KEYNOTE-048 Trial Research Articles

The use of pembrolizumab monotherapy for the management of head and neck squamous cell carcinoma (HNSCC) in the UK.

Pembrolizumab has received approval in the UK as first-line monotherapy for recurrent and/or metastatic HNSCC (R/M HNSCC) following the results of the KEYNOTE-048 trial, which demonstrated a longer overall survival (OS) in comparison to the EXTREME chemotherapy regimen in patients with a combined positive score (CPS) ≥1. In this article, we provide retrospective real-world data on the role of pembrolizumab monotherapy as first-line systemic therapy for HNSCC across 18 centers in the UK from March 20, 2020 to May 31, 2021. 211 patients were included, and in the efficacy analysis, the objective response rate (ORR) was 24.7%, the median progression-free survival (PFS) was 4.8 months (95% confidence interval [CI]: 3.6-6.1), and the median OS was 10.8 months (95% CI 9.0-12.5). Pembrolizumab monotherapy was well tolerated, with 18 patients having to stop treatment owing to immune-related adverse events (irAEs). 53 patients proceeded to second-line treatment with a median PFS2 of 10.2 months (95% CI: 8.8-11.5). Moreover, patients with documented irAEs had a statistically significant longer median PFS (11.3 vs. 3.3 months; log-rank p value = <.001) and median OS (18.8 vs. 8.9 months; log-rank p value <.001). The efficacy and safety of pembrolizumab first-line monotherapy for HNSCC has been validated using real-world data.

Pembrolizumab-based first-line treatment for PD-L1-positive, recurrent or metastatic head and neck squamous cell carcinoma: a retrospective analysis

BackgroundThe KEYNOTE-048 trial showed that pembrolizumab-based first-line treatment for R/M HNSCC led to improved OS in the PD-L1 CPS ≥ 1 population when compared to the EXTREME regimen. However, the R/M HNSCC real-world population is generally frailer, often presenting with multiple comorbidities, worse performance status and older age than the population included in phase III clinical trials.MethodsThis is a retrospective, single-centre analysis of patients with R/M HNSCC treated with pembrolizumab-based first-line treatment.ResultsFrom February 2021 to March 2023, 92 patients were treated with pembrolizumab-based first-line treatment. Patients treated with pembrolizumab-based chemoimmunotherapy had better ECOG PS and younger age than those treated with pembrolizumab monotherapy. Median PFS and OS were 4 months and 8 months, respectively. PFS was similar among patients treated with pembrolizumab-based chemoimmunotherapy and pembrolizumab monotherapy, while patients treated with pembrolizumab monotherapy had worse OS (log-rank p =.001, HR 2.7). PFS and OS were improved in patients with PD-L1 CPS > = 20 (PFS: log-rank p =.005, HR 0.50; OS: log-rank p =.04, HR 0.57). Patients with higher ECOG PS scores had worse PFS and OS (PFS, log-rank p =.004; OS, log-rank p = 6e-04). In multivariable analysis, ECOG PS2 was associated with worse PFS and OS.ConclusionsPFS in our real-world cohort was similar to the KEYNOTE-048 reference while OS was numerically inferior. A deeper understanding of clinical variables that might affect survival outcomes of patients with R/M HNSCC beyond ECOG PS and PD-L1 CPS is urgently needed.

Network meta-analysis of pembrolizumab as monotherapy and in combination with chemotherapy for first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma

Pembrolizumab monotherapy or in combination with chemotherapy is approved as first-line treatment in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) based on improved overall survival (OS) versus EXTREME regimen in the KEYNOTE-048 trial. The clinical outcomes of pembrolizumab were compared with other recommended first-line treatments in R/M HNSCC in this study through a Bayesian network meta-analysis. A systematic literature review was conducted in July 2022, from which six trials that matched the KEYNOTE-048 patient eligibility criteria were included in the network. The OS and progression-free survival (PFS) outcomes were compared in the approved pembrolizumab indication (i.e., total population for pembrolizumab in combination with chemotherapy and combined positive score [CPS] ≥ 1 population for pembrolizumab monotherapy). A significant OS improvement was observed for pembrolizumab in combination with chemotherapy and pembrolizumab monotherapy versus EXTREME regimen (hazard ratio, 95% credible interval: 0.72, 0.60-0.86; 0.73, 0.60-0.88), platinum+5- FU (0.58, 0.43-0.76; 0.58, 0.44-0.78), and platinum+paclitaxel (0.53, 0.35-0.79; 0.53, 0.35-0.81), respectively. A non-significant numeric trend in OS improvement was observed versus the TPEx regimen. PFS was comparable with most first-line treatments and was improved versus platinum+5-FU (0.48, 0.36-0.64; 0.59, 0.45-0.79). Additional analyses in higher CPS subgroups also showed consistent results. Overall, our study results showed an improvement in OS outcomes versus alternative first-line treatments, consistent with the findings of the KEYNOTE-048 trial. These data support using pembrolizumab as a suitable firstline treatment option in R/M HNSCC.

