KEYNOTE-048 Leads to First-Line Advances in Monotherapy, Chemotherapy for Head and Neck Cancer

July 17, 2019

In his editorial note, Robert L. Ferris, MD, PhD, discussed how immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have drastically changed treatment and improved outcomes across numerous solid tumors over the past 5 years. He discussed data from the 2019 ASCO Annual Meeting surrounding treatment options for head and neck cancers.

Robert L. Ferris, MD, PhD

Immune checkpoint inhibitors (ICIS) targeting the PD-1/PD-L1 pathway have drastically changed treatment and improved outcomes across numerous solid tumors over the past 5 years. For recurrent/metastatic squamous cell carcinoma of the head and neck (R/M HNSCC), both nivolumab (Opdivo) and pembrolizumab (Keytruda) were approved in 2016 for the treatment of patients who had progressed during or after platinum-based chemotherapy, with nivolumab being the first systemic therapy to significantly improve overall survival (OS) in the platinum failure setting. That led to multiple trials evaluating anti—PD-1/PD-L1 monoclonal antibodies in both the first-line R/M and the up-front curative intent settings.

On June 10, 2019, the FDA approved pembrolizumab as first line for R/M HNSCC in combination with platinum and fluorouracil (5-FU) in all patients or as monotherapy in tumors with a PD-L1 combined positive score (CPS) ≥1 (see page 26). This approval was based on the randomized, 3-arm, phase III KEYNOTE-048 trial (NCT02358031), with final analysis presented May 31, 2019, at the American Society of Clinical Oncology Annual Meeting (see page 70).1

The trial examined 882 patients who received either pembrolizumab monotherapy versus a novel combination of pembrolizumab, 5-FU, and cisplatin or carboplatin versus the EXTREME regimen of cisplatin, 5-FU, and cetuximab (Erbitux). Chemotherapy plus an anti—PD-1 therapy is a rational combination strategy. Chemotherapy disrupts the architecture in the tumor microenvironment, which may help overcome immune exclusion and produce antigen shedding. Unlike ICIs, chemotherapy also produces rapid responses. In the study, chemotherapy was given for up to 6 cycles, pembrolizumab for up to 24 months, and cetuximab open-ended in either arm, until treatment was discontinued for progressive disease or toxicity. Approximately 25% of patients had human papillomavirus–associated (p16+) oropharynx cancers.

This trial is the first in HNSCC to prospectively use a biomarker of PD-L1 expression level in the primary endpoint analysis. The trial used combined proportion score (CPS) as a biomarker. CPS includes tumor cells and surrounding immune cells to measure PD-L1 level, compared with the tumor proportion score (TPS), which includes just tumor cells.

The primary outcomes were OS and progression-free survival (PFS), tested sequentially for CPS ≥20, CPS ≥1, and the total population. Overall response rate (ORR) was 36% with EXTREME, 36% with pembrolizumab plus chemotherapy, and 16% with pembrolizumab monotherapy in the overall population. The ORR was improved for pembrolizumab plus chemotherapy (43%) versus the EXTREME regimen (38%) in the CPS ≥20 population. PFS was similar for all 3 regimens. This study identified that pembrolizumab plus chemotherapy significantly improved OS for the CPS ≥20 (HR, 0.60; 95% CI 0.45- 0.82), CPS ≥1 (HR, 0.65, 95% CI 0.53- 0.80), and overall populations. Pembrolizumab monotherapy also significantly improved OS for the CPS ≥20 and CPS ≥1 groups and was noninferior to EXTREME in the overall population (HR, 0.83; 95% CI 0.70-0.99; P = .0199). In the overall population, pembrolizumab plus chemotherapy improved OS to 13 months compared with 11 months in the EXTREME regimen.

Despite the inferior ORR, the OS benefit was driven by a longer duration of response (DOR) in the pembrolizumab cohort (20.9 vs 4.5 months in the CPS ≥1 population). Grade 3 to 5 treatment-related adverse events were observed in 71% of patients receiving pembrolizumab plus chemotherapy, 69% with the EXTREME regimen, and 17% with pembrolizumab monotherapy.

These findings indicate that pembrolizumab can be safely added to platinum-based combination chemotherapy with a similar safety profile to the EXTREME regimen. Exposure to subsequent ICIs after progression has not yet been reported; however, it would be expected that any exposure to subsequent ICIs in patients treated on the EXTREME regimen would blunt the OS benefit observed in this study.

Pembrolizumab plus chemotherapy and pembrolizumab monotherapy as first-line treatments for R/M HNSCC represent new standards of care in the 85% of patients with CPS ≥1 in KEYNOTE-048. These findings are significant because many patients with R/M HNSCC have multiple comorbidities and may not be eligible to receive multiple lines of therapy. In the 85% of patients with R/M HNSCC who are PD-L1 positive (CPS ≥1), these results also pose new questions about whether to use pembrolizumab alone or pembrolizumab with chemotherapy as first-line therapy.

