Keytruda, as monotherapy or in combination with platinum and 5 fluorouracil (5 FU) chemotherapy, is indicated for the first line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma in adults whose tumours express PD L1 with a CPS ≥ 1.

Keytruda, as monotherapy or in combination with platinum and 5 fluorouracil (5 FU) chemotherapy, is indicated for the first line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma in adults whose tumours express PD L1 with a CPS ≥ 1.

KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated:...as a single agent for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test.

Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers....Recommendation 2.1….Pembrolizumab monotherapy or pembrolizumab, platinum, and fluorouracil should be offered as first-line treatment for patients with recurrent or metastatic HNSCC with a CPS ≥ 1

Pembrolizumab in combination with platinum/5-FU and pembrolizumab monotherapy are two approved regimens for patients with recurrent/metastatic SCCHN expressing PD-L1 (CPS 1) [I, A; ESMO-MCBS v1.1 score:4].

…pembrolizumab monotherapy for PD-L1 positive tumors and combined with platinum and 5-FU are recommended in the panel as first-line options for patients with recurrent, unresectable, or metastatic disease.

Pembrolizumab in combination with platinum/5-FU and pembrolizumab monotherapy are two approved regimens for patients with recurrent/metastatic SCCHN expressing PD-L1 (CPS 1)…

…pembrolizumab monotherapy for PD-L1 positive tumors and combined with platinum and 5-FU are recommended in the panel as first-line options for patients with recurrent, unresectable, or metastatic disease. The combination regimen is a preferred option.

PFS2 improved with pembrolizumab in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.84) and CPS ≥ 1 (HR, 0.79; 95% CI, 0.66 to 0.95) populations and with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.86), CPS ≥ 1 (HR, 0.66; 95% CI, 0.55 to 0.81), and total (HR, 0.73; 95% CI, 0.61 to 0.88) populations....With a 4-year follow-up, first-line pembrolizumab and pembrolizumab-chemotherapy continued to demonstrate survival benefit versus cetuximab-chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma.

PFS2 improved with pembrolizumab in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.84) and CPS ≥ 1 (HR, 0.79; 95% CI, 0.66 to 0.95) populations and with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.86), CPS ≥ 1 (HR, 0.66; 95% CI, 0.55 to 0.81), and total (HR, 0.73; 95% CI, 0.61 to 0.88) populations....With a 4-year follow-up, first-line pembrolizumab and pembrolizumab-chemotherapy continued to demonstrate survival benefit versus cetuximab-chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma.

Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. PD-L1 CPS < 1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS ≥ 1 tumors.

Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. PD-L1 CPS < 1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS ≥ 1 tumors.

Long-term follow-up confirmed the statistically significant improvement in OS established at the protocol-specified interim and final analyses for pembro vs E in pts with PD-L1 CPS ≥20 and CPS ≥1 and for pembro+C vs E in pts with PD-L1 CPS ≥20 and CPS ≥1, and total pop. Safety was favorable for pembro vs E and comparable for pembro+C vs E.

Long-term follow-up confirmed the statistically significant improvement in OS established at the protocol-specified interim and final analyses for pembro vs E in pts with PD-L1 CPS ≥20 and CPS ≥1 and for pembro+C vs E in pts with PD-L1 CPS ≥20 and CPS ≥1, and total pop. Safety was favorable for pembro vs E and comparable for pembro+C vs E.

In the CPS 1-19 subgroup, HR (95% CI) for OS showed a slight advantage of P (n = 124) vs E (n =133) (0.86 [0.66-1.12]) and favored P+C (n = 116) vs E (n = 125) (0.71 [0.54-0.94])….There was overall evidence of increased efficacy with increasing PD-L1 expression.

In patients with R/M HNSCC, longer median PFS2 was observed in the CPS ≥20 and CPS ≥1 populations for P vs E, and in the CPS ≥20, CPS ≥1, and total populations for P+C vs E.

In patients with R/M HNSCC, longer median PFS2 was observed in the CPS ≥20 and CPS ≥1 populations for P vs E, and in the CPS ≥20, CPS ≥1, and total populations for P+C vs E.

At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45–0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64–0·96], p=0·0086) ...pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.

...Subject has tumor that expresses PD-L1 (Combined Positive Score [CPS] > 1) as determined by an FDA-approved test or subject has experienced disease progression on or after platinum-containing chemotherapy....

...Disease free survival`PD-L1 expression...

...- Patients must have PD-L1 positive (CPS ≥1) tumor as determined by PD-L1 testing performed at the local laboratory, from a core or excisional biopsy (fine needle aspirate is...

...- Availability of tumor tissue (≥ 10 slides) for PD-L1, gene expression profiling (GEP), and additional testing....

...PFS is reported here for all participants in the pembro combo arm and control arm with PD-L1 biomarker positive expression defined by immunohistochemistry (IHC) as Combined Positive Score ≥1 (hereafter referred to as CPS ≥1). ...

