Table 1.
Studies included in the systematic review
| Ref. | Design | Population | Intervention (I) | Control (C) | OS | PFS | ORR | QOL measures/symptom burden | Biomarker effect | AE Grade 3 or more |
| Phase-3 clinical trials evaluating ICI as second line therapy in R/M HNSCC | ||||||||||
| Ferris et al[22], 2016 | RCT (2:1), open-label phase-3 trial | Patients with R/M HNSCC not amenable to curative therapy | Nivolumab 3 mg/kg IV Q2W | SOC: Investigator’s, choice of methotrexate 40 mg/m2 IV weekly, docetaxel 30 mg/m2 IV weekly, or cetuximab 400 mg/m2 IV once followed by 250 mg/m2 weekly | Nivolumab: 7.5 mo (95%CI: 5.5-9.1) | Nivolumab: 2.0 mo, 95%CI: 1.9-2.1 | Nivolumab: 13.3%, 95%CI: 9.3-18.3 | Between group differences in favor of Nivolumab group | OS | Nivolumab: 13.1% |
| Checkmate 141 | n = 361 | MoA: PD-1 inhibition | n = 121 | SOC: 5.1 mo, 95%CI: 4.0-6.0; HR 0.69, 95%CI: 0.53-0.91, P = 0.01 | SOC: 2.3 mo, 95%CI: 1.9-3.1; HR 0.89, 95%CI: 0.70-1.13, P = 0.32 | SOC: 5.8%, 95%CI: 2.4-11.6 | Physical functioning: at 9 wk P = 0.01; at 15 wk, P < 0.001 | PD-L1 ≥ 1%: Nivolumab 8.7mo; SOC: 4.6 mo, HR for death 0.55 (95%CI: 0.36-0.83) | Two treatment related deaths | |
| n = 240, median follow up = 5.1 mo (range: 0 to 16.8) | Estimated 1-yr survival rate 36.0% in the nivolumab group vs 16.6% in the control group | Role functioning: at 9 wk, P = 0.003; at 15 wk, P < 0.001 | PD-L1 < 1%: Nivolumab, 5.7 mo; SOC: 5.8 mo, HR for death 0.89 (95%CI: 0.54-1.45) P for int. = 0.17 | SOC: 35.0% | ||||||
| Social functioning: at 9 wk P = 0.002; at 15 wk P < 0.001 | P16 + ve tumors: Nivolumab 9.1 mo; SOC: 4.4 mo, HR for death 0.56 (95%CI: 0.32-0.99) | One treatment related death | ||||||||
| Symptom burden pain: at 9 wk, P < 0.001; at 15 wk, P = 0.02 | P16 -ve tumours: Nivolumab 7.5 mo; SOC: 5.8 mo, HR 0.73 (95%CI: 0.42-1.25), P for Interaction = 0.55 | |||||||||
| Sensory problems: at 9 wk, P = 0.01; at 15 wk, P < 0.001 | ||||||||||
| Social contact problems: at 9 wk, P = 0.26; at 15 wk, P < 0.001 | ||||||||||
| Cohen et al[23], 2019 | RCT (1:1), open-label phase-3 trial | Patients with R/M HNSCC | Pembrolizumab: 200 mg IV Q3W | SOC: methotrexate 40 mg/m2 weekly (in absence of toxicity could increase to 60 mg/m2), docetaxel 75 mg/m2 Q3W, or cetuximab loading dose of 400 mg/m2 followed by 250 mg/m2 weekly | Pembrolizumab: 8.4 mo, 95%CI: 6.4-9.4 | Pembrolizumab: 2.1 mo 95% CI: 2.1-2.3 | Pembrolizumab: 14.6%, 95%CI: 10.4-19.6 | Exploratory HRQOL analysis (published separately) by means of EORTC QOLQ-C30, EORTC QOLQ- H&N35, and EuroQOL-5 dimensions questionnaires | OS | Pembrolizumab: 13%, treatment related death in four patients |
