Table 1.
Studies evaluating the efficacy of pembrolizumab, larotrecrinib and entrectinib among patients with breast cancer and MSI-H/dMMR, NRTK fusions or TMB-H alterations.
| Molecular alteration | Reference | Study design | Treatment | Study population | Results |
|---|---|---|---|---|---|
| MSI-H/dMMR | KEYNOTE-016, 164, 012, 028, 1585,6,19 | Pooled analysis of five phase II, open-label, single arm trials | Pembrolizumab 200 mg q3w or 10 mg/kg q2w |
N = 149 CRC and non-CRC 2 BC pts |
ORR 39.6% (general cohort) 2 PR in BC pts DOR (BC) range 7.6 to 15.9mo |
| KEYNOTE-1586 | Phase 2, non-randomized, open-label | Pembrolizumab 200 mg q3w |
N = 233 5 BC pts |
ORR 34% (general cohort), mDOR NR, mTTR 2.1mo Data from BC unknown |
|
| NTRK | LOXO-TRK-14001, NAVIGATE, SCOUT40 | Expanded pooled analysis of three phase I/II trials in adults and pediatric pts | Larotrectinib 100 mg twice daily q28d (phase 2 dose) |
N = 159 5 BC pts |
ORR 79% (general cohort) ORR 75% BC |
| Meric-Bernstam et al.60 | Case series: NAVIGATE (1 pts) and compassionate use-protocols (5 pts) | Larotrectinib 100 mg twice daily q28d |
N = 5 BC pts 2 TNBC pts 4 pts ETV6-NTRK3 |
ORR 80% (4/5 PR) All responses within 2 cycles |
|
| ALKA-372-001, STARTRK-1, STARTRK-28,41 | Pooled analysis of three phase I/II trials | Entrectinib 600 mg once a day |
N = 54 6 BC pts |
ORR 57% (general cohort) ORR 83% (BC), 2 CR, mDOR 4.2 to 14.8mo |
|
| TMB-H | KEYNOTE-1585 | Pre-planned retrospective analysis | Pembrolizumab 200 mg q3w |
N = 102 (TMB-H) 0 BC pts TMB-H cut-off ≥10 mut/Mb (FoundationOne CDx) |
ORR 29%, mDOR NR |
| TAPUR65 | Phase II basket study | Pembrolizumab |
N = 28 MBC pts TMB-H cut-off ≥ 9 mut/Mb (FoundationOne CDx in 71% of specimens) |
ORR = 21%, DC = 37% mPFS 10.6w, mOS 30.6w |
|
| KEYNOTE-11966 | Phase 3 trial (exploratory analysis for TMB) | Pembrolizumab vs chemotherapy |
N = 601 mTNBC 2d/3d lines TMB evaluable for 253 pts (42%) 10% TMB-H (cut-off≥10 mut/Mb by FoundationOne CDx) |
Positive association among TMB and PFS (p = 0.014) and OS (p = 0.018) for pembrolizumab arm | |
| IMpassion-13071 | Phase 3 trial (exploratory retrospective analysis for TMB) | Atezolizumab(A) + nab-paclitaxel(nP) vs placebo(PL) + nP |
N = 902 TMB evaluable for 579 pts (FoundationOne CDx) |
mTMB 4.39 mut/Mb PFS (highest quartile; 7.02 mut/Mb) HR 0.31 (95% IC:0.17,0.57) in PD-L1 + vs HR 0.84 (95%IC:0.48,1.47) in PD-L1- OS (all TMB quartiles) HR 0.71 (95% IC:0.52, 0.97) in PD-L1 + |
|
| Barroso-Sousa et al.70 | Prospective cohort | Anti-PD-1/L1 inhibitors alone (23%) or plus chemo (58%) or targeted therapy (19%) |
N = 62 mTNBC 18% TMB-H (cut-off≥10mut/Mb) TMB assessed with WES (France Study 2016, MBCproject andTCGA-BRCA) and NGS (DFCI-ONCOPANEL, MSK-IMPACT and VICC) |
ORR 58% TMB-H vs 30% TMB-L (p = 0.09) mPFS 12.5mo TMB-H vs 3.7mo TMB-L (p = 0.03) mOS 29.2mo TMB-H vs 14.2mo TMB-L (p = 0.06) |
q3w: every 3 weeks, q2w: every 2 weeks, CRC: colorectal cancer, BC: breast cancer, pts: patients, ORR: overall response rate, PR: partial response, DOR: duration of response, NR: not reached, mTTR: median time to response, mo: months, q28d: every 28 days, TNBC: triple negative breast cancer, DC: disease control, MBC: metastatic breast cancer, mPFS: median progression free-survival, mOS: median overall survival, mTNBC: metastatic triple negative breast cancer, pembro: pembrolizumab, chemo: chemotherapy, m: median, TMB-L: low mutational tumor burden.