Table II.
Summary of the crucial clinical trials which are the basis of the guidelines.
| Name of the trial | Expression of PD-L1 | Histology | Stage | Aim of the study | Median OS (IT vs. ChT) | Median PFS (IT vs. ChT) | ORR (IT vs. ChT) | AE (G3-G4) (IT vs. ChT) | QoL for IT | (Refs.) |
|---|---|---|---|---|---|---|---|---|---|---|
| First-line therapy | ||||||||||
| KEYNOTE 024 | ≥50% | SCC and NSCC | IV | To compare pembrolizumab (at a fixed dose of 200 mg every 3 weeks) vs. the investigator's choice of platinum-based chemotherapy | 30 (95% CI, 18.3 months to NR) vs. 14.2 (95% CI, 9.8–19.0) months (HR = 0.63; 95% CI 0.47–0.86 months) | 10.3 (95% CI, 6.7 to not reached) vs. 6.0 months (95% CI, 4.2 to 6.2) | 45.5 vs. 29.8 % | G3-G5 31.2 vs. 53.3% | Improved (statistically significant) | (9–11) |
| KEYNOTE 189 | Benefit regardless of it | SCC and NSCC | IV | To compare pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy | 22.0 (19.5–25.2) vs. 10.7 (8.7–13.6) months (HR=0.56; 95% CI, 0.45–0.70) | 9.0 (8.1–9.9) vs. 4.9 (8.1–9.9) months (HR, 0.49; 95% CI, 0.40–0.59) | 48.0 vs. 19.4% | G3-G5 71.9 vs. 66.8% | Improved (statistically significant) | (12,13) |
| CheckMate 227 IT - ipi +nivo | Benefit regardless of it | SCC and NSCC | IV | To compare nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone | 17.1 (15.0–20.1) vs. 14.9 (12.7–16.7) months (HR=0.79; 97.72% CI, 0.65–0.96, P=0.007) | 7.2 (patients with high TMB) (95% CI, 5.5–13.2) vs. 5.5 months (95% CI, 4.4–5.8) (HR 0.58; 97.5% CI, 0.41–0.81; P<0.001) | 35.9 vs. 30.0% | 32.8 vs. 36.0% | Improved (statistically significant) | (14–16) |
| ImPower150 | Benefit regardless of it | NSCC | IV | To compare 3 treatments: atezolizumab+carboplatin+ paclitaxel (ACP), atezolizumab +carboplatin+paclitaxel +bevacizumab (ABCP) or carboplatin+paclitaxel +bevacizumab (BCP) | 19.2 for ABCP vs. 14.7 for BCP months (HR=0.78; 95% CI, 0.64–0.96; P=0.02) | 8.3 for ABCP vs. 6.8 for BCP months (HR 0.62; 95% CI, 0.52–0.74; P<0.001) | 63.5 in the ABCP group vs. 48.0 % in the BCP group | Treatment tolerability differed between induction and maintenance phases across treatment arms, more patients had grade 3/4 treatment-related AEs during the induction versus maintenance phase (ACP, 40.5 vs. 8.2%; ABCP, 48.6 vs. 21.2%; BCP, 44.7 vs. 11.1% | Similar across study's arms | (17,18) |
| Second-line therapy | ||||||||||
| CheckMate 017 | Benefit regardless of it | SCC | IIIB/IV | To compare nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, and docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks | 9.2 (95% CI, 7.3–13.3) vs. 6.0 (95% CI, 5.1–7.3) months (HR=0.59; 95% CI, 0.44–0.79; P<0.001) | 3.5 vs. 2.8 months (HR 0.62; 95% CI, 0.47–0.81; P<0.001) | 20 vs. 9% | 7 vs. 55% | Improved (statistically significant) | (19,20) |
| CheckMate 057 | Benefit regardless of it | NSCC | IIIB/IV | To compare nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks to docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks | 12.2 (95% CI, 9.7 to 15.0) vs. 9.4 (95% CI, 8.1–10.7) months (HR=0.73; 96% CI, 0.59–0.89; P=0.002) | No difference | 19 vs. 12% | 10 vs. 54% | Improved (statistically significant) | (21,22) |
| KEYNOTE 010 | >1% | SCC, NSCC | IV | To compare two doses of pembrolizumab (2 and 10 mg/kg) vs. docetaxel 75 mg per square meter of body-surface area every 3 weeks | 10.4 (pembro 2 mg/kg), 12.7 (pembro 10 mg/kg) vs. 8·5 months pembro 2 mg/kg vs docetaxel (HR=0.71, 95% CI 0.58–0.88; p=0·0008) pembro 10 mg/kg vs. docetaxel (HR 0.61, 0.49–0·75; P<0·0001) | No significant difference between groups | 30% (pembro 2mg/kg), 29% pembro 10 mg/kg) vs. 8% | 13% (pembro 2mg/kg), 16% pembro 10 mg/kg vs. 35% | Improved (statistically significant) | (23,24) |
| OAK | Benefit regardless of it | SCC, NSCC | IIIB/IV | To compare atezolizumab (fixed dose 1,200 mg every 3 weeks) with docetaxel 75 mg per square meter of body-surface every 3 area weeks | 15.7 (95% CI 12.6–18.0) vs. 10.3 (8.8–12.0) months (HR 0.74, 95% CI 0.58–0.93; P=0.0102) | Similar in both groups | Similar in both groups | 37 vs. 54% | Improved (statistically significant) | (23,24) |
ABCP, atezolizumab+ccarboplatin+paclitaxel+bevacizumab; ACP, atezolizumab+carboplatin+paclitaxel; AE, adverse events; BCP, carboplatin+paclitaxel+bevacizumab; ChT, chemotherapy; CI, confidence interval; G, grade; HR, hazard ratio; IT, immunotherapy; NSCC, non-squamous cell cancer; OS, overall survival; ORR, overall response rate; PFS, progression-free survival; PDL-1, programmed cell death protein ligand 1; QoL, quality of life; SCC, squamous cell cancer.