| KEYNOTE 040 | 3-6 mo after multimodal treatment with platinum or progression after platinum-based treatment | MoA: PD-1 inhibition | n = 248, median follow-up 7.1 mo (IQR 3.7-12.4) | SOC: 6.9 mo, 95%CI: 5.9-8.0; HR 0.80, 95%CI: 0.65-0.98, nominal p = 0.0161 | SOC: 2.3 mo, 95%CI: 2.1-2.8; HR 0.96, 95%CI: 0.79-1.16, nominal P = 0.325 | SOC: 10.1%, 95%CI: 6.6-14.5, nominal P = 0.061 | At 15 wk, GHS/QOL scores were stable with pembrolizumab: least square mean (LSM) 0.39; 95%CI: -3.00 to 3.78 | TPS ≥ 50% | SOC: 36.1%, treatment related death in two patients | |
| n = 495 | n = 247, median follow up = 7.5 mo (IQR 3.4-13.3) until data cut-off /8.4 mo (IQR 3.3-14.5) until death | PFS based on modified RECIST 1.1 | At 15 wk, GHS/QOL scores declined with SOC; (LSM -5.86; 95%CI: -9.68 to -2.04) | Pembrolizumab 11.6 mo (95%CI: 8.3-19.5); SOC: 6.6 mo (95%CI: 4.8-9.2), HR 0.53 (95%CI: 0.35-0.81; nominal P = 00014) | ||||||
| Pembrolizumab: 3.5 mo | LSM between-group difference was 6.25 points (95%CI: 1.32-11.18: nominal 2-sided P = 0.01) | TPS < 50% | ||||||||
| SOC: 4.8 mo | Pembrolizumab: 6.5 mo (95% CI 5.6-8.8); SOC: 7.1 mo (95%CI: 5.7-8.1), HR for death 0.93 (95%CI: 0.73-1.17; nominal P = 0.2675), P for int. = 0.015 | |||||||||
| CPS ≥ 1 | ||||||||||
| Pembrolizumab: 8.7 mo (95%CI: 6.9-11.4); SOC: 7.1 mo (95%CI: 5.7-8.3), HR for death = 0.74 (95%CI: 0.58-0.93) nominal P = 0.0049) | ||||||||||
| CPS < 1 | ||||||||||
| Pembrolizumab: 6.3 mo (95% CI 3.9-8.9); SOC: 7 mo (95%CI: 5.1-9.0), HR for death 1.28 (95%CI: 0.8-2.07; P = 08476) P for int.= 0.07 | ||||||||||
| PFS | ||||||||||
| Based on modified RECIST1.1 | ||||||||||
| TPS ≥ 50%: PFS longer with Pembrolizumab than with SOC | ||||||||||
| CPS ≥ 1: PFS almost equal to that in the overall population for both Pembrolizumab and SOC (3.6 mo vs 4.8 mo) | ||||||||||
| CPS < 1, & TPS < 50%: PFS longer with SOC than with Pembrolizumab | ||||||||||
| Ferris et al[24], 2020 | RCT (1:1:1), open-label phase-3 trial | R/M HNSCC not amenable to curative therapy | Arm 1 | SoC | Durvalumab: 7.6 mo 95%CI: 6.1-9.8 | Durvalumab: 2.1 mo, 95%CI: 1.9-3.0 | Durvalumab: 17.9%, 95%CI: 13.3-23.3 | Not assessed | OS | Durvalumab: 10.1%, four treatment related deaths |
| EAGLE | n = 736 | Durvalumab MoA: PD-L1 inhibition 10 mg/kg every 2 wk | Single-agent systemic therapy using one of the following: cetuximab paclitaxel, docetaxel, methotrexate, 5 FU, TS-1, or capecitabine | Durvalumab + Tremelimumab: 6.5 mo, 95%CI: 5.5-8.2 | Durvalumab + Tremelimumab: 2.0 mo, 95%CI: 1.9-2.3 | Durvalumab + Tremelimumab: 18.2%, 95%CI: 13.6-23.6 | TC ≥ 25% | Durvalumab + Tremelimumab, 16.3 %, two treatment related deaths | ||
| n = 240, median follow-up: 7.6 mo | n = 249, median follow-up = 7.8 mo | SoC: 8.3 mo, 95%CI: 7.3-9.2 | SoC: 3.7 mo, 95%CI: 3.1-3.7 | SoC: 17.3%, 95%CI: 12.8-22.5 | Durvalumab: 9.8 mo (95%CI: 4.3-14.1); Durvalumab + Tremelimumab: 4.8 mo (95%CI: 3.3-6.4); SoC: 9 mo (95%CI: 6.8-11.0) | SoC: 24.2%, No treatment related deaths | ||||
