Table III.
Combination of molecular targeting drugs with PD-1/PD-L1 inhibitors.
| Author(s) (year) | Interventions | Primary end point(s) | Results | (Refs.) |
|---|---|---|---|---|
| Zhao et al, 2019 | PD-L1 inhibitors + VEGFR2 | TILs | Increased | (38) |
| small molecule inhibitors (apatinib) | TAMs, MDSCs, TGF-β, Tumor growth | Hindered | ||
| Decreased | ||||
| Survival | Prolonged | |||
| Reck et al, 2019 | Anti-PD-L1+ Bevacizuma + | PFS | 10.2 months vs. 6.9 months | (42) |
| Chemotherapy vs. Bevacizuma + Chemotherapy | OS | 13.3 months vs. 9.4 months | ||
| Haratani et al, 2017 | PD-1/PD-L1 inhibitors+ EGFR-TKIs | ORR | T790M-negative patients (24%) vs. T790M-positive patients (13%) | (48) |
| Yang et al, 2019 | Pembrolizumab + Erlotinib | ORR | 41.7% vs. 14.3% | (50) |
| vs. Pembrolizumab+ Gefitinib | PFS | 19.5 months vs. 1.4 months | ||
| Siu et al, 2017 | IDO1 inhibitor (BMS-986205) + Nivolumab vs. BMS-986205 | Safety | All treatment-related adverse events were grade 1/2 except three grade 3 toxicities | (52) |
| Zakharia et al, 2016 | IDO inhibitor (Indoximod) + Ipilimumab, Nivolumab or Pembrolizumab | ORR | 52% | (56) |
| Hamid et al, 2017 | IDO inhibitor (Epacadostat) + Pembrolizumab | ORR | 75% of melanoma and 4% of colorectal cancer | (57) |
| Huang et al, 2015 | Anti-LAG3 + Anti-PD-1 vs. Anti-PD-1 | Tumor clearance | 100% vs. 50% | (59) |
| Goding et al, 2013 | Anti-PD-L1 + anti-LAG-3 antibodies | Tumor area | Reduced | (60) |
| Sakuishi et al, 2010 | Co-blocking Tim-3 and PD-1 pathways | Tumor Size | Reduced | (67) |
| Friedlaender et al, 2019 | Co-blocking Tim-3 and PD-1 pathways | An ongoing phase I trials | Anti-tumor study of TIM3 and PD-L1 inhibitors is under way (NCT03099109; NCT02608268) | (71) |
| Davar et al, 2018 | Anti-Tim-3(TSR-022)+ anti-PD-1(TSR-042) | PR | 1 case of 11 evaluable patients with 100 mg dose vs. 3 cases of 20 evaluable patients with 300 mg dose | (72) |
| SD | 3 cases of 11 evaluable patients with 100 mg dose vs. 8 cases of 20 evaluable patients with 300 mg dose | |||
| Chauvin et al, 2015 | Anti-TIGIT+ anti-PD-1 vs. anti-TIGIT vs. anti-PD-1 | NY-ESO-1-specific CD8+ T cell | Anti-TIGIT+ anti-PD-1>anti- TIGIT/anti-PD-1 | (74) |
| Johnston et al, 2014 | Anti-TIGIT + anti-PD-L1 vs. anti-TIGIT vs. anti-PD-L1 | Tumor volume | Anti-TIGIT+ anti-PD-L1 <anti-TIGIT/anti-PD-L1 | (76) |
| Percent survival | Anti-TIGIT+ anti-PD-L1 >anti-TIGIT/anti-PD-L1 | |||
| Morales-Kastresana et al, 2013 | Combination of anti-4-1BB, anti-OX40 and anti-PD-L1 | Survival | Extended | (80) |
| Tumor-infiltrating lymphocytes | Increased | |||
| Tolcher et al, 2017 | 4-1BB (Utomilumab) + Pembrolizumab | Safety | Treatment-emergent adverse events were mostly grades1-2 | (83) |
| Activated memory/effector CD8+ T cells | Increased | |||
| Postow et al, 2015 | Nivolumab + Ipilimumab vs. Ipilimumab | ORR | 61% vs. 11% | (87) |
| The median reduction in tumor volume | 68.1% vs. 5.5% | |||
| Larkin et al, 2015 | Nivolumab + Ipilimumab vs. Ipilimumab vs. Nivolumab | PFS | 11.5 months vs. 2.9 months vs. 6.9 months, | (88) |
| Safety | Grade 3 or 4 adverse events: 55.0% vs. 27.3% vs. 16.3% | |||
| Omuro et al, 2018 | Nivolumab + Ipilimumab vs. Ipilimumab vs. Nivolumab | Tolerance | 80% vs. 70% vs. 90%, | (89) |
| Safety | Fatigue: 55% vs. 80% vs. 30% | |||
| Diarrhea: 30% vs. 70% vs. 10% |
PD-1, programmed cell death protein-1; PD-L1, programmed death protein ligand-1.