Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for treatment of recurrent or metastatic head and neck squamous cell carcinoma: a systematic review and network meta-analysis

Abstract

Background: Multiple therapies including immune-checkpoint inhibitors are emerging as effective treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSSC). However, the optimal first-line and second-line treatments remains controversial.

Methods: We systematically searched databases and conducted a systematic review of phase II/III randomized controlled trials (RCTs) that compared two or more treatments for R/M HNSSC. Progression-free survival (PFS), overall survival (OS) and adverse events (AEs) ⩾3 with hazard ratios (HRs) were extracted and synthesized based on a frequentist network meta-analysis.

Results: Twenty-six trials involving 8908 patients were included. Of first-line treatments, pembrolizumab plus cisplatin plus 5-fluorouracil is associated with significantly improved OS (P-score = 0.91) and TPEx ranked first for prolonging PFS (0.91). EXTREME plus docetaxel (0.18) ranked lowest for AEs ⩾3. Of second-line treatments, nivolumab was the highest-ranked treatment for prolonging OS (0.95), while buparlisib plus paclitaxel was the highest-ranked treatment for PFS (0.94). Subgroup analyses suggested that nivolumab was significantly associated with improvement of OS in patients with high PD-L1 expression (HR 0.55, 0.43-0.70), whereas its OS benefit is similar with conventional chemotherapy for those with low PD-L1 expression. Buparlisib plus paclitaxel showed the best OS benefit in subgroups of patients with HPV-negative status, and with oral cavity or larynx as primary tumor sites.

Conclusions: Pembrolizumab plus cisplatin plus 5-fluorouracil is likely to be the best first-line treatment when OS is a priority. Otherwise, TPEx should be the optimal first-line option due to its superior PFS prolongation efficacy, best safety profile, and similar OS benefit with pembrolizumab plus cisplatin plus 5-fluorouracil. Nivolumab appears to be the best second-line option with best OS prolongation efficacy and outstanding safety profile in the overall population. Future RCTs with meticulous grouping of patients and detailed reporting are urgently needed for individualized treatment.

Keywords: chemotherapy; immune-checkpoint inhibitor; network meta-analysis; recurrent or metastatic head and neck carcinoma.

Figure 1.

PRISMA flowchart.

Figure 2.

Network and treatment efficacy of first-line treatments. (A) Comparisons of progression-free survival (PFS) (blue line), overall survival (OS) (orange line), and unacceptable adverse events (green line) among first-line treatments. The node size is proportional to the total number of patients who received treatment. Each line represents a type of head-to-head comparison. The width of lines is proportional to the number of trials comparing the connected treatments. (B) The abscissa value corresponding to a point on the two-dimensional map is the Pooled hazard ratios (95% CI) for OS of a particular treatment, and the ordinate value is the odds ratios (95% CI) for AEs ⩾ grade 3. The more to the left and lower the point is, the longer the OS is and fewer AEs ⩾ grade 3 are associated with the corresponding therapy. (C) Forest plots depicting PFS results of first-line comparisons. (D) Forest plots depicting OS results of first-line comparisons. AEs, grade ⩾3 adverse events; Beva+P+D, bevacizumab plus cisplatin plus docetaxel; CI, confidence interval; E+CIL1W, EXTREME plus CIL1W; E+CIL2W, EXTREME plus CIL2W; E+D, EXTREME plus docetaxel; E+Moto, EXTREME plus motolimod; GEX+P+F, CetuGEX plus 5-fluorouracil plus cisplatin; HR, hazard ratio; Nivo, nivolumab; P+C, platinum plus cetuximab; Pani+P+D, panitumumab plus cisplatin plus docetaxel; Pani+P+F, panitumumab plus cisplatin plus 5-fluorouracil; Patr+P+C, patritumab plus cetuximab plus platinum; PBC, platinum-based chemotherapy; Pemb, pembrolizumab; Pemb+P+F, pembrolizumab plus cisplatin plus 5-fluorouracil; PFS, progression-free survival; TPEx, cisplatin plus cetuximab plus taxane.

Figure 3.

Network and treatment efficacy of second-line treatments. (A) Comparisons of progression-free survival (PFS) (blue line), overall survival (OS) (orange line), and unacceptable adverse events (green line) among second-line treatments. The node size is proportional to the total number of patients who received treatment. Each line represents a type of head-to-head comparison. The width of lines is proportional to the number of trials comparing the connected treatments. (B) The abscissa value corresponding to a point on the two-dimensional map is the Pooled hazard ratios (95% CI) for OS of a particular treatment, and the ordinate value is the odds ratios (95%CI) for AEs ⩾ grade 3. The more to the left and lower the point is, the longer the OS is and fewer AEs ⩾ grade 3 are associated with the corresponding therapy. (C) Forest plots depicting PFS results of second-line comparisons. (D) Forest plots depicting OS results of second-line comparisons.AEs, grade ⩾3 adverse events; Afat, afatinib; Bupa+Pacl, buparlisib plus paclitaxel; CI, confidence interval; Durv, durvalumab; Durv+Trem, durvalumab plus tremelimumab; EMD+C, EMD1201081 plus cetuximab; G+D, gefitinib (250 mg) plus docetaxel; G250, gefitinib (250 mg); G500, gefitinib (500 mg); HR, hazard ratio; Nivo, nivolumab; P+C, platinum plus cetuximab; PBC, platinum-based chemotherapy; Pemb, pembrolizumab; PFS, progression-free survival; SOC, standard of care.