Systematic Reviews
Copyright ©The Author(s) 2022.
World J Clin Oncol. May 24, 2022; 13(5): 388-411
Published online May 24, 2022. doi: 10.5306/wjco.v13.i5.388
Table 1 Studies included in the systematic review
Ref.DesignPopulationIntervention (I)Control (C)OSPFSORRQOL measures/symptom burdenBiomarker effectAE Grade 3 or more
Phase-3 clinical trials evaluating ICI as second line therapy in R/M HNSCC
Ferris et al[22], 2016RCT (2:1), open-label phase-3 trialPatients with R/M HNSCC not amenable to curative therapyNivolumab 3 mg/kg IV Q2WSOC: 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 weeklyNivolumab: 7.5 mo (95%CI: 5.5-9.1)Nivolumab: 2.0 mo, 95%CI: 1.9-2.1Nivolumab: 13.3%, 95%CI: 9.3-18.3Between group differences in favor of Nivolumab groupOSNivolumab: 13.1%
Checkmate 141n = 361MoA: PD-1 inhibitionn = 121SOC: 5.1 mo, 95%CI: 4.0-6.0; HR 0.69, 95%CI: 0.53-0.91, P = 0.01SOC: 2.3 mo, 95%CI: 1.9-3.1; HR 0.89, 95%CI: 0.70-1.13, P = 0.32SOC: 5.8%, 95%CI: 2.4-11.6Physical functioning: at 9 wk P = 0.01; at 15 wk, P < 0.001PD-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 < 0.001PD-L1 < 1%: Nivolumab, 5.7 mo; SOC: 5.8 mo, HR for death 0.89 (95%CI: 0.54-1.45) P for int. = 0.17SOC: 35.0%
Social functioning: at 9 wk P = 0.002; at 15 wk P < 0.001P16 + 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 = 0.02P16 -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], 2019RCT (1:1), open-label phase-3 trialPatients with R/M HNSCCPembrolizumab: 200 mg IV Q3WSOC: 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 weeklyPembrolizumab: 8.4 mo, 95%CI: 6.4-9.4Pembrolizumab: 2.1 mo 95% CI: 2.1-2.3Pembrolizumab: 14.6%, 95%CI: 10.4-19.6Exploratory HRQOL analysis (published separately) by means of EORTC QOLQ-C30, EORTC QOLQ- H&N35, and EuroQOL-5 dimensions questionnairesOSPembrolizumab: 13%, treatment related death in four patients
KEYNOTE 0403-6 mo after multimodal treatment with platinum or progression after platinum-based treatmentMoA: PD-1 inhibitionn = 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 = 0.0161SOC: 2.3 mo, 95%CI: 2.1-2.8; HR 0.96, 95%CI: 0.79-1.16, nominal P = 0.325SOC: 10.1%, 95%CI: 6.6-14.5, nominal P = 0.061At 15 wk, GHS/QOL scores were stable with pembrolizumab: least square mean (LSM) 0.39; 95%CI: -3.00 to 3.78TPS ≥ 50%SOC: 36.1%, treatment related death in two patients
n = 495n = 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 deathPFS based on modified RECIST 1.1At 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 moLSM between-group difference was 6.25 points (95%CI: 1.32-11.18: nominal 2-sided P = 0.01)TPS < 50%
SOC: 4.8 moPembrolizumab: 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], 2020RCT (1:1:1), open-label phase-3 trialR/M HNSCC not amenable to curative therapyArm 1SoCDurvalumab: 7.6 mo 95%CI: 6.1-9.8Durvalumab: 2.1 mo, 95%CI: 1.9-3.0Durvalumab: 17.9%, 95%CI: 13.3-23.3Not assessedOSDurvalumab: 10.1%, four treatment related deaths
EAGLEn = 736Durvalumab MoA: PD-L1 inhibition 10 mg/kg every 2 wkSingle-agent systemic therapy using one of the following: cetuximab paclitaxel, docetaxel, methotrexate, 5 FU, TS-1, or capecitabineDurvalumab + Tremelimumab: 6.5 mo, 95%CI: 5.5-8.2Durvalumab + Tremelimumab: 2.0 mo, 95%CI: 1.9-2.3Durvalumab + Tremelimumab: 18.2%, 95%CI: 13.6-23.6TC ≥ 25%Durvalumab + Tremelimumab, 16.3 %, two treatment related deaths
n = 240, median follow-up: 7.6 mon = 249, median follow-up = 7.8 moSoC: 8.3 mo, 95%CI: 7.3-9.2SoC: 3.7 mo, 95%CI: 3.1-3.7SoC: 17.3%, 95%CI: 12.8-22.5Durvalumab: 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 2Durvalumab vs SoC: HR = 0.88, 95%CI: 0.72-1.08, P = 0.20Durvalumab vs SoC: HR = 1.02, 95%CI: 0.84-1.25, P = 0.75TC < 25%
Durvalumab plus Tremelimumab MoA: CTLA-4 blockadeDurvalumab + Tremelimumab vs SoC.: HR = 1.04, 95%CI: 0.85-1.26, P = 0.76Durvalumab + Tremelimumab vs SoC: HR = 1.09, 95%CI: 0.90-1.33, P = 0.54Durvalumab: 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 wkTC ≥ 1%: Both treatment arms vs SoC had no difference in OS
n = 247, median follow-up: 6.3 moTC < 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], 2019RCT (1:1:1), open-label phase-3 trialPatients with R/M HNSCCArm 1: Pembrolizumab (MoA: PD-1 inhibition), monotherapy; Pembrolizumab 200 mg once every 3 wkEXTREME 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 wkArm 1: Pembrolizumabalone, 11.6 mo, 95%CI: 10.5-13.6Arm 1: Pembrolizumab alone, 2.3 mo (95%CI: 2.2-3.3)Arm 1: Pembrolizumab, 17%NAOSPembrolizumab alone: 55% (all cause), 17% (TRAE)AE led to death in 8% of pts