Immune checkpoint inhibitor monotherapy is sufficient to promote microenvironmental normalization via the type Iinterferon pathway in PD-L1-expressing head and neck cancer.

Immune checkpoint blockers (ICBs) targeting programmed cell death protein 1 (PD-1) have been proven to be an effective first-line therapy against programmed cell death 1 ligand 1 (PD-L1; also known as CD274 molecule)-expressing head and neck squamous cell carcinoma (HNSCC) in recent KEYNOTE-048 trial. However, associated changes in the tumor microenvironment (TME) and underlying mechanisms remain elusive. Oral tumors in C57/BL6 mice were induced by administering 7,12-dimethylbenzanthracene into the buccal mucosa. Single-cell suspension was isolated from tumor tissue; proliferating cells were injected subcutaneously into the left flank of mice to establish Ajou oral cancer (AOC) cell lines. Subsequently, a syngeneic PD-L1-expressing HNSCC model was developed by injecting AOC cells into the buccal or tongue area. The model recapitulated human HNSCC molecular features and showed reliable in vivo tumorigenicity with significant PD-L1 expression. ICB monotherapy induced global changes in the TME, including vascular normalization. Furthermore, the antitumor effect of ICB monotherapy was superior to those of other therapeutic agents, including cisplatin and inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2). The ICB-induced antitumorigenicity and TME normalization were alleviated by blocking the type I interferon pathway. In summary, ICB monotherapy is sufficient to induce TME normalization in the syngeneic model; the type I interferon pathway is indispensable in realizing the effects of ICBs. Furthermore, these results explain the underlying mechanism of the efficacy of ICB monotherapy against PD-L1-expressing HNSCC in the KEYNOTE-048 trial.

EE199 Cost-Effectiveness of Pembrolizumab for the First-Line Treatment of Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma in Colombia

Phase III KEYNOTE-048 trial showed that programmed death receptor 1 (PD-1) inhibitor pembrolizumab, in the combined positive score (CPS) ≥1 population and combined with platinum + 5-fluorouracil (5-FU) in the total population, improves overall survival (OS) over cetuximab + platinum + 5-fluorouracil in patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). This study evaluated the cost-effectiveness of pembrolizumab as combination therapy with platinum-based therapies (cisplatin or carboplatin) plus 5-FU in the CPS≥1 population versus cetuximab + platinum + 5-FU from a third payer perspective in Colombia.

Real-world Data of Palliative First-line Checkpoint Inhibitor Therapy for Head and Neck Cancer.

Pembrolizumab alone or combined with chemotherapy is now approved in PD-L1-positive patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Since real-world data are pending, our goal was to evaluate the efficacy and safety of immune checkpoint inhibitor (CPI) therapy in an unselected cohort of patients with SCCHN. We analyzed 78 patients with recurrent or metastatic SCCHN from three Austrian cancer centers that received CPI therapy alone or with chemotherapy as palliative first-line systemic treatment for this retrospective study. Patient characteristics, details on treatment, and survival were analyzed by a chart-based review. Of the 78 patients analyzed, 55 patients were treated with CPI alone (45 with Pembrolizumab, 10 with Nivolumab) and 23 patients received chemotherapy with a platinum and 5-FU in addition to CPI. With a median follow-up of twelve months, the median PFS of all patients was 4 months [95% confidence interval (CI)=2.2-5.8] and the median OS was 11 months (95% CI=7.1-14.9). The overall response and disease control rates were 20.5% and 46.1%, respectively. There was no statistically significant difference in clinical outcome between patient groups with a different combined positive score (CPS). The rate of reported immune related adverse events was comparable to existing data. Our findings confirm the results of the KEYNOTE-048 trial that CPI therapy alone or together with chemotherapy is an effective treatment for patients with recurrent or metastatic CPS-positive SCCHN.

651O Pembrolizumab (pembro) + carboplatin (carbo) + paclitaxel (pacli) as first-line (1L) therapy in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): Phase VI KEYNOTE-B10 study

Based on the phase 3 KEYNOTE-048 trial, 1L SOC treatment (tx) for R/M HNSCC, regardless of PD-L1 status, is pembro + platinum + 5-FU. 5-FU alternatives are needed because of associated cardiovascular, dihydropyrimidine dehydrogenase deficiency–related toxicities and patient (pt) inconvenience, costs, and complications associated with continuous 4-day infusion. In clinical studies, platinum + pacli was no less efficacious than platinum + 5-FU in R/M HNSCC. We present initial results of the first global prospective trial of pembro + carbo + pacli in 1L R/M HNSCC.

