Laura Q.M. Chow, MD
WITH THE RECENT efficacy findings, improvements in survival, and resultant U.S. Food and Drug Administration (FDA) approvals of programmed cell death protein 1 (PD-1) immune checkpoint inhibitors across multiple solid tumor indications, the publication of yet another positive trial adds to the literature without any new surprises. The phase II KEYNOTE-055 trial—reported by Bauml et al and reviewed in this issue of The ASCO Post—confirms the activity of the anti–PD-1 antibody pembrolizumab (Keytruda) in previously platinum-and cetuximab (Erbitux)-treated recurrent or metastatic squamous cell carcinoma of the head and neck in the setting of second-line therapy and beyond.1 Riding on the coattails of the recent FDA approvals of pembrolizumab and nivolumab (Opdivo) in platinum-pretreated squamous cell carcinoma of the head and neck, this trial confirms the activity of anti–PD-1 blockade in this disease in heavily pretreated patients, with durable responses, tolerability, and survival benefits.
Accelerated FDA approval of pembrolizumab in platinum-pretreated head and neck cancer was granted based on data from the phase I KEYNOTE-012 study, which included 174 patients with recurrent and/ or metastatic head and neck cancer who had disease progression on or after platinum-containing chemotherapy.2-5 The study showed a favorable durable overall response rate of 16% (95% confidence interval [CI] = 11%–22%) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (as determined by an independent review committee with central imaging review), with a median duration of response that was not reached (range = 2.4–27.7 months, with responses ongoing). The approval data included the large expansion of 132 patients treated with pembrolizumab at 200 mg intravenously every 3 weeks that demonstrated an overall response rate of 18% (95% CI = 12%–26%) by central imaging review, with the median duration of response (range = 2+ to 11+ months) not reached at the time of publication.3
Although the full long-term efficacy and toxicity data in both the preliminary and expansion cohorts of KEYNOTE-012 are pending publication, the last update presented by Dr. Ranee Mehra at the 2016 ASCO Annual Meeting showed that at long-term follow-up of the 192 patients with recurrent and/or metastatic head and neck cancer, the overall response rate was 17.7% (95% CI = 12.6%–23.9%), with 7 complete responses and 27 partial responses.4 Median follow-up duration in responders was 12.5 months (range = 8.4–24.4 months), and at the data cutoff, the median duration of response was not reached, with a range from 1.8+ to 21.8+ months, and responses were ongoing in 22 patients (76%). Still pending are the confirmatory results of the phase III multicenter KEYNOTE-040 study of pembrolizumab vs investigator’s choice of standard-of-care therapy in recurrent/metastatic head and neck cancer patients who failed to response to prior platinum therapy.
The FDA approval of nivolumab was based on results of the phase III multicenter CheckMate 141 study, which randomized 361 patients in a 2:1 ratio to nivolumab vs investigator’s choice of standard single-agent treatment (methotrexate, docetaxel, or cetuximab) for recurrent/ metastatic squamous cell carcinoma of the head and neck in platinum-pretreated patients.6 This study demonstrated a response rate of 13.3% (95% CI = 9.3%–18.3%), including 6 complete responses and 26 partial responses for nivolumab, vs 5.8% (95% CI = 2.4%–11.6%) in the standard-therapy group, an improved 6-month progression-free survival of 19.7% (95% CI = 14.6%–25.4%) vs 9.9% (95% CI = 5.0%–16.9%), and a longer median overall survival of 7.5 months (95% CI = 5.5–9.1 months) vs 5.1 months (95% CI = 4.0–6.0 months).6
THE SINGLE-ARM phase II KEYNOTE-055 study assessed 171 head and neck cancer patients with disease progression within 6 months of platinum and cetuximab treatment before receiving pembrolizumab at a flat dose of 200 mg every 3 weeks. The incidence of treatment-related adverse events, with 15% experiencing grade ≥ 3 toxicity in this heavily pretreated population, appeared in line with reported toxicity data for pembrolizumab, nivolumab, and other PD-1 checkpoint inhibitors. Furthermore, the overall response rate of 16% (95% CI = 11%– 23%), with a median duration of response of 8 months (range = 2+ to 12+ months) and 75% of responses still ongoing at the time of analysis, appeared promising and demonstrated efficacy consistent with that reported in the KEYNOTE-012 and CheckMate 141 studies.
“[The KEYNOTE-055 trial] confirms the activity of anti–PD-1 blockade in squamous cell carcinoma of the head and neck in heavily pretreated patients, with durable responses, tolerability, and survival benefits.”— Laura Q.M. Chow, MD
The KEYNOTE-055 trial sought to capture a more heavily pretreated population, for which no effective standard therapy exists, and successfully demonstrated pembrolizumab’s efficacy without increased toxicity. Among the 171 patients treated with prior cisplatin and cetuximab, 75% of patients had received two or more prior lines of therapy for recurrent/metastatic disease.
In reality, the patients in this trial were not entirely dissimilar from those in the KEYNOTE-012 and CheckMate 141 trials. Most head and neck cancer patients have been previously exposed to cisplatin or cetuximab with radiation in the locally advanced definitive or adjuvant setting. Furthermore, since the first-line standard of care for recurrent/metastatic squamous cell carcinoma of the head and neck involves the combination of cetuximab, platinum, and fluorouracil (the EXTREME regimen), the majority of patients in the studies were refractory to both agents.7
The phase I KEYNOTE-012 eligibility criteria did not limit the number of prior therapies, and chemotherapy-naive patients were allowed. In the expansion cohort of 132 patients, 40% had received previous adjuvant or neoadjuvant therapy, 18% had not received any therapy in the recurrent/metastatic setting, and 25% had received one line of therapy, with the majority of patients (57%) having received two or more lines of therapy. Interestingly, 222 (61.5%) of the 361 platinum-refractory patients in the CheckMate 141 study had also previously received cetuximab, and 197 (54.6%) had received two or more lines of therapy.
HPV Infection and PD-L1 Expression
THE ASSOCIATION of human papillomavirus (HPV) infection with the response to PD-1 checkpoint inhibition in squamous cell carcinoma of the head and neck is still not clear. Efficacy in KEYNOTE-055 appeared to be similar in patients who were positive for p16 status or HPV infection vs those who were negative. These results were in keeping with the similar overall survival benefit in the much larger CheckMate 141 study observed for nivolumab in both HPV-positive and HPV-negative patients compared to standard therapy.
On the other hand, in the expansion cohort of KEYNOTE-012, there was a suggestion of a higher response rate of 32% in HPV-associated cancers compared with 16% in patients without HPV-associated disease.3 However, limitations for these findings exist, since the number of HPV-positive patients was small, there was a lack of consistent method for HPV testing, and the definition of HPV positivity outside the oropharynx was inconsistent.
Early-phase clinical trials first established the activity of PD-1 checkpoint inhibitors in heavily pretreated patients.8,9 The lines of prior therapy did not appear to adversely affect the efficacy or tolerability of these agents. In fact, in advanced non–small cell lung cancer (NSCLC) patients, there is a suggestion that the immune environment in treatment-naive patients may differ from that in patients who are previously treated with chemotherapy and other systemic therapies. Among NSCLC patients with high levels of programmed cell death ligand 1 (PD-L1) expression, it has been suggested that previously untreated patients may have greater responses to pembrolizumab than those who are heavily pretreated.10-12 However, whether this hypothesis can be fully substantiated or extrapolated to the head and neck cancer population is unknown.
Need for Biomarkers
THE MOVEMENT of PD-1 checkpoint blockade into earlier lines of therapy requires better biomarkers of response. Although high expression of PD-L1 (≥ 50%) has been an effective biomarker moving pembrolizumab into use in the first-line NSCLC setting, the utility of PD-L1 as a predictive biomarker has been less clear for head and neck cancer.
PD-L1 expression has been assessed in multiple tumor types as a predictor of response to PD-1 checkpoint blockade. However, its utility as a biomarker, the level of expression, the need for incorporation of immune cells, the differences in antibody assays, the timing of the biopsy, the heterogeneity of expression, and the changes in expression with therapy have been topics of significant controversy and uncertainty.
Biomarker data in KEYNOTE-012 demonstrated that the incorporation of tumor-infiltrating immune cells into PD-L1–expression analyses of tumor cells improved the ability to predict response to pembrolizumab.13 PD-L2 as a biomarker and the interferon-gamma gene signature also predicted response to pembrolizumab in squamous cell carcinoma of the head and neck.14
KEYNOTE-055 assessed PD-L1 expression incorporating both immune and tumor cells (combined positive score, or CPS) using a cutoff of 1% and found a response rate of 18% (95% CI = 12%–25%) in those who were PD-L1–positive (CPS ≥ 1%) and 12% (95% CI = 2%–30%) in those who were PD-L1–negative (CPS < 1%). Progression-free survival and overall survival were similar in PD-L1–positive and PD-L1–negative patients.
In CheckMate 141, there was a suggestion of slightly improved overall survival for patients with PD-L1 expression ≥ 1% on tumor cells vs those with PD-L1 < 1% via a different assay. However, beyond this cutoff, higher levels of PD-L1 expression did not strongly correlate with improved survival.
“Much more work needs to be done to find effective biomarkers to move PD-1 checkpoint blockade into earlier lines of therapy—including the neoadjuvant and adjuvant settings—in head and neck cancer.— Laura Q.M. Chow, MD
From all three of these studies, despite the differences in assays and cell type, anti–PD-1 therapy appears to have better efficacy and potentially better survival in patients with PD-L1–positive disease. Yet, it is clear that PD-L1–negative patients still responded to anti–PD-1 therapy and also had improvements in survival. Therefore, negative PD-L1 status should not preclude therapy with anti–PD-1 antibodies. Further work is definitely still needed to assess the role of PD-L1 and other biomarkers to predict response to PD-1 checkpoint blockade.
KEYNOTE-055 is not groundbreaking in terms of new information, but it confirms the activity of pembrolizumab in squamous cell carcinoma of the head and neck and adds to the available knowledge and literature. Since there is a paucity of any effective therapeutic options available to the platinum- and cetuximab-refractory population, anti– PD-1 antibody therapy is an attractive therapeutic option in this area of high unmet need.
Nevertheless, much more work needs to be done to find effective biomarkers to move PD-1 checkpoint blockade into earlier lines of therapy—including the neoadjuvant and adjