Immunotherapy with pembrolizumab, given alone or in combination with chemotherapy (CT), is now considered as one of the first-line therapeutic options for relapsed/metastatic head and neck squamous cell carcinoma (R/M HNSCC).1 It was approved with new data from the final analysis of KEYNOTE-48 trial, which was presented at the American Society of Clinical Oncology (ASCO) Annual Meeting held at Chicago, USA, on 1-3rd June 2019.
Background and overview of KEYNOTE-48
Prior to the latest approval, immunotherapy for head and neck cancer was only approved for second-line use, after a patient has progressed with first-line CT.2 The lead author of the study, Professor Danny Rischin, MD, from the Peter MacCallum Cancer Centre, Melbourne, Australia, gave an overview of the study stating, “These data support pembrolizumab plus platinum-based CT and pembrolizumab monotherapy as new first-line standard-of-care therapies for R/M HNSCC.“3
KEYNOTE-48: Study design
KEYNOTE-48 was a randomized, open-label study that enrolled 882 patients with R/M HNSCC, which was incurable with first-line therapies. The median age of the participants was 61 years and were predominantly men with a majority of current or former smokers.1 Approximately 30% of patients had episodes of locoregional recurrence. Patients were randomized to three groups: The first group received pembrolizumab monotherapy at 200mg every 3 weeks for 35 cycles (n=301), while the second group received pembrolizumab 200mg every 3 weeks for 6 cycles along with standard CT (n=281) followed by maintenance pembrolizumab 200mg every 3 weeks for an additional 29 cycles. The third group only received CT alone (n=300).1 CT was a combination of cetuximab, carboplatin, or cisplatin, and 5-fluorouracil given at standard dosages every 3 weeks for 6 cycles followed by cetuximab 250mg/m2 once a week as maintenance therapy. This was known as the EXTREME regimen and was the accepted care at the setting at the given time.
OS, as the primary end point, was assessed in three patient populations. In order to divide the patients into three categories, program cell death ligand-1 (PD-L1) combined positive score (CPS) was used. CPS was defined as the percentage of PD-L1-positive cells (tumor cells, lymphocytes and macrophages) compared with the total tumor cell numbers. When considering the total population, 44% of patients had PD-L1 CPS of ≥20 and 85% had PD-L1 CPS ≥1.1
Superior OS achieved by the combination of pembrolizumab and CT
The data cut-off point for the final analysis was February 2019. Combination of pembrolizumab and CT was superior to CT alone in terms of survival benefits. For patients with CPS ≥20, the median OS was higher in the combination group (14.7 months vs. 11.0 months for CT alone) (HR=0.6; 95% CI: 0.45-0.82; p=0.0004) (Figure 1). Similarly, for patients with CPS ≥1, the median OS was also higher in the combination group (13.6 months vs. 10.4 months for CT alone) (HR=0.65; 95% CI: 0.53-0.80; p<0.0001).1 However, the objective response rate (ORR) and progression free survival (PFS) were considered not significant, as they did not meet the threshold of protocol-defined superiority for patients with tumors expressing CPS ≥1 or CPS ≥20 compared with CT alone.1
In fact, when considering the total population, pembrolizumab plus CT combination also showed superior OS compared with CT alone. The median OS was 13.0 months for the combination and 10.7 months for CT alone . Additionally, adverse effects of grade 3 to 5 were similar across the two groups. The discontinuation rates were also similar, 32.6% for patients receiving the combination and 27.5% for patients receiving CT alone.
Professor Rischin also reported updated data on the comparison of pembrolizumab monotherapy and CT alone. “In this patient population, OS did not meet the criteria for significance at the superiority threshold [p=0.0059],“ he said. OS with pembrolizumab monotherapy was superior to CT alone in patients with tumors expressing CPS ≥20 and CPS ≥1. However, the durability of pembrolizumab monotherapy was lower than CT alone.