Important considerations in treatment selection for patients with R/M HNSCC include prior exposure to systemic therapy, symptom burden, PD-L1 positivity, and toxicity. First, it is critical to confirm the patient’s exposure to systemic therapy in the locally advanced setting and the timing of chemotherapy to determine if they are eligible for first or second-line therapy. Second, it is necessary to consider a patient’s symptom burden and overall bulk of disease. Pembrolizumab plus chemotherapy produces a higher response rate than pembrolizumab monotherapy. Combination pembrolizumab and chemotherapy increases ORR in the overall population to 36% compared with 17% using pembrolizumab monotherapy. Pembrolizumab plus chemotherapy should be considered when ORR is critical, such as for patients who have severely symptomatic disease or are at risk of airway or bleeding issues because of bulky locoregional disease. Third, it is now crucial to determine the PD-L1 level, as measured by the CPS. Based on the approval label, patients with CPS ≥1 are eligible for first-line pembrolizumab monotherapy. Further, the likelihood of response to anti—PD-1 therapy increases in parallel with the score. In patients with a score ≥20, the median OS with pembrolizumab monotherapy versus pembrolizumab plus chemotherapy was similar (14.8 vs 14.7 months) but with considerably less toxicity. Patients with CPS ≥20 are better candidates for pembrolizumab monotherapy and may avoid the toxicity of adding chemotherapy. Those with CPS ≤19 did not clearly benefit from pembrolizumab monotherapy. This treatment algorithm provides general guidelines regarding first-line treatment of R/M HNSCC but needs to be tailored to account for patient preferences and individual circumstances.

As highlighted in KEYNOTE-048, high levels of PD-L1 expression are associated with an increased likelihood of response to anti—PD-1 therapy. Interpreting PD-L1 expression as a biomarker across trials is challenging because of the variety of cut points and assays that are used. Around 50% to 60% of HNSCC tumor cells express PD-L1 (measured using TPS), but this percentage increases to 85% when considering tumor cells and surrounding immune cells (measured with CPS).

The predictive value of PD-L1 expression rises when considering the combined expression on tumor cells and infiltrating immune cells. In the KEYNOTE-012 study, the response rate was 21% in PD-L1—positive patients versus 6% in PD-L1 negative by CPS compared with 18% in PD-L1 positive versus 19% in PD-L1 negative by TPS assessment. In CheckMate 141, the presence of PD-L1–expressing immune cells in the tumor microenvironment was more predictive of response than was PD-L1 expression in tumor cells.2 Relevantly, the FDA approval of pembrolizumab monotherapy only in patients with CPS ≥1 represents the first mandated biomarker testing for selection of immunotherapy in HNSCC.

In conjunction with the first-line approval for pembrolizumab, the FDA extended the use of the PD-L1 IHC 22C3 pharmDx kit as a companion diagnostic device to measure CPS and help select patients for treatment with pembrolizumab monotherapy. Currently, most laboratories do not routinely employ CPS in their reporting of PD-L1 expression. In response to the FDA approval of pembrolizumab monotherapy only in biomarker-selected populations, it will be critical to expand availability of the CPS biomarker into routine practice.

Although PD-L1 expression levels may help select patients in the first-line R/M setting for pembrolizumab in combination with chemotherapy versus monotherapy, it should not be used to exclude patients from being offered the potential benefit of ICIs. Select patients with PD-L1—negative cancers still derive benefit from anti–PD-1 agents. PD-L1 testing should not be used to exclude patients from second-line ICI treatment.

As with any change in standard of care, subsequent therapy brings significant implications. For patients who receive and fail first-line pembrolizumab monotherapy, second-line standard-of-care systemic therapy options will include platinum doublets and the EXTREME regimen. For patients who progress on first-line platinum/5-FU plus pembrolizumab, a taxane or cetuximab will be subsequent options.

This is just the second randomized phase III trial to show a survival benefit in the frontline setting for nonnasopharyngeal R/M HNSCC and the first since 2008, when the efficacy of the EXTREME regimen was reported. This changes the standard of care for frontline systemic therapy in R/M HNSCC, and PD-L1 expression by CPS will be our first required biomarker for selection of therapy in HNSCC. We eagerly await the superiority analysis of pembrolizumab monotherapy in the total population and also the results of the 2 other first-line R/M HNSCC phase III trials: CheckMate 651 (ipilimumab plus nivolumab vs EXTREME) and KESTREL (durvalumab [Imfinzi] with or without tremelimumab vs EXTREME), which are ongoing. The positive results of KEYNOTE-048 represent significant progress in our field for our patients facing the challenges of R/M HNSCC.


  1. Rischin D, Harrington KJ, Greil R, et al. Protocol-specified final analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab (pembro) as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). J Clin Oncol. 2019;37(suppl 15; abstr 6000). doi: 10.1200/JCO.2019.37.15_suppl. 6000.
  2. Oliva M, Spreafico A, Taberna M, et al. Immune biomarkers of response to immune- checkpoint inhibitors in head and neck squamous cell carcinoma. Ann Oncol. 2019;30(1):57-67. doi: 10.1093/annonc/mdy507.