Studies Show Durable Activity of Pembrolizumab in Head and Neck Cancer

Ranee Mehra, MD

Pembrolizumab (Keytruda), when studied in 2 clinical trials for the treatment of patients with pretreated recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), showed an objective response rate (ORR) of 18%, according to findings presented at the 2016 ASCO Annual Meeting.

In the first study, known as KEYNOTE-012,¹the ORR was 18% in patients with recurrent/metastatic HNSCC treated with pembrolizumab. The stable disease rate was 17%. In the second study, KEYNOTE-055,²the ORR with pembrolizumab was also 18% in a similar population, with a stable disease rate of 19%.

In April 2016, the FDA granted a priority review designation to the PD-1 inhibitor as a potential treatment for patients with recurrent/metastatic HNSCC. The application was based on data from the first 50 patients enrolled in the phase II KEYNOTE-055 trial and full findings from the KEYNOTE-012 study. In the first 50 patients enrolled in the phase II study, the ORR was 18% and the stable disease rate was 18%.

Under the Prescription Drug User Fee Act, the FDA is scheduled to make an approval decision for pembrolizumab by August 9, 2016.

"Pembrolizumab has robust and durable antitumor activity in heavily pretreated patients with recurrent/metastatic head and neck squamous cell carcinoma," said KEYNOTE-012 lead investigator Ranee Mehra, MD, chief of head and neck oncology, Fox Chase Cancer Center. "To see this level of response with pembrolizumab in patients with head and neck cancer is encouraging and provides further evidence of the potential for pembrolizumab in the treatment of this disease."

In the phase II KEYNOTE-055 study, 171 patients with recurrent or metastatic HNSCC received pembrolizumab at a flat 200 mg dose every 3 weeks. The median age of patients was 61 years, and 81% were male. The most common ECOG performance status was 1 (70%), and HPV status was positive for 41% of patients. The median number of prior therapies was 2, and nearly half of patients (42%) had received ≥3 prior systemic therapies.

After a median follow-up of 7 months, 54% of patients experienced a decrease in target lesion size. Median time to response was 2 months, and 75% of responses continued at the time of the analysis.

The median progression-free survival (PFS) was 2.1 months and the 6-month PFS rate was 24%. The median overall survival (OS) was 8 months (95% CI, 8-11), with a 6-month OS rate of 65%.

"This is the first report of phase II data showing efficacy of pembrolizumab in refractory or metastatic head and neck squamous cell carcinoma," said Joshua M. Bauml, MD, from the University of Pennsylvania. "This is particularly encouraging when you consider the fact that our historical record for this group is only a 6 month overall survival."

In HPV-positive patients (n = 18), the ORR was 22% (95% CI, 6-48). In the HPV-negative group (n = 74), the ORR was 16% (95% CI, 9-27). The ORR was 17% (95% CI, 9-28) in patients with PD-L1-positive tumors (n = 76). In the PD-L1-negative group (n = 13), the ORR was 8% (95% CI, 0.2-36).

"I think it is fair to say that pembrolizumab is a promising therapy for a potential population with limited options," said Bauml.

In the KEYNOTE-012 trial, 192 total patients with recurrent/metastatic HNSCC received two doses of pembrolizumab. In the first arm, patients with PD-L1-postive HNSCC received the PD-1 inhibitor at 10-mg/kg (n = 60). In the second group, patients received pembrolizumab at 200 mg every 3 weeks regardless of PD-L1 status (n = 132).

The median age of patients was 60 years (range, 20-84), and the majority were males (83%). Overall, the median number of prior therapies was 2, with 45% having received ≥3 lines of systemic therapy. Fifty-seven percent of patients had received prior platinum therapy and cetuximab. The ECOG performance status was primarily 1 (70%) and most patients had M1 disease (88%).

At the data cutoff in April 2016, 4% of patients had experienced a complete response (CR) and 14% had a partial response. Sixty percent of patients experienced a decrease in target lesion size, and 65% of responders remained on therapy. The median duration of response was not yet reached, with 71% of responses lasting 12 months.

In those with HPV-positive disease, the ORR was 24% and in those with HPV-negative disease the response rate was 16%. There were 4 CRs in each of the HPV groups. In patients treated with a prior platinum based agent (n = 174), the ORR was 17% (95% CI, 12-23), with a CR rate of 5%. In patients treated with prior cetuximab and platinum therapy (n = 110), the ORR was 15% (95% CI, 9-23) and the CR rate was 5%.

Median PFS was 2.0 months with pembrolizumab (95% CI, 1.9-2.1). The 6-month PFS rate was 25% and the 12-month rate was 17%. Median overall survival (OS) across evaluable patients was 8.0 months (95% CI, 6-10). The 6-month OS rate was 58%. At 12 months, 38% of patients remained alive.

"This dataset represents a longitudinal experience with greater than 16 months since the last patient was enrolled," said Mehra. "The survival was encouraging. Pembrolizumab was well-tolerated, and there were no treatment-related deaths."

In the KEYNOTE-055 study, 60% of the 171 patients enrolled experienced a treatment-related adverse event (AE) of any grade, which included fatigue (15%), hypothyroidism (8%), diarrhea (6%), decreased appetite (5%), nausea (5%), AST increase (5%), and rash (5%). Grade 3 to 5 AEs occurred in 12% of patients, and included anemia, AST increase, alkaline phosphatase increase, and hepatitis (in 1% of patients each). There was 1 treatment-related death from pneumonitis and 3 patients discontinued due to AEs.

In KEYNOTE-012, treatment-related adverse events AEs were experienced by 64% of the 192 patients enrolled. Grade 3/4 AEs occurred in 13% of patients. Overall, 6% of patients discontinued therapy due to treatment-related AEs. The most common treatment-related AEs were fatigue (22%), hypothyroidism (10%), rash (10%), pruritus (8%), decreased appetite (8%), pyrexia (6%), and nausea (6%). Treatment-related grade 3/4 AEs included ALT and AST increase, fatigue, decreased appetite, hyponatremia, pneumonitis, facial swelling, and hypothyroidism.

"There is a manageable safety profile with this drug that is consistent with prior experience with this agent," said Bauml. "There are ongoing phase III trials that are investigating the clinical benefit of pembrolizumab versus traditional cytotoxic chemotherapy."

In the phase III KEYNOTE-040 study, pembrolizumab is being compared with methotrexate, docetaxel, or cetuximab in 466 patients with recurrent or metastatic head and neck cancer. The primary completion date for this study is January 2017, and the study has fully accrued. (NCT02252042).

In a second phase III study, pembrolizumab is being explored as a frontline treatment for patients with recurrent or metastatic HNSCC. The PD-1 inhibitor is being compared with platinum-based chemotherapy plus 5-FU and cetuximab or in combination with platinum-based therapy and 5-FU. This study plans to enroll 780 patients, with an estimated primary completion date of November 2017 (NCT02358031).

Mehra R, Seiwert TY, Mahipal A, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): Pooled analyses after long-term follow-up in KEYNOTE-012.J Clin Oncol.2016;34 (suppl; abstr 6012).

Bauml J, Seiwert TY, Pfister DG, et al. Preliminary results from KEYNOTE-055: Pembrolizumab after platinum and cetuximab failure in head and neck squamous cell carcinoma (HNSCC).J Clin Oncol.2016;34 (suppl; abstr 6011).