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 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.

…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.

These findings, in addition to the primary analysis of KEYNOTE-048, support 1L pembro and pembro + chemo in PD-L1–positive R/M HNSCC.

These findings, in addition to the primary analysis of KEYNOTE-048, support 1L pembro and pembro + chemo in PD-L1–positive R/M HNSCC.

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.

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

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

...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). ...

...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....

...- 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...

...PD-L1 CPS is defined as Combined positivity score (CPS) was calculated by summing the numbers of PD-L1-positive tumor cells and immune cells and dividing by the total number of viable tumor cells. ...

...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. ...

...Likewise, the PD activity of ICT01 (by dose and patient population) will include the change from baseline in counts and activation status of Vγ9Vδ2 T cells and other immune cells in the peripheral blood, peripheral blood mononuclear cells (PBMCs) and tumor biopsies, circulating cytokine levels (including IFN gamma, TNF alpha, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17a and MCP-1), and expression of PD-L1, PD-1 and other immune cell markers in tumor biopsies and PBMCs. ...

...Detectable PD-L1 expression in tumor, defined as CPS ≥20 determined by a Food and Drug Administration-approved test....

...- PD-L1 expression level Combined Positive Score (CPS) ≥ 1 by immunohistochemistry (IHC) testing....

...Subjects with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [CPS ≥20] 3....

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

...Patients who have a tumor expressing PD-L1 [CPS ≥1] as determined by the FDA-approved test PD L1 22C3 pharmDx kit performed and evaluated according to the manufacturer's specifications. ...

...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...

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.