	No PFS (p = 0.20) or OS benefit seen in the PD-L1+ subgroup
NCT02819518 KEYNOTE-355 Phase 3 Double-blind Placebo-controlled	TNBC 1^st line TFI ≥ 6 months	n = 566 n = 281	Pembrolizumab + nab-paclitaxel, Paclitaxel, or Gemcitabine/Carboplatin Placebo + nab-paclitaxel, Paclitaxel, or Gemcitabine/Carboplatin	41.0% 35.9%	7.5 5.6 (not formally tested)	NA	PFS benefit reached significance only in the CPS ≥ 10 subgroup (median 9.7 mo vs 5.6 mo, p = 0.0014)
NCT02299999 SAFIR02 Breast Phase 2 Open label	≤2 prior CTs Received 6–8 cycles CT without PD No targetable molecular alteration	n = 131 n = 68	Maintenance Durvalumab Maintenance CT	NA NA	2.7 4.6 (p = 0.047)	21.7 17.9 (p = 0.423)	OS prolonged in TNBC subgroup (median 21.2 mo vs 14.0 mo, p = 0.0377)
NCT03051659 Phase 2 Open label	HR+, HER2- 2+ prior ET	n = 44 n = 44	Pembrolizumab + Eribulin Placebo + Eribulin	27% 34%	4.1 4.2 (p = 0.33)	13.4 12.5 (p = 0.65)	PFS and OS not significantly prolonged in PD-L1 positive patients
NCT02924883 KATE2 Phase 2 Double-blind Placebo-controlled	HER2+ Prior trastuzumab Prior taxane Any PD-L1 status	n = 133 n = 69	Atezolizumab + T-DM1 Placebo + T-DM1	45% 43%	8.2 6.8 (p = 0.33)	NA	1 year OS 89% in both arms

HER2 = human epidermal growth factor receptor 2. HR = hormone receptor. ORR = overall response rate. PFS = progression-free survival. OS = overall survival. NR = not reached. NA = not available. PD-L1 = programmed death ligand-1. CPS = combined positive score. CT = chemotherapy. ET = endocrine therapy.

Table 2. Randomized clinical trials of neoadjuvant/adjuvant immunotherapy for breast cancer. Outcomes listed for immunotherapy containing arm vs non-immunotherapy arm

Study	Patient Population	Sample Size	Treatment	pCR Rate	Comment
NCT03036488 KEYNOTE-522 Phase 3 Double-blind Placebo-controlled	T1cN1-2 or T2-4N0-2	n = 784 n = 390	Paclitaxel + Carboplatin + Pembrolizumab → AC/EC + Pembrolizumab → Surgery → Pembrolizumab Paclitaxel + Carboplatin + Placebo → AC/EC + Placebo → Surgery → Placebo	63.0% 55.6% (not formally tested)	Results listed for IA3. Significant pCR difference at IA1 (p = 0.00055) and IA2 (p = 0.00221), not tested at IA3. At IA4, 3-year EFS 84.5% vs 76.8% (p = 0.00031)
NCT03197935 IMpassion031 Phase 3 Double-blind Placebo-controlled	Unilateral tumor >2 cm	n = 165 n = 168	nab-paclitaxel + Atezolizumab → EC + Atezolizumab nab-paclitaxel + Placebo → EC + Placebo	58% 41% (p = 0.0044)	PD-L1+ pCR rates: 69% vs 49% (p = 0.021)
NCT03726879 IMpassion050 Phase 3 Double-blind Placebo-controlled	T2-4N1-3 disease HER2+	n = 226 n = 228	AC + Atezolizumbab → Paclitaxel + HP + Atezolizumab → Surgery → HP + Atezolizumab AC + Placebo → Paclitaxel + HP + Placebo → Surgery → HP + Placebo	62.4% 62.7% (p = 1.0)	PD-L1+ pCR rates: 64.2% vs 72.5% (p = 0.2)
NCT02620280 NeoTRIPaPDL1 Phase 3 Open label	T1cN1+ or T3N0+ Unilateral IDC High Ki-67 or Grade	n = 142 n = 138	nab-paclitaxel + Carboplatin + Atezolizumab → Surgery → AC/EC/FEC nab-paclitaxel + Carboplatin → Surgery → AC/EC/FEC	43.5% 40.8% (p = 0.66)	Difference in pCR not significant
NCT01042379 I-SPY2 Phase 2 Adaptively randomized Open label	HER2- Tumor > 2 cm on imaging/2.5 cm on exam MammaPrint low-risk excluded	n = 69 n = 181	Paclitaxel + Pembrolizumab → AC Paclitaxel → AC	44% 17% (not formally tested)	TNBC pCR rates: 60% vs 22% HR+ pCR rates: 30% vs 13%
		n = 73 n = 295	Paclitaxel + Pembrolizumab → Pembrolizumab Paclitaxel → AC	15% 15% (not formally tested)	Protocol amended so patients no longer received pembro monotherapy due to 3 progressions
		n = 73 n = 299	Paclitaxel + Olaparib + Durvalumab → AC Paclitaxel → AC	37% 20% (not formally tested)	TNBC pCR rates: 47% vs 27% HR+ pCR rates: 28% vs 14%
		n = 73 n = 299	Paclitaxel + SD-101 + Pembrolizumab → AC Paclitaxel → AC	34% 20% (not formally tested)	TNBC pCR rates: 44% vs 28% HR+ pCR rates: 26% vs 14%
NCT02685059 GeparNuevo Phase 2 Double-blind Placebo-controlled	Tumor ≥ 2 cm	n = 88 n = 86	nab-paclitaxel + Durvalumab → EC + Durvalumab nab-paclitaxel + Placebo → EC + Placebo	53.4% 44.2% (p = 0.224)	Improvement seen in DDFS (HR 0.37, p = 0.0148) and OS (HR 0.26, p = 0.0076) with addition of durvalumab

pCR = pathologic complete response. HER2 = human epidermal growth factor receptor 2. HR = hormone receptor. TNBC = triple negative breast cancer. A = adriamycin. C = cyclophosphamide. E = epirubicin. F = 5-fluorouracil. PD-L1 = programmed death ligand-1. IDC = invasive ductal carcinoma. IA = interim analysis. HP = trastuzumab + pertuzumab.