KEYNOTE 048Three armsn = 301, median follow-up: 11.5 mon = 300, median follow-up: 10.7 moArm 2: Pembrolizumab + CT, 13.0 mo, 95%CI: 10.9-14.7Control 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 = 0.0007Pembrolizumab + CT: 85% (all cause), 72%(TRAE), AE led to death in 12% of pts
n = 882Arm 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 wkControl arm: Cetuximab + CT, 10.7 mo, 95%CI: 9.3-11.7Arm 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 = 0.0004Cetuximab + CT: 83% (all cause), 69%(TRAE), AE led to death in 10% of pts
n = 281, median follow-up: 13.0 moPembrolizumab alone vs EXTREMEHR 0.85, 95%CI: 0.71-1.03, P = 0.0456Control 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 = 0.0034Pembrolizumab alone vs EXTREME: HR = 1.34; 95%CI: 1.13-1.59Pembrolizumab + 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 = 0.169PFS
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], 2020RCT (1:1) double blind placebo-controlledPatients with pathologically confirmed previously untreated LA HNSCC who were eligible for definitive CRT with curative intentAvelumab (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 wkPlacebo plus CRT with cisplatin 100 mg/m2 every 3 wk plus standard fractionation of 70 Gy in 35 fractions over 7 wkOS: not reached, HR: 1.31, 95%CI: 0.93-1.85; one sided P = 0.94PFS: not reached, HR: 1.21, 95%CI: 0.93-1.57; one sided P = 0.92Avelumab + CRT: 74%, 95%CI: 69-79; based on modified RECIST 1.1NAPFSIntervention: 80 %, serious AEs in 36% pts, treatment related death 1%, 7% pts discontinued due to TRAEs
Lee et al[31], 2021Phase-3 trialn = 697n = 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 armFavors control armPlacebo + CRT: 75%; 95%CI: 70-79; based on modified RECIST 1.1Avelumab + 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. = 0.03Control: 74%, serious AEs in 32% pts, treatment related death < 1%, 3% pts discontinued due to TRAEs
JAVELIN head and neck 100 trialOR = 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.
Table 2 Major ongoing phase-3 studies investigating immunotherapy in head and neck squamous cell carcinoma
Study
Status/trial ID
Population
Intervention
Control
No of participants
Target receptor
KESTREL[47]Active, not recruiting/NCT02551159R/M HNSCCArm 1: DurvalumabEXTREMEregime823PDL-1, CTLA-4
Arm 2: Durvalumab with Tremelimumab
Checkmate 651[48]Active, not recruiting/NCT02741570R/M HNSCCNivolumab with IpilimumabEXTREME regime947PD-1, CTLA-4
LEAP-10[49]Active, recruiting/NCT04199104R/M HNSCCPembrolizumab with LenvatinibPembrolizumabwith placebo500PD-1, VEGF-multiple kinase
ECHO-304/KEYNOTE 669[50]Active, not recruiting/NCT03358472R/M HNSCCArm1: Pembrolizumab with EpacadostatEXTREME625PD-1,IDO1
Arm 2: Pembrolizumab alone
KEYNOTE 412[51]Active, not recruiting/NCT03040999LAHNSCCPembrolizumab with CRT concurrently and as maintenance Standard CRT plus placebo780PD-1
REACH[52]Active, not recruiting/NCT02999087LAHNSCCAvelumab in combination with RT-cetuximabCisplatin-RT and/or RT-cetuximab alone707PD-L1
HN004[53]Active, recruiting/NCT03258554LAHNSCCDurvalumab plus RTCetuximab plus RT474PD-L1
Platinum in eligible patients
CheckMate 9TM[54]Completed awaiting results/NCT03349710LAHNSCCNivolumab plus RTCetuximab plus RT68PD-1
Platinum ineligible cohort
LAHNSCCNivolumab pluscisplatin plus RTCisplatin plus RT
Platinum eligible cohort
KEYNOTE 689[55]Active, recruiting/NCT03765918LAHNSCCPembrolizumab with RT (with or without cisplatin) before and after surgeryRT (with or without cisplatin) given after surgery704PD-1
iMvoke010[56]Active, recruiting/NCT03452137LAHNSCCAtezolizumab as adjuvant therapy after definitive local therapyPlacebo400PD-L1
IMSTAR-HN[57]Active, not recruiting/NCT03700905Surgically resectable LAHNSCCNivolumab alone or in combination Ipilimumab as follow up after adjuvant therapyStandard follow-up after adjuvant therapy276PD-1, CTLA-4
NIVOPOSTOP[58]Active, recruiting/NCT03576417LAHNSCCAdjuvant Nivolumab with CRT postoperativelyCRT alone post operatively680PD-1
CRT: Chemoradiation therapy; R/M HNSCC: Recurrent or metastatic head and neck squamous cell carcinoma; LAHNSCC: Locally advanced head and neck squamous cell carcinoma; PD-1: Programmed cell death protein-1; PD-L1: Programmed death-ligand 1; CTLA-4: Cytotoxic T- lymphocyte associated protein-4; IDO1: Indoleamine 2,3-dioxygenase 1; VEGF: Vascular endothelial growth factor.