Real-world Therapeutic Outcomes of the Pembrolizumab Regimen as First-line Therapy for Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: A Single-center Retrospective Cohort Study in Japan

Background/Aim: This Japanese single-center retrospective cohort study aimed to evaluate the real-world therapeutic outcomes of pembrolizumab or pembrolizumab plus chemotherapy (pembrolizumab regimen) as first-line therapy for patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Patients and Methods: Thirty-two Japanese patients with R/M SCCHN treated with the pembrolizumab regimen between January 2020 and January 2022 were analyzed. The primary endpoint of the study was overall survival. Results: The median follow-up duration was 9.8 months (range=1.6-25.1 months). Fourteen patients received pembrolizumab alone, whereas the others received pembrolizumab with chemotherapy. The 1-year overall and progression-free survival rates were 64.5% (95% CI=38.9-81.6) and 54.9% (95% CI=33.9-71.8), respectively. The objective response rate was 56.2%. The Kaplan–Meier analysis showed that patients with favorable objective responses and an Eastern Cooperative Oncology Group performance status of 0 had longer survival. Immune-related adverse events (irAEs) occurred in 16 out of 32 patients (50.0%) during treatment; however, there were no irAEs greater than grade 4. Conclusion: The observed therapeutic efficacy and safety of pembrolizumab in real-world clinical practice was consistent with the data of the KEYNOTE-048 trial.

Cost-effectiveness of pembrolizumab for the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma in the United States

Aims Pembrolizumab, as monotherapy in first-line recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) with a combined positive score (CPS) ≥1 and in combination with platinum and 5-fluorouracil (5-FU) in the overall R/M HNSCC population, received US FDA approval based on the KEYNOTE-048 trial. Using public drug prices, from a US payer perspective, we evaluated the cost-effectiveness of each pembrolizumab regimen vs. cetuximab + platinum+5-FU (EXTREME regimen, trial comparator), cisplatin + docetaxel + cetuximab (TPEx regimen), cisplatin + paclitaxel, and platinum+5-FU. Methods A three-state partitioned-survival model was used to project costs and outcomes over 20 years with 3% annual discounting. Progression-free and overall survival were modeled using long-term extrapolation of KEYNOTE-048 data and, for alternative comparators, data from a network meta-analysis was used. Time-on-treatment was derived from KEYNOTE-048 or approximated using network meta-analysis progression-free survival estimates. Costs included first-line and subsequent treatments, disease management, adverse events, and terminal care costs. Utilities were derived from the KEYNOTE-048 Euro-QoL five-dimension data and using a US algorithm. Results In the CPS ≥1 R/M HNSCC population, pembrolizumab monotherapy was dominant vs. EXTREME and TPEx regimens, and cost-effective (at $100,000/QALY threshold) vs. platinum+5-FU ($86,827/QALY) and cisplatin + paclitaxel ($81,473/QALY). Pembrolizumab combination therapy in the overall R/M HNSCC population was dominant vs. TPEx regimen, and cost-effective vs. EXTREME regimen ($1769/QALY), platinum+5-FU ($81,989/QALY), and cisplatin + paclitaxel ($89,505/QALY). Sensitivity analyses showed a high cost-effectiveness probability for pembrolizumab at the $100,000/QALY threshold. Conclusions First-line pembrolizumab monotherapy in patients with CPS ≥1, and pembrolizumab combination therapy in the overall R/M HNSCC population is cost-effective from the perspective of the US payers.

Pembrolizumab alone or with chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: Health-related quality-of-life results from KEYNOTE-048

ObjectivesTo assess health-related quality of life (HRQoL) with first-line pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the phase 3 KEYNOTE-048 trial (NCT02358031). Materials and MethodsHRQoL was measured using the European Organisation for Research and Treatment of Cancer 30-question quality-of-life (EORTC QLQ-C30), the EORTC 35-question quality-of-life head and neck cancer–specific module (EORTC QLQ-H&N35), and the EuroQol 5-dimension 3-level instruments (EQ-5D-3L). Secondary endpoints included mean change from baseline in EORTC QLQ-C30 global health status/quality of life (GHS/QoL) at week 15 and time to deterioration (TTD) in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing. ResultsOf 882 enrolled participants, 844 received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment; adherence was ≥ 79% at week 15 across treatment groups. At week 15, EORTC QLQ-C30 GHS/QoL scores remained stable; no clinically meaningful between-group differences were observed (least squares mean difference, pembrolizumab vs cetuximab-chemotherapy, 0.24; 95% CI, −3.34 to 3.82; pembrolizumab-chemotherapy vs cetuximab-chemotherapy, 0.40; 95% CI, −3.46 to 4.26). Median TTD in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing scores was not reached over 51 weeks across groups, showing stable HRQoL. TTD was similar between groups for EORTC QLQ-C30 GHS/QoL (pembrolizumab vs cetuximab-chemotherapy: HR, 1.38; 95% CI, 0.95–2.00; pembrolizumab-chemotherapy vs cetuximab-chemotherapy: HR, 1.37; 95% CI, 0.94–2.00), as was TTD in EORTC QLQ-H&N35 pain and swallowing scores. ConclusionsPembrolizumab monotherapy and pembrolizumab-chemotherapy extended OS while maintaining HRQoL, further supporting first-line use for R/M HNSCC.