Table 3. Select ongoing randomized clinical trials of checkpoint inhibitors in breast cancer. TNBC = triple negative breast cancer. HR = hormone receptor. HER2 = human epidermal growth factor receptor 2. RT = radiation therapy. NAC = neoadjuvant chemotherapy

Study	Treatment	Patient Population	Phase
NCT01898117 Triple-B	Carboplatin + Cyclophosphamide ± Atezolizumab versus Paclitaxel ± Atezolizumab	Advanced TNBC	Phase II
NCT03164993 ALICE	Cyclophosphamide + Pegylated Liposomal Doxorubicin ± Atezolizumab	Advanced TNBC	Phase II
NCT04177108	Paclitaxel ± Atezolizumab ± Ipatasertib	Advanced TNBC	Phase III
NCT03371017 IMpassion132	Gemcitabine + Carboplatin + Capecitabine ± Atezolizumab	Advanced TNBC	Phase III
NCT04191135 KEYLYNK-009	Pembrolizumab + Carboplatin + Gemcitabine → Olaparib versus Chemotherapy Maintenance	Advanced TNBC	Phase II/III
NCT04683679	RT + Pembrolizumab ± Olaparib	Advanced TNBC	Phase II
NCT04468061 Saci-IO TNBC	Sacituzumab govitecan ± Pembrolizumab	Advanced TNBC	Phase II
NCT03567720	Tavokinogene telseplasmid + Pembrolizumab ± nab-paclitaxel	Advanced TNBC	Phase II
NCT02755272	Carboplatin + Gemcitabine ± Pembrolizumab	Advanced TNBC	Phase II
NCT03167619 DORA	Olaparib ± Durvalumab	Advanced TNBC	Phase II
NCT03616886 SYNERGY	Paclitaxel + Carboplatin + Durvalumab ± Oleclumab	Advanced TNBC	Phase I/II
NCT03742102 BEGONIA	Durvalumab + Paclitaxel ± Experimental Agents	Advanced TNBC	Phase Ib/II
NCT04159818 TONIC-2	Nivolumab ± Induction Cisplatin or Doxorubicin	Advanced TNBC	Phase II
NCT02849496	Olaparib ± Atezolizumab	Advanced TNBC, germline/somatic BRCA	Phase II
NCT03281954 GeparDouze	NAC ± Atezolizumab	Early TNBC	Phase III
NCT03498716 IMpassion030	Adjuvant Chemotherapy ± Atezolizumab	Early TNBC	Phase III
NCT02883062	NAC ± Atezolizumab	Early TNBC	Phase II
NCT04443348	Pembrolizumab + NAC ± RT	Early TNBC	Phase II
NCT02954874	Adjuvant Pembrolizumab versus Observation	Early TNBC	Phase III
NCT03872505 PANDoRA	Carboplatin + Paclitaxel + Durvalumab ± RT	Early TNBC	Phase II
NCT03818685 BreastImmune03	Adjuvant Capecitabine versus Nivolumab + Ipilimumab	Early TNBC	Phase II
NCT04331067	NAC + Nivolumab ± Cabiralizumab	Early TNBC	Phase Ib/II
NCT03487666 OXEL	Adjuvant Nivolumab, Capecitabine or Both	Early TNBC	Phase II
NCT04732598 AMBITION	Paclitaxel + Bevacizumab ± Atezolizumab	Advanced HR+	Phase III
NCT04448886 Saci-IO HR+	Sacituzumab Govitecan ± Pembrolizumab	Advanced HR+	Phase II
NCT03409198 ICON	Pegylated Doxorubicin + Cyclophosphamide ± Ipilimumab and Nivolumab	Advanced HR+	Phase II
NCT03095352	Carboplatin ± Pembrolizumab	Advanced HR+ or TNBC	Phase II
NCT04740918 KATE3	T-DM1 ± Atezolizumab	Advanced HER2+	Phase III
NCT03199885	Paclitaxel + Trastuzumab + Pertuzumab ± Atezolizumab	Advanced HER2+	Phase III
NCT03515798 PELICAN	NAC ± Pembrolizumab	HER2- Inflammatory Breast Cancer	Phase II
NCT03725059 KEYNOTE-756	NAC ± Pembrolizumab	Early HR+	Phase III
NCT04109066 CheckMate 7FL	NAC ± Nivolumab	Early HR+	Phase III
NCT04075604 CheckMate 7A8	Neoadjuvant Anastrazole + Pablociclib ± Nivoumab	Early HR+	Phase II
NCT03875573 Neo-CheckRay	NAC + RT ± Durvalumab ± Oleclumab	Early Luminal B	Phase II
NCT03356860 B-IMMUNE	NAC ± Durvalumab	Early Luminal B	Phase II
NCT03726879 IMpassion050	NAC ± Atezolizumab	Early HER2+	Phase III
NCT03595592 APTneo	NAC ± Atezolizumab	Early HER2+	Phase III
NCT03747120 neoHIP	NAC + Pertuzumab, Pembrolizumab, or Both	Early HER2+	Phase II