Co-author Professor Barbara Burtness, MD, of Yale Cancer Center in New Haven, Connecticut, commented that the monotherapy arm failed to show superiority among the total population, saying the OS number was still “quite good.“
Considerations for clinical practice
In light of these findings, “That was the first evidence showing pembrolizumab could prolong survival in the first-line setting and those data are now published before the FDA’s approval,“ said Professor Burtness. Furthermore, she predicted the future approval by saying, “We don’t have an approval there, but it would be surprising if one didn’t come.“4
Further adding to the discussion on approval, Professor Rischin said the safety profile was comparable between the pembrolizumab combination arm and EXTREME, while the safety profile in the monotherapy arm was favorable. He remarked, “The data from KEYNOTE-048 supports pembrolizumab plus platinum-based chemotherapy and pembrolizumab monotherapy as new first-line standard of care therapies for recurrent head and neck squamous cell carcinoma.“3 Professor Burtness emphasized that higher ORR was seen with CT compared with pembrolizumab monotherapy and stated that is important to keep in mind, especially when a positive response is needed in patients.4
During the panel discussion, an algorithm for treating patients with HNSCC was discussed. It was suggested that the monotherapy with immunotherapy to be the treatment of choice for patients with a disease-free interval of 6 months or less (platinum-refractory patients). Moreover, patients with a disease-free interval of more than 6 months with a good physical status and controlled comorbidities are eligible to continue CT and are likely to be dictated by the disease severity. In severe disease, the recommendation was pembrolizumab in combination with CT.3
PD-L1 level is the determining factor of treatment approach for patients with mild-to-moderate disease. Subsequently, in patients with tumors showing CPS ≥20, pembrolizumab monotherapy may be appropriate, while those with CPS ≥1 should opt for pembrolizumab monotherapy or pembrolizumab combination therapy.3
Challenges in the first-line therapy of pembrolizumab
Applauded as the “most important“ study during the day, Professor Francis P. Worden, MD, from the University of Michigan Rogel Cancer Center, Ann Arbor, predicted that the pembrolizumab plus CT combination should replace the EXTREME regimen as first-line therapy in HNSCC.4
However, Professor Worden stated that the superiority of OS seen with the pembrolizumab combination in patient subgroup of CPS ≥20 had an influence on the positive outcome of patients with CPS ≥1 and the total patient population. Therefore, he insisted that it would be interesting to observe whether patients with CPS ≥1 to 19 and CPS 0 benefit from the combination of pembrolizumab and CT.3
Most importantly, Professor Worden recommended clinicians to undertake PD-L1 CPS testing and carefully evaluate patients with respect to their disease progression and of the stage of the disease before the therapeutic application approved.3
Additionally, due to the difficulties in administering the EXTREME regimen with 5-fluorouracil, Professor Worden noted it is compulsory to assess if similar results could be seen when pembrolizumab was given in combination with another CT regimen. He concluded re-emphasizing the role of first-line immunotherapy in second-line therapies by saying, “Exposure to immunotherapy as first-line may have greater benefits for second-line therapies.“3
FDA approval for pembrolizumab in R/M HNSCC
Pembrolizumab has been recently approved by FDA as first-line treatment for patients with R/M HNSCC and for use in combination with platinum and fluorouracil (FU) for all patients, and as a single agent for patients whose tumors express PD‑L1 (CPS ≥1).5 The recommended pembrolizumab dose for HNSCC is 200mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
“This approval is a very exciting milestone in the treatment of head and neck cancer and has the potential to transform the way we treat patients with this debilitating disease by offering important new therapeutic options,“ said Professor Barbara Burtness, Yale Cancer Center, New Haven, United States.6
Treating R/M HNSCC has been an area of significant unmet need for long time. With the approval of pembrolizumab as first-line, either as monotherapy in a subgroup of patients with HNSCC whose tumors express PD-L1, or in combination with chemotherapy, patients can benefit from prolonged survival and fewer side effects during the treatment journey, that is highly encouraging.
1. Rischin D, Harrington KJ, Greil R, et al. Abstract. 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). ASCO 2019, Abstract 171051 (Accessed July 22, 2019, at https://meetinglibrary.asco.org/record/171051/abstract)
2. Patil VM, Noronha V, Joshi A, et al. A prospective randomized phase II study comparing metronomic chemotherapy with chemotherapy (single agent cisplatin), in patients with metastatic, relapsed or inoperable squamous cell carcinoma of head and neck. Oral Oncol. 2015 Mar;51(3):279-86.
3. Pembro now approved for first-line use in head and neck cancer. Medscape. (Accessed July 22, 2019, at http://www.medscape.com/viewarticle/914230)
4. New first-line option in head and neck cancer: ‘practice changing’. Medscape. (Accessed July 22, 2019, at http://www.medscape.com/viewarticle/913825)
5. FDA approves pembrolizumab for first-line treatment of head and neck squamous cell carcinoma. FDA (2019).
6. Pembro Now Approved for First-Line Use in Head and Neck Cancer. Medscape.(Accessed on July 22, 2019, at http://www.medscape.com/viewarticle/914230)