| Arm 2 | Durvalumab vs SoC: HR = 0.88, 95%CI: 0.72-1.08, P = 0.20 | Durvalumab vs SoC: HR = 1.02, 95%CI: 0.84-1.25, P = 0.75 | TC < 25% | |||||||
| Durvalumab plus Tremelimumab MoA: CTLA-4 blockade | Durvalumab + Tremelimumab vs SoC.: HR = 1.04, 95%CI: 0.85-1.26, P = 0.76 | Durvalumab + Tremelimumab vs SoC: HR = 1.09, 95%CI: 0.90-1.33, P = 0.54 | Durvalumab: 7.6 mo (95%CI: 6.2-9.5); Durvalumab + Tremelimumab: 7.8 mo (95%CI: 5.9-10.3); SoC: 8 mo (95%CI: 6.7-8.9) | |||||||
| Durvalumab: 20 mg/kg plus Tremelimumab 1 mg/kg every 4 wk-4 times, then Durvalumab: 10 mg /kg every 2 wk | TC ≥ 1%: Both treatment arms vs SoC had no difference in OS | |||||||||
| n = 247, median follow-up: 6.3 mo | TC < 1%: OS was longer for Durvalumab vs SoC; but no difference for Durvalumab + Tremelimumab vs SOC | |||||||||
| Phase-3 clinical trials evaluating ICI as first line therapy in R/M HNSCC | ||||||||||
| Burtness et al[25], 2019 | RCT (1:1:1), open-label phase-3 trial | Patients with R/M HNSCC | Arm 1: Pembrolizumab (MoA: PD-1 inhibition), monotherapy; Pembrolizumab 200 mg once every 3 wk | EXTREME regime: cetuximab 400 mg/m² loading dose, then 250 mg/m², per week plus, carboplatin (AUC 5 mg/m2) or cisplatin (100 mg/m2) and 5-FU (1000 mg/m2 for 4 consecutive days) every 3 wk | Arm 1: Pembrolizumabalone, 11.6 mo, 95%CI: 10.5-13.6 | Arm 1: Pembrolizumab alone, 2.3 mo (95%CI: 2.2-3.3) | Arm 1: Pembrolizumab, 17% | NA | OS | Pembrolizumab alone: 55% (all cause), 17% (TRAE)AE led to death in 8% of pts |
| KEYNOTE 048 | Three arms | n = 301, median follow-up: 11.5 mo | n = 300, median follow-up: 10.7 mo | Arm 2: Pembrolizumab + CT, 13.0 mo, 95%CI: 10.9-14.7 | Control arm: Cetuximab + CT 5.2 mo (95%CI: 4.9-6) | Arm 2: Pembrolizumab + CT, 36% | CPS of ≥ 20: Pembrolizumab alone vs EXTREME: 14.9 mo vs 10.7 mo, HR 0.61; 95%CI: 0.45-0.83, P = 0.0007 | Pembrolizumab + CT: 85% (all cause), 72%(TRAE), AE led to death in 12% of pts | ||
| n = 882 | Arm 2: Pembrolizumab + CT (platinum-FU), Pembrolizumab 200 mg once every 3 wk plus carboplatin (AUC 5 mg/m2) or cisplatin (100 mg/m2) and 5-FU (1000 mg/m2 for 4 consecutive days) every 3 wk | Control arm: Cetuximab + CT, 10.7 mo, 95%CI: 9.3-11.7 | Arm 2: Pembrolizumab + CT, 4.9 mo (95%CI: 4.7-6) | Control arm: Cetuximab + CT, 36% | Pembrolizumab + CT vs EXTREME: 14.7 mo vs 11.0 mo, HR 0.60; 95%CI: 0.45-0.82, P = 0.0004 | Cetuximab + CT: 83% (all cause), 69%(TRAE), AE led to death in 10% of pts | ||||
| n = 281, median follow-up: 13.0 mo | Pembrolizumab alone vs EXTREMEHR 0.85, 95%CI: 0.71-1.03, P = 0.0456 | Control arm: Cetuximab + CT, 5.1 mo (95%CI:4.9-6) | CPS of ≥ 1: Pembrolizumab alone vs EXTREME: 12.3 mo vs 10.3 mo, HR 0.78 [0.64-0.96], P = 0.0086 | |||||||
| Pembrolizumab + CT vs EXTREME, HR 0.77, 95%CI: 0.63-0.93, P = 0.0034 | Pembrolizumab alone vs EXTREME: HR = 1.34; 95%CI: 1.13-1.59 | Pembrolizumab + CT vs EXTREME: 13.6 mo vs 10.4 moHR 0.65; 95%CI: 0.53-0.80, P < 0.0001 | ||||||||