Real-World Patient Characteristics and Time on Treatment Outcomes Among Patients Receiving First-Line Pembrolizumab in the Treatment of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC) in the United States

<h3>Purpose/Objective(s)</h3> In July 2019, the FDA approved pembrolizumab in combination with platinum and fluorouracil (P+C), or as monotherapy [P, in combined positive score (CPS) ≥1 population], for the first-line (1L) treatment of patients with R/M HNSCC based on KEYNOTE-048 trial results. Limited evidence exists on the real-world use of pembrolizumab therapy post-approval. The objective of this study was to assess demographic and clinical characteristics, and treatment patterns among patients initiating pembrolizumab therapy in 1L R/M HNSCC. <h3>Materials/Methods</h3> A retrospective cohort study was conducted using the Flatiron Health Advanced Head and Neck database. The study cohort included adult R/M HNSCC patients, who initiated 1L P or P+C between 07/01/2019 - 12/31/2020. Patients were excluded if they received prior platinum treatment ≤6 months of 1L pembrolizumab therapy, had other primary cancers before R/M HNSCC diagnosis, or were treated with a clinical study drug. Real-world time on treatment (rwToT) was assessed using Kaplan-Meier methods. <h3>Results</h3> A total of 402 patients initiated 1L pembrolizumab therapy, [P (n=264), P+C (n=138)]. Descriptive analyses showed differences between patients receiving P versus P+C (Table 1). Patients receiving P were older, and more likely to have a history of smoking, being HPV positive, and have higher ECOG score at 1L initiation. Other patient characteristics were similar between P versus P+C. Treatment pattern results showed that 68.2% (P: 72.0%, P+C: 60.9%) of pembrolizumab treated patients had a record of PD-L1 test before or within 30 days of 1L initiation in the data. Majority of these PD-L1 tests assessed CPS scores (71.8%) with 82.2% of patients CPS≥1 (P 85.8%, P+C 73.2%). The median 1L rwToT was 3.9 months (IQR: 1.4-8.5) for P and 4.9 months (IQR: 1.6−10.4) for P+C, consistent with the results of the KEYNOTE-048 trial [P: 3.5 months (IQR: 1.4-7.6), P+C: 5.8 months (IQR: 2.8-9.7)]. <h3>Conclusion</h3> In our real-world study, some patient differences regarding patient characteristics were observed between patients initiating P vs. P+C. Furthermore, 1L use of pembrolizumab was observed in a severe R/M HNSCC population (ECOG ≥ 2). rwTOT with P and P+C were consistent with results of the KEYNOTE-048 trial, thus validating trial results. Table 1. Baseline characteristics of patients initiating 1L P versus P+C

Paradigm Change in First-Line Treatment of Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.

Simple SummaryImmunotherapy has made a breakthrough in the treatment of patients with recurrent and/or metastatic head and neck squamous cell carcinoma in the second line setting with anti-PD-1/PD-L1 immune checkpoint inhibitors. Furthermore, the KEYNOTE-048 study has established a new standard of care with immunotherapy in the first line setting, leading to a paradigm change for the treatment of patients with recurrent and/or metastatic head and neck squamous cell carcinoma. No study since 2008 could demonstrate an improvement in survival of these patients until the publication of the KEYNOTE-048 study. Here we will decipher this new paradigm in the first-line line setting and discuss associated challenges.Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) in combination with platinum-based chemotherapy has been for the decade standard of care for the treatment of head and neck squamous cell carcinomas (HNSCC) patients in the first-line recurrent and/or metastatic setting. The KEYNOTE-048 trial published last year established a new paradigm in this setting with the demonstration that immunotherapy should be given either alone or in combination with chemotherapy. Indeed, pembrolizumab, an antiprogrammed cell death 1 (PD-1) immune checkpoint inhibitor, improved overall survival as compared to the EXTREME regimen in patients expressing PD-L1 in the tumor microenvironment, which represents a large majority of the patient population. In this review, we will decipher this important change of paradigm in the first-line treatment of recurrent and/or metastatic HNSCC, and discuss associated challenges.

