There is a new first-line treatment option for patients with newly diagnosed, recurrent, or metastatic head and neck squamous cell carcinoma. As reported by Burtness et al in The Lancet, pembrolizumab improved overall survival vs the standard-of-care regimen of cetuximab and platinum-based chemotherapy for patients with programmed cell death ligand 1 (PD-L1)-positive tumors in the KEYNOTE-048 trial.¹ In this three-arm trial, the substitution of pembrolizumab for cetuximab improved overall survival in the overall study population, regardless of tumor PD-L1 status.¹

Maura L. Gillison, MD, PhD

The programmed cell death protein 1 (PD-1) checkpoint inhibitors pembrolizumab and nivolumab were approved by the U.S. Food and Drug Administration in 2017 for patients with recurrent or metastatic squamous cell carcinoma of the head and neck whose disease progressed within 6 months of treatment with platinum-based chemotherapy. Pembrolizumab gained accelerated approval for this patient population based upon an overall response rate of 16% in KEYNOTE-012,² subsequently supported by results of KEYNOTE-040.³ In the CheckMate 141 trial, nivolumab improved overall survival (hazard ratio [HR] = 0.70, 95% confidence interval [CI] = 0.51–0.96, P = .01) relative to single-agent chemotherapy of investigators’ choice (ie, docetaxel, cetuximab, methotrexate).⁴ These trials changed the standard of care for patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck.

Since 2008, the three-drug combination of cetuximab, fluorouracil (5-FU), and cisplatin or carboplatin, known as “the extreme regimen,” has been the regulatory standard of care for the first-line treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck.⁵

In a randomized controlled trial conducted by Vermorken et al, the addition of cetuximab to 5-FU and cisplatin or carboplatin significantly improved overall survival (median = 10.1 vs 7.4 months, HR = 0.80, 95% CI = 0.64–0.99, P = .04), progression-free survival (5.6 vs 3.3 months, HR = 0.54, P < .001), and objective response rate (36% vs 20%, P < .001).⁵ Moreover, the regimen provided a median duration of response (defined as the time from first documented complete or partial response to radiographically confirmed disease progression or death) of 5.6 months.

However, the extreme regimen was associated with high rates (82%) of moderate-to-severe (grade 3 or 4) adverse events, including a significantly higher rate of sepsis.⁵ Therefore, patients and treating physicians have anxiously awaited the development of a less toxic first-line regimen with potential to improve both overall survival and quality of life relative to this standard of care.

“In this three-arm trial [KEYNOTE-048], the substitution of pembrolizumab for cetuximab improved overall survival in the overall study population, regardless of tumor PD-L1 status.”

— Maura L. Gillison, MD, PhD

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KEYNOTE-048: Details and Results

In KEYNOTE-048, a multicenter, three-arm, randomized trial, 882 patients with newly diagnosed recurrent or metastatic squamous cell carcinoma of the head and neck were stratified by PD-L1 Tumor Proportion Score (TPS; ≥ 50% vs < 50%), Eastern Cooperative Oncology Group performance status (0 vs 1), and tumor p16 status (positive vs negative). They were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab with chemotherapy, or cetuximab with chemotherapy.¹ In one experimental arm, patients received pembrolizumab at 200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or a maximum of 35 doses. In the second experimental arm, patients received pembrolizumab and six cycles of chemotherapy (5-FU at 1,000 mg/m² for 4 days and cisplatin at 100 mg/m² or carboplatin AUC = 5). The experimental arms were compared with the standard of care (eg, the extreme regimen) of cetuximab at a 400-mg/m² loading dose followed by 250 mg/m² weekly (continued until disease progression or unacceptable toxicity) with six cycles of chemotherapy.

The principal outcomes of KEYNOTE-048 and the data analysis plans were amended during the study and were quite complex. In the end, 14 different hypotheses were tested at the second-interim and final analysis time points.¹ Principal among the outcomes were superiority of overall and progression-free survival for pembrolizumab and pembrolizumab plus chemotherapy vs cetuximab plus chemotherapy in the study populations who had a tumor PD-L1 Combined Positive Score (CPS) ≥ 20 and a CPS ≥ 1. In the overall study population, principal outcomes included noninferiority for overall survival for pembrolizumab vs cetuximab plus chemotherapy and superiority for pembrolizumab plus chemotherapy vs cetuximab plus chemotherapy.