| Pembrolizumab + CT vs EXTREME: HR = 0.92, 95%CI: 0.77-1.10, P = 0.169 | PFS | |||||||||
| CPS of ≥ 20: Pembrolizumab alone vs EXTREME, 3.4 mo vs 5.0 mo, HR 0.99; 95%CI: 0.75-1.29, P = 0.456 | ||||||||||
| Pembrolizumab + CT vs EXTREME: 5.8 mo vs 5.2 mo, HR 0.73; 95%CI: 0.55-0.97, P = 0.0162 | ||||||||||
| CPS of ≥ 1: Pembrolizumab alone vs EXTREME, 3.2 mo vs 5.0 mo, HR 1.16; 95%CI: 0.96-1.39 | ||||||||||
| Pembrolizumab + CT vs EXTREME: 5.0 mo vs 5.0 mo, HR 0.82; 95% CI: 0.67-1.00 | ||||||||||
| Phase-3 clinical trials evaluating ICI for treatment of LAHNSCC | ||||||||||
| Cohen et al[26], 2020 | RCT (1:1) double blind placebo-controlled | Patients with pathologically confirmed previously untreated LA HNSCC who were eligible for definitive CRT with curative intent | Avelumab (PD-L1 inhibitor) 10 mg/kg iv every 2 wk plus CRT with cisplatin 100 mg/m2 every 3 wk plus standard fractionation of 70 Gy in 35 fractions over 7 wk | Placebo plus CRT with cisplatin 100 mg/m2 every 3 wk plus standard fractionation of 70 Gy in 35 fractions over 7 wk | OS: not reached, HR: 1.31, 95%CI: 0.93-1.85; one sided P = 0.94 | PFS: not reached, HR: 1.21, 95%CI: 0.93-1.57; one sided P = 0.92 | Avelumab + CRT: 74%, 95%CI: 69-79; based on modified RECIST 1.1 | NA | PFS | Intervention: 80 %, serious AEs in 36% pts, treatment related death 1%, 7% pts discontinued due to TRAEs |
| Lee et al[31], 2021 | Phase-3 trial | n = 697 | n = 350, median follow-up for PFS = 14.6 mo (IQR 8.5-19.6) for OS =16.7 mo (IQR 12.8-21.2) | n = 347, median follow-up for: PFS = 14.8 mo (11.6-18.8), OS =16.8 mo (IQR 13.1-20.8) | Favors control arm | Favors control arm | Placebo + CRT: 75%; 95%CI: 70-79; based on modified RECIST 1.1 | Avelumab + CRT vs Placebo + CRT, PD-L1 ≥ 25%: HR 0.59 (95%CI: 0.28-1.22); PD-L1 < 25%, HR: 1.37 (95%CI: 1.00-1.88), P for int. = 0.03 | Control: 74%, serious AEs in 32% pts, treatment related death < 1%, 3% pts discontinued due to TRAEs | |
| JAVELIN head and neck 100 trial | OR = 0.95; 95%CI: 0.66-1.35, P = 0.62 | |||||||||
QOL: Quality of life; HRQOL: Health-related QOL; CRT: Chemoradiation therapy; OS: Overall survival; PFS: Progression-free survival; ORR: Objective response rate; ICI: Immune checkpoint inhibitors; R/M HNSCC: Recurrent or metastatic head and neck squamous cell carcinoma; LAHNSCC: Locally advanced head and neck squamous cell carcinoma; RCT: Randomized controlled trial; PD-1: Programmed cell death protein-1; PD-L1: Programmed death-ligand 1; CTLA-4: Cytotoxic T- lymphocyte associated protein-4; AE: Adverse event; TRAE: Treatment-related AEs; SOC: Standard of care; CPS: Combined positive score; CI: Confidence interval; IV: Intravenously; MoA: Mechanism of action; HR: Hazard ratio; IQR: Interquartile range; LSM: Least mean square; TPS: Tumor proportion score; Mab: Monoclonal antibody; CT: Chemotherapy.