Cost-effectiveness (CE) analysis of pembrolizumab as first-line (1L) treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the United States (US).

e18013 Background: Pembrolizumab received FDA approval in 1L R/M HNSCC as monotherapy (P) in patients with combined positive score (CPS) ≥1, and in combination with platinum + 5-Fluorouracil (5-FU) chemotherapy (P + C) in the total population, based on KEYNOTE 048 (KN048) trial. Taking a US payer perspective, we evaluated the CE of P and P + C versus KN048 trial comparator cetuximab + platinum + 5-FU (EXTREME regimen), and other comparators commonly used in the US (i.e. cisplatin+docetaxel+cetuximab [TPEx regimen], platinum + paclitaxel/taxane [Pt + T] and platinum+5-FU [Pt + F]). Methods: A 3-state partitioned-survival model was used to project costs and outcomes over 20 years with a 3% annual discount rate. For P, P + C and EXTREME, health state occupancy was based on KN048 trial results with long-term parametric extrapolation of progression-free survival (PFS) and overall survival (OS) guided by statistical criteria. A network meta-analysis (NMA) was applied to the P and P + C interventions in KN048 to project the PFS and OS outcomes for other comparators. The time on treatment (ToT) for P, P+C and EXTREME was derived from the KN048 trial, whereas for other comparators, ToT was approximated by PFS. Costs of 1L and subsequent treatments, disease management, adverse event, and terminal care were included. Utilities were derived using the EuroQoL five-dimension data from KN048 and a US value set. Results: CE ratios, total and incremental costs and quality-adjusted life years (QALYs) from the base case analysis are summarized in the table below. P was more effective and less costly (i.e. dominant) versus EXTREME and TPEx. P + C was highly cost-effective versus EXTREME ($1,789/QALY) and TPEx regimen (dominant). CE ratios for both P and P + C versus all comparators were below a $100,000/QALY willingness-to-pay threshold. Probabilistic sensitivity analysis also showed a 100% CE probability for P and P + C at the $100,000/QALY threshold. Conclusions: P and P + C are cost-effective treatment options in the US with CE ratios below $100,000/QALY gained versus commonly used therapies in 1L R/M HNSCC.[Table: see text]

Network meta-analysis (NMA) of pembrolizumab for first-line (1L) treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

e18012 Background: In the KEYNOTE-048 trial, pembrolizumab as monotherapy (P) and in combination with platinum+5FU chemotherapy (P+C) versus cetuximab+platinum+5FU (EXTREME regimen) significantly improved overall survival (OS) in the combined positive score (CPS) ≥1 (hazard ratio: 0.74; 95% confidence interval: 0.61-0.90) and total (0.72; 0.60-0.87) R/M HNSCC populations, respectively, and was approved by the FDA in these patient populations. While the EXTREME regimen is considered standard of care in 1L R/M HNSCC, other systemic treatment options including cetuximab+platinum+docetaxel (TPEx regimen), platinum+paclitaxel/taxane (Pt+T), and platinum+5FU (Pt+F) are also commonly used. Due to lack of head-to-head comparisons with pembrolizumab, an NMA was conducted to estimate the comparative efficacy of P and P+C versus these interventions in 1L R/M HNSCC. Methods: A systematic literature review (SLR) was conducted on November 13, 2019 to identify randomized controlled trials for the relavant interventions. Data were extracted for the OS and progression-free survival (PFS) outcomes. NMA analyses were conducted for the total population and for the CPS ≥1 and CPS ≥20 subgroups in a Bayesian framework using proportional hazards (base case) and time-varying (sensitivity analysis) treatment-effect models. The deviance information criterion was used to compare the goodness-of-fit of the alternative survival models. Results: The SLR identified 28 trials, of which six trials matched the trial eligibility criteria of KEYNOTE-048 and were included in the NMA. Results from the fixed-effects NMA for P and P+C are summarized in table below for the FDA indicated population. Improvement in OS was noted for P and P+C versus EXTREME, Pt+T, and Pt+F, and a trend in improved OS versus TPEx was observed. The sensitivity analysis showed improved OS over time across all comparisons. PFS was improved with P and P+C versus Pt+F and comparable versus other interventions. These results were generally consistent for P and P+C in the CPS (CPS ≥1 or CPS ≥20) patient subgroups. Additionally, NMA results versus EXTREME were consistent with the KEYNOTE-048 trial results. Conclusions: Pembrolizumab (P or P+C), showed improved OS and comparable PFS outcomes versus alternative 1L R/M HNSCC interventions, consistent with the efficacy results versus EXTREME observed in the KEYNOTE-048 trial. [Table: see text]

Treatment patterns for patients with metastatic or recurrent head and neck cancer in a large integrated health-care system.

e18015 Background: Since publication of the landmark KEYNOTE-048 Trial, pembrolizumab alone or with platinum-based chemotherapy and 5-fluorouracil (5FU) was established as a standard of care for the frontline treatment of patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC), replacing the EXTREME regimen of Cetuximab with platinum and 5FU. In clinical practice, some clinicians modify the KEYNOTE-048 regimen by substituting a taxane for 5FU (i.e., Paclitaxel + Carboplatin + Pembrolizumab, PCT). Within the Kaiser Permanente Northern California (KPNCAL) network, we identified a cohort of 123 patients who received palliative first-line therapy for metastatic HNSCC to identify practice patterns in a real-world setting within a large health care delivery system. Methods: This is a data-only cohort study of all adult KPNCAL members diagnosed with metastatic HNSCC treated with palliative combination chemotherapy and/or immunotherapy between January 1, 2018 and July 31, 2020. Results: Among a cohort of 123 patients, 28 patients received the EXTREME regimen (platinum + 5FU + cetuximab), 10 received modified EXTREME (platinum + taxane + cetuximab), 14 received platinum + 5FU + pembrolizumab, 9 received platinum + taxane + pembrolizumab and 62 received single agent immunotherapy. From 2018 through mid-2020, there was an apparent shift away from cetuximab based regimens and a concurrent rise in immunotherapy-based regimens. By mid-2020, the majority of patients received an immunotherapy-based regimen (28 patients), while only 5 patients received a cetuximab based regimen (Table). Conclusions: Data from our cohort reported clinical practice patterns within a large multispecialty integrated health-care system in Northern California. Our findings highlight the marked variability in practice patterns within a single health care system for first-line metastatic therapy. While we identified trends away from cetuximab based therapy and toward immunotherapy-based therapy in clinical practice there remained wide practice variations among clinical oncologist treating patients with newly diagnosed metastatic HNSCC. This further emphasizes the need for prospective clinical trials to identify the optimal regimen or to confirm clinical equipoise between regimens among patients with metastatic or recurrent head and neck cancer. [Table: see text]

Cost-Effectiveness of Pembrolizumab Regimens for the First-Line Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma in Argentina.

IntroductionThe phase III KEYNOTE-048 trial showed that the programmed death receptor 1 (PD-1) inhibitor pembrolizumab, in the combined positive score (CPS) ≥ 1 population and combined with platinum + 5-fluorouracil in the total population, improves survival over cetuximab + platinum + 5-fluorouracil in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). We evaluated the cost-effectiveness of pembrolizumab as monotherapy in the CPS ≥ 1 population or combined with platinum + 5-fluorouracil in the total population versus cetuximab + platinum + 5-fluorouracil from the social security perspective in Argentina.MethodsA partitioned survival model projected costs and outcomes over 20 years with 3% annual discounting. Health state occupancy was modeled using KEYNOTE-048 Kaplan–Meier curves until the final analysis data cutoff, followed by parametric extrapolations guided by statistical criteria. Costs for initial and subsequent treatments, disease and adverse events management, and terminal care were included (AR $74.00 = 1 USD). Time-on-treatment and EuroQol five-dimension scores were taken from KEYNOTE-048. Utilities were derived using an Argentina-specific algorithm.ResultsWith pembrolizumab monotherapy, patients accrued 1.1040 additional life-years and 0.8768 additional quality-adjusted life-years (QALYs), for incremental cost-effectiveness ratios (ICERs) of AR $135,801/life-year and AR $170,985/QALY gained over cetuximab + platinum + 5-fluorouracil. Additional life-years and QALYs gained with pembrolizumab combination therapy versus cetuximab + platinum + 5-fluorouracil were 1.3296 and 1.0536, respectively (ICERs of AR $680,143/life-year and AR $858,306/QALY). Considering a threshold of AR $1,676,122/QALY gained, pembrolizumab monotherapy and combination therapy had an 88.0% and a 77.1% probability of being cost-effective, respectively.ConclusionPembrolizumab either as monotherapy or in combination with chemotherapy offers substantial survival gains for patients with R/M HNSCC at small additional costs, making it a cost-effective treatment versus cetuximab + platinum + 5-FU in Argentina.

Pembrolizumab vs the EXTREME Regimen in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Cost-Effectiveness Analysis.

The KEYNOTE-048 clinical trial revealed that pembrolizumab improved the overall survival time of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) vs cetuximab plus chemotherapy (EXTREME regimen). The current study examined the cost effectiveness of pembrolizumab monotherapy and pembrolizumab plus chemotherapy compared with the EXTREME regimen in patients with HNSCC from the perspectives of USA and China. A partitioned survival model was implemented for patients with R/M HNSCC, and the cost effectiveness of pembrolizumab monotherapy and pembrolizumab plus chemotherapy compared with the EXTREME regimen was compared. Survival information was derived from the KEYNOTE-048 trial. The model was designed as a 20-year time horizon, a 3-week cycle, and a 3% discount rate for costs and utilities. An incremental cost-effectiveness ratio (ICER) value less than $100,000/quality-adjusted life-year (QALY) was considered cost effective in the USA and $27,538/QALY in China. We analyzed the uncertainty by performing one-way and probabilistic sensitivity analyses. From the base-case analysis, we found that the pembrolizumab monotherapy scheme had a lower cost and better efficacy compared with the EXTREME regimen in the USA. In China, the ICER of the comparison was $62,401/QALY. The ICER of pembrolizumab plus chemotherapy vs the EXTREME regimen was $66,630/QALY in the USA and $90,538/QALY in China. The observations suggested that treatment with pembrolizumab monotherapy or pembrolizumab plus chemotherapy is a cost-effective strategy for patients with R/M HNSCC in the USA. However, the conclusion is the opposite for China: the EXTREME regimen is still a cost-effective choice.

Abstract LB-258: Efficacy of first-line (1L) pembrolizumab by PD-L1 combined positive score &amp;lt;1, 1-19, and ≥20 in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): KEYNOTE-048 subgroup analysis

Abstract Introduction: In the phase 3 KEYNOTE-048 trial (NCT02358031) in R/M HNSCC, first-line pembrolizumab (P) monotherapy vs EXTREME (E; chemotherapy [C] + cetuximab) improved overall survival (OS) in PD-L1 combined positive score (CPS) ≥20 and CPS ≥1 populations and led to noninferior OS in the total population with favorable safety; first-line P+C vs E had superior OS in CPS ≥20, CPS ≥1, and total populations with comparable safety. Outcomes in CPS &amp;lt;1 and CPS 1-19 subgroups were not prospectively defined end points; we present a post hoc analysis in these subgroups. Methods: Patients with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to P, P+C, or E. Progression-free survival (PFS), objective response rate (ORR), and duration of response were assessed by RECIST v1.1 per blinded independent central review. OS and PFS were estimated by the Kaplan-Meier method. Hazard ratios and 95% CIs were based on a Cox regression model with Efron's method of tie handling, with treatment as a covariate. Data cutoff was Feb 25, 2019. Results: Baseline characteristics of the CPS &amp;lt;1, CPS 1-19, and CPS ≥20 subgroups were similar to those of the total population. In the CPS &amp;lt;1 subgroup, the HR (95% CI) for OS was 1.51 (0.96-2.37) for P (n = 44) vs E (n = 45) and 1.21 (0.76-1.94) for P+C (n = 39) vs E (n = 43) (Table). 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]). Conclusions: There was overall evidence of increased efficacy with increasing PD-L1 expression. In the CPS 1-19 subgroup, P+C vs E results were consistent with treatment benefit. Analysis of the CPS &amp;lt;1 subgroup was limited by small patient numbers. Future exploratory analyses of tumor mutational burden and inflamed signatures could further evaluate predictors of benefit in patients with low PD-L1-expressing HNSCC. Table.Efficacy in subgroups of patients with PD-L1 CPS &amp;lt;1, CPS 1-19, and CPS ≥20CPS subgroupTreatmentMedian OS, moOS HR12-mo OS rate, %Median PFS, moPFS HRORR, nMedian DOR, mo(95% CI)(95% CI)(95% CI)(95% CI)(95% CI)(%)(range)&amp;lt;1Pembrolizumab7.91.5138.62.14.3122.6n = 44(4.7-13.6)(0.96-2.37)(24.5-52.6)(1.9-2.3)(2.63-7.08)(4.5)(2.2-3.0)&amp;lt;1EXTREME11.3_48.96.2_197.8n = 45(9.1-15.9)(33.7-62.4)(5.1-7.6)(42.2)(2.0-38.6+)&amp;lt;1Pembrolizumab + Chemotherapy11.31.2141.04.71.46125.7n = 39(9.5-14.0)(0.76-1.94)(25.7-55.8)(3.4-6.2)(0.93-2.30)(30.8)(2.6-20.6+)&amp;lt;1EXTREME10.7_46.56.2_174.3n = 43(8.5-15.9)(31.2-60.4)(5.0-7.3)(39.5)(2.0-31.2+)1-19Pembrolizumab10.80.8644.02.21.2518NRn = 124(9.0-12.6)(0.66-1.12)(35.1-52.5)(2.1-2.9)(0.96-1.61)(14.5)(1.5+-38.9+)1-19EXTREME10.1_42.44.9_455.0n = 133(8.7-12.1)(33.9-50.7)(3.8-6.0)(33.8)(1.4+-38.7+)1-19Pembrolizumab + Chemotherapy12.70.7152.64.90.93345.6n = 116(9.4-15.3)(0.54-0.94)(43.1-61.2)(4.2-5.3)(0.71-1.21)(29.3)(1.6+-25.6+)1-19EXTREME9.9_41.14.9_424.6n = 125(8.6-11.5)(32.4-49.6)(3.7-6.0)(33.6)(1.4+-31.4+)≥20Pembrolizumab14.80.5856.43.40.993122.6n = 133(11.5-20.6)(0.44-0.78)(47.5-64.3)(3.2-3.8)(0.76-1.29)(23.3)(2.7-43.0+)≥20EXTREME10.7_44.95.3_444.2n = 122(8.8-12.8)(35.9-53.4)(4.8-6.3)(36.1)(1.2+-31.5+)≥20Pembrolizumab + Chemotherapy14.70.6057.15.80.76547.1n = 126(10.3-19.3)(0.45-0.82)(48.0-65.2)(4.7-7.6)(0.58-1.01)(42.9)(2.1+-39.0+)≥20EXTREME11.0_46.15.3_424.2n = 110(9.2-13.0)(36.6-55.1)(4.9-6.3)(38.2)(1.2+-31.5+) Citation Format: Barbara Burtness, Danny Rischin, Richard Greil, Denis Soulières, Makoto Tahara, Gilberto de Castro, Amanda Psyrri, Neus Basté, Prakash Neupane, Åse Bratland, Thorsten Fuereder, Brett G. Hughes, Ricard Mesia, Nuttapong Ngamphaiboon, Tamara Rordorf, Wan Zamaniah Wan Ishak, Joy Ge, Ramona Swaby, Burak Gumuscu, Kevin Harrington. Efficacy of first-line (1L) pembrolizumab by PD-L1 combined positive score &amp;lt;1, 1-19, and ≥20 in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): KEYNOTE-048 subgroup analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-258.