Of note, CPS was defined as the number of PD-L1–positive cells (tumor, lymphocyte, or macrophages) divided by the total number of tumor cells times 100 in evaluable samples (with a minimum of 100 viable tumor cells) as measured by PD-L1 immunohistochemistry with the 22C3 pharm DX assay. This definition contrasts with the stratification factor of TPS, which restricts PD-L1 expression to the tumor cells alone.

At the second interim analysis, pembrolizumab significantly improved overall survival vs cetuximab plus chemotherapy in 43% of patients with tumors of a CPS ≥ 20 (HR = 0.62, 95% CI = 0.45–0.83, P < .008) and in 85% of patients with tumors of a CPS ≥ 1 (HR = 0.78, 95% CI = 0.64–0.96, P = .0086).¹ However, pembrolizumab was noninferior in overall survival vs cetuximab plus chemotherapy in the overall study population.

In the final analysis, pembrolizumab plus chemotherapy significantly improved overall survival vs cetuximab plus chemotherapy in the CPS ≥ 20 (HR = 0.60, 95% CI = 0.45–0.82, P = .004), the CPS ≥ 1 population (HR = 0.65, 95% CI = 0.53–0.80, P < .0001), and the overall study population (HR = 0.77, 95% CI = 0.63–0.93, P = .0086).¹ These outcomes were remarkable, given that 25% of patients in the cetuximab-plus-chemotherapy arm subsequently received PD-1 or PD-L1 therapy. With regard to progression-free survival, neither pembrolizumab nor pembrolizumab plus chemotherapy showed improvement vs cetuximab plus chemotherapy in any study population.

Notable Findings of Interest

Not included in the KEYNOTE-048 design or analysis were comparisons between the two experimental arms (pembrolizumab and pembrolizumab plus chemotherapy). However, experimental arms were compared with the same cetuximab-plus-chemotherapy control arm (with the exception of a few patients). Therefore, a few findings of interest are notable.

First, objective response rates were higher in all patients (eg, CPS ≥ 20, CPS ≥ 1, and overall study populations) treated with cetuximab plus chemotherapy (range = 36%–38%) than with pembrolizumab alone (range = 17%–23%). And the combination of pembrolizumab plus chemotherapy did not further increase the objective response rate (range = 36%–43%).

Second, the duration of response in all patients (eg, CPS ≥ 20, CPS ≥ 1, and overall study population) was markedly shorter with pembrolizumab plus chemotherapy (range = 6.7–7.1 months) than with pembrolizumab alone (range = 22.6–23.4 months), raising some concern of detriment in the duration of response with the pembrolizu­mab-plus-chemotherapy combination. For example, does chemotherapy-­associated lymphopenia impair antitumor immunity or generation of a CD8-positive T-cell memory response?

Third, 12-month overall survival was quite similar with pembrolizu­mab alone and pembrolizumab plus chemotherapy for the CPS ≥ 20 (57% and 57%) and CPS ≥ 1 (57% and 55%) populations. The same was true for 24-month overall survival (38% and 35% with CPS ≥ 20; 38% and 31% with CPS ≥ 1). However, moderate-to-severe adverse events (grade 3 or 4) were more frequent with pembrolizumab plus chemotherapy than pembrolizumab alone (85% and 55%), as were treatment discontinuations (12% and 8%) and treatment-related deaths (4% and 1%). These findings raise legitimate questions regarding the risk-benefit analysis of pembrolizumab plus chemotherapy relative to pembrolizumab alone in patients with PD-L1–positive tumors (eg, CPS ≥ 1).

Finally, the small proportion of patients with PD-L1–negative tumors (eg, CPS < 1, 15%) appears to negatively affect overall survival outcomes in the pembrolizumab-alone and pembrolizumab-plus-chemotherapy arms. This finding raises the question of benefit of pembrolizumab alone or pembrolizumab plus chemotherapy relative to cetuximab plus chemotherapy in this patient population.

