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Copyright ©The Author(s) 2022.
World J Clin Oncol. Mar 24, 2022; 13(3): 219-236
Published online Mar 24, 2022. doi: 10.5306/wjco.v13.i3.219
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
NeoadjuvantNCT03639948II100Carboplatin + Docetaxel + PembrolizumabRecruiting
NCT03289819II50Pembrolizumab + Nab-paclitaxel → Pembrolizumab + Epirubicin and CyclophosphamideRecruiting
NCT03356860 (B-IMMUNE)II57Paclitaxel + Epirubicin + Cyclophosphamide + DurvalumabRecruiting
NCT02685059 (GeparNuevo) (June 2018)II174Epirubicin + Nab-paclitaxel + Cyclophosphamide + DurvalumabActive, no recruiting--
Population: Early TNBCpCR 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/AdjuvantNCT03036488 (KEYNOTE-522) (August 2020)III1174Carboplatin + Paclitaxel + AC (anthracycline + cyclophosphamide) +/- Pembrolizumab → Adjuvant PembrolizumabActive, no recruiting--Co-primary endpoints were pCR and EFS
Population: Early TNBCpCR: 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)III280Carboplatin/nab-paclitaxel +/- Atezolizumab → anthracycline (AC/EC)Active, no recruiting--Primary endpoint was pCR
Population: Early TNBCThe 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
NCT03281954III1520Doxorubicin + Cyclophosphamide + Paclitaxel + Carboplatin +/- Atezolizumab → AtezolizumabRecruiting
NCT03197935 (IMpassion031) (September 2020)III204AC (doxorubicin + cyclophosphamide) + Nab-paclitaxel +/- Atezolizumab → Adjuvant AtezolizumabActive, no recruitingpCR was 58% in Atezolizumab group vs 41% in placebo group (P = 0.0044)
Population: Early TNBCIn 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)NCT02954874III1000Pembrolizumab vs observationRecruiting
NCT03756298II284Capecitabine +/- AtezolizumabRecruiting
AdjuvantNCT03498716 (IMpassion030)III2300Paclitaxel → dd Doxorubicin/Epirubicin + Cyclophosphamide +/- AtezolizumabRecruitingPrimary 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)III335Avelumab vs observationRecruitingThis 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 mTNBCNCT02768701II40Cyclophosphamide + PembrolizumabActive, no recruiting
NCT03121352II30Carboplatin, Nab-paclitaxel y PembrolizumabRecruiting
NCT02499367 (TONIC)II67Control or irradiation 3 x 8 Gy or oral cyclophosphamide or Cisplatin or Doxorubicin → anti-PD-1 (Nivolumab)Active, no recruitingFive 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)III858Nab-paclitaxel or Paclitaxel or Carboplatin/Gemcitabine +/- PembrolizumabActive, no recruiting9.7 vs 5.6 (HR: 0.82) in CPS ≥ 10-Co-primary endpoints were PFS and OS (this latter is pending outcome)
Population: First-line mTNBCPembro 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)III600Capecitabine, Eribulin, Gemcitabine, or Vinorelbine vs PembrolizumabActive, no recruiting2.1 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 mTNBCOS 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)II285Pembrolizumab monotherapyActive, 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)III902Atezolizumab + Nab-paclitaxel (comparator: placebo + Nab-paclitaxel)Active, no recruiting7.5 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 mTNBCIn 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)III600Paclitaxel +/- Atezolizumab (comparator: placebo + paclitaxel)Active, no recruiting5.7 vs 6.0 (HR: 0.82, P = .20) in PD-L1 (+) population22.1 vs 28.3 (HR: 1.12) in PD-L1 (+) populationPrimary endpoint was PFS
Population: First-line mTNBCIn 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)III350Carboplatin + Gemcitabine or Capecitabine +/- AtezolizumabRecruitingPrimary endpoint was OS
Estimated completion date: July 2023
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
22C3PembrolizumabDAKOTPS ≥ 1%1L
TC ≥ 1%2L
28-8NivolumabDAKOTC ≥ 1%2L
SP142AtezolizumabVentanaTC ≥ 50% and/or IC ≥ 10%1L
TC ≥ 1% and/or IC ≥ 1%2L
SP263DurvalumabVentanaTC ≥ 1%1L maintenance, in unresectable stage III after chemoradiation therapy
NivolumabTC ≥ 1%2L
PembrolizumabTC ≥ 50%1L
73-10AvelumabDAKOTC ≥ 1%2L (not approved)