...OS for Participants With Programmed Cell Death-Ligand 1 (PD-L1)-Positive Expression Defined by ≥1% Combined Positive Score (CPS)(PD-L1 ≥1% CPS)`Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 for All Participants`PFS Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS`Objective Response Rate (ORR) Per RECIST 1.1 in All Participants`ORR Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS`Duration of Response (DOR) Per RECIST 1.1 in All Participants`DOR Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS`Time to Progression (TTP) Per RECIST 1.1 in All Participants`TTP Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS`PFS Per Modified RECIST in All Participants`PFS Per Modified RECIST 1.1 in Participants With PD-L1 ≥1% CPS`Number of Participants Who Experienced At Least One Adverse Event (AE) in All Participants`Number of Participants Who Experienced At Least One AE in Participants With PD-L1 ≥1% CPS`Number of Participants Who Discontinued Study Treatment Due to an AE in All Participants`Number of Participants Who Discontinued Study Treatment Due to an AE in Participants With PD-L1 ≥1% CPS...

...changes in PD-L1 expression`overall response rate`median progression free survival`overall survival...

...Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants`Participants with a strong PD-L1 expression status were evaluated for ORR by RECIST 1.1. ...

In this small retrospective series of heavily pretreated patients, pembro + CP was well tolerated, and compliance was high. Studies should be conducted to prospectively evaluate the safety and efficacy of this combination in patients with R/M SCCHN.

The 5-year OS rate for pembrolizumab + chemotherapy vs EXTREME was, respectively, 23.9% vs 6.4% in CPS ≥20, 18.2% vs 4.3% in CPS ≥1, and 16.0% vs 5.2% in total populations. 5-yr OS and PFS rates, ORR, and DOR are shown in the table...With an extended follow-up of 5 years, first-line pembrolizumab and pembrolizumab + chemotherapy continued to show durable antitumor activity and manageable safety in R/M HNSCC. These results further support pembrolizumab and pembrolizumab + chemotherapy as first-line standard of care in R/M HNSCC.

In the first-line setting, in R/M HNSCC, pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in OS of 2.3 mo (HR = 0.77, P = 0.0034) in the overall population and a net gain in OS of 4.2 mo in the PD-L1 positive (combined positive score > 20) population compared to standard of care (EXTREME regime). In patients with PD-L1 positive R/M HNSCC, monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to EXTREME.

In the first-line setting, in R/M HNSCC, pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in OS of 2.3 mo (HR = 0.77, P = 0.0034) in the overall population and a net gain in OS of 4.2 mo in the PD-L1 positive (combined positive score > 20) population compared to standard of care (EXTREME regime). In patients with PD-L1 positive R/M HNSCC, monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to EXTREME.

To characterize genomic determinants of response to pembrolizumab in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 study….TMB, clonality-weighted TMB, and TcellinfGEP were significantly associated with objective response (p=0.0276, p=0.0201, and p=0.006, respectively), and a positive trend was observed between NL and PD-L1 CPS and clinical response (p=0.0550 and p=0.0682, respectively)....TMB and inflammatory biomarkers (TcellinfGEP and PD-L1) may represent distinct and complementary biomarkers predicting response to anti-programmed death 1 therapies in HNSCC.

Eligible patients received pembro (200 mg I.V. x 1) 1-3 weeks before resection. Adjuvant pembro (q3 wks x 6 doses) was administered with RT (60-66Gy) with or without weekly cisplatin...PR to neoadjuvant pembro is associated with PD-L1 CPS≥1 and high DFS in patients with resectable, local-regionally advanced, HNSCC.

Eligible patients received pembro (200 mg I.V. x 1) 1-3 weeks before resection. Adjuvant pembro (q3 wks x 6 doses) was administered with RT (60-66Gy) with or without weekly cisplatin...PR to neoadjuvant pembro is associated with PD-L1 CPS≥1 and high DFS in patients with resectable, local-regionally advanced, HNSCC.

Twenty-two patients were enrolled. The median age was 63 (44-77) years. Nine patients (40.9%) had a primary tumor in the oropharynx, 8 (36.4%) in the oral cavity, 3 (13.6%) in the hypopharynx and 2 (9.1%) in the larynx. While 4 (50%) oropharyngeal carcinoma patients were p16 positive, all patients showed PDL-1 expression defined as a combined positive score (CPS) ≥1...DXT in combination with P shows promising activity accompanied with a manageable side effect profile in pre-treated R/M HNSCC patients and warrants further investigations in larger clinical trials.

Among 171 patients treated, 75% received two or more prior lines of therapy for metastatic disease, 82% were PD-L1 positive…Overall response rate was 16% (95% CI, 11% to 23%), with a median duration of response of 8 months (range, 2+ to 12+ months); 75% of responses were ongoing at the time of analysis. Pembrolizumab exhibited clinically meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab.

Higher expression of PD-L1, PD-L2, and INF-γ in pre-treatment samples were associated with tumor response after one dose of Pembrolizumab (Welch’s t-test, p = 0.015, 0.021, 0.006)....Inflamed tumor microenvironment, evidenced by increased INF-γ irrespective of lymphocyte infiltration is associated with pathological response after a single dose of Pembrolizumab in HNSCC.

TMB, PD-L1 and T-cell inflamed GEP were independently predictive of response to pembrolizumab in HNSCC patients, in general regardless of HPV status.