Optimizing Treatment for Head and Neck Cancers: Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

Immunotherapy has changed the game in the treatment of head and neck cancer (HNC). Practice-changing results from the phase III KEYNOTE-048 trial led to the approval of pembrolizumab immunotherapy alone or in combination with chemotherapy for the treatment of recurrent/metastatic HNC in the first-line setting. Testing for combined positive score (CPS) is now part of routine practice, because patients with CPS ≥1 can be started on single-agent immunotherapy in the first-line. Pembrolizumab replaces the “old” standard of care established by the EXTREME study, as trials looking at targets besides immunotherapy have proved “disappointing.” Additionally, nivolumab and pembrolizumab are both approved for use in the second-line.

Pembrolizumab (P) or P + chemotherapy (C) versus EXTREME (E) as first-line (1L) therapy for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): analysis of KEYNOTE-048 by disease state.

6530 Background: In the phase 3 KEYNOTE-048 trial ( NCT02358031 ) in R/M HNSCC (N = 882), 1L P vs E showed superior OS in PD-L1 CPS ≥20 and CPS ≥1 populations, noninferior OS in the total population, no PFS benefit, and favorable safety; 1L P+C vs E showed superior OS in CPS ≥20, CPS ≥1, and total populations, no PFS benefit, and comparable safety. Results of P or P+C vs E in incurable recurrent only, metastatic only, and R/M subgroups are shown. The metastatic only and R/M subgroups were combined and classified as metastatic. Methods: Patients with incurable recurrent (local and/or regional node recurrent disease) or metastatic HNSCC were randomly assigned 1:1:1 to P, P+C, or E. OS and PFS were estimated using the Kaplan-Meier method. Hazard ratios and 95% CIs were based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG performance status, HPV status, and PD-L1 status. Data cutoff: Feb 25, 2019. Results: In the incurable recurrent only subgroup (n = 252), median OS was 11.5 vs 12.1 mo (P vs E) and 13.0 vs 11.1 mo (P+C vs E). In the metastatic subgroup (n = 620), median OS was 11.4 vs 9.7 mo (P vs E) and 13.0 vs 10.1 mo (P+C vs E). Median follow-up, OS, and PFS are shown in Table. Treatment-related adverse events (TRAE) in the incurable recurrent only subgroup: 49.4% (P), 94.7% (P+C), and 97.8% (E); grade 3-5 TRAEs rates: 16.0%, 78.7%, and 73.3%, respectively. TRAE rates in the metastatic subgroup: 61.6% (P), 96.4% (P+C), and 96.4% (E); grade 3-5 TRAEs rates: 17.6%, 69.5%, and 67.0%, respectively. Conclusions: P and P+C vs E were efficacious in the metastatic subgroup; in the relatively smaller subgroup of patients with incurable recurrent only HNSCC, the effect was less pronounced. Consistent with the total study population and regardless of disease state, the safety profile was favorable with P vs E and comparable with P+C vs E. These data further support use of 1L P or P+C in patients with R/M HNSCC. Clinical trial information: NCT02358031 . [Table: see text]