New Questions Raised

“Nivolumab has technically been available as ‘first-line’ therapy for a subset of patients with recurrent or metastatic squamous cell carcinoma of the head and neck since 2017.”

— Maura L. Gillison, MD, PhD

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The findings previously mentioned raise some important new questions for the field. Do patients with PD-L1–positive tumors (eg, CPS ≥ 1) benefit from pembrolizumab plus chemotherapy? Although the overall response rate is higher, the duration of response decreased dramatically, moderate-to-severe toxicity was more frequent, and the 12-month and 24-month overall survival rates were remarkably similar to those with pembrolizumab alone. Do patients with PD-L1–negative tumors (CPS < 1) receive a greater benefit from cetuximab plus chemotherapy relative to pembrolizumab or pembrolizumab plus cetuximab? With regard to sequence, should cetuximab plus chemotherapy remain the standard of care in this patient population, followed by pembrolizumab or nivolumab in the second-line setting?

It is important to note that patients with disease progression within 6 months of curative-intent primary therapy were ineligible for ­KEYNOTE-048. In contrast, in the previously mentioned CheckMate 141 trial of nivolumab in this setting, 28% of patients had disease progression within 6 months of treatment with platinum-based chemotherapy in the induction, concurrent, or adjuvant setting.⁴

In an unplanned retrospective analysis, ­single-agent nivolumab improved overall survival vs single-agent investigators’ choice chemotherapy (median = 7.7 vs 3.3 months, HR = 0.56, 95% CI = 0.33–0.95) and resulted in a remarkable 12-month overall survival of 39.2% in this treatment-refractory patient population.⁴ Therefore, nivolumab has technically been available as “first-line” therapy for a subset of patients with recurrent or metastatic squamous cell carcinoma of the head and neck since 2017.

Clinical Implications

Pembrolizumab improved overall survival and reduced toxicity relative to cetuximab plus chemotherapy in the 85% of patients with newly diagnosed recurrent or metastatic squamous cell carcinoma of the head and neck with PD-L1–positive tumors (eg, CPS ≥ 1) eligible for immunotherapy. Thus, pembrolizumab represents a new standard-of-care option. For this patient population, pembrolizumab may be preferable to pembrolizumab plus chemotherapy because of the increased duration of response and reduced toxicity. For all symptomatic patients in need of response (regardless of tumor PD-L1 status), pembrolizumab plus chemotherapy is preferable to cetuximab plus chemotherapy due to improved overall survival without increased overall toxicity.

For PD-L1–negative patients, pembrolizumab plus chemotherapy or sequential cetuximab plus chemotherapy followed by pembrolizu­mab³ or nivolumab⁴ at disease progression are reasonable options. For patients with an unknown tumor PD-L1 status, pembrolizumab plus chemotherapy may be preferable over cetuximab plus chemotherapy. For patients who experience disease progression within 6 months of receipt of platinum-based chemotherapy as curative-intent therapy, nivolu­mab also remains a first-line option.⁴ 

DISCLOSURE: Dr. Gillison has served as a consultant or advisor to BioMimetix, Bristol-Myers Squibb, EMD Serono, Genocea Biosciences, Merck, and Roche; has received honoraria from Roche; and has received institutional research funding from Bristol-Myers Squibb, Genocea Biosciences, and Cullinan Oncology.

REFERENCES

1. Burtness B, Harrington KJ, Greil R, et al: Pembrolizumab alone or with chemotherapy vs cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study. Lancet 394:1915-1928, 2019.

2. Mehra R, Seiwert TY, Gupta S, et al: Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: Pooled analyses after long-term follow-up in KEYNOTE-012. Br J Cancer 119:153-159, 2018.

3. Cohen EEW, Soulières D, Le Tourneau C, et al: Pembrolizumab vs methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): A randomised, open-label, phase 3 study. Lancet 393:156-167, 2019.

4. Ferris RL, Blumenschein G Jr, Fayette J, et al: Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375:1856-1867, 2016.

5. Vermorken JB, Mesia R, Rivera F, et al: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116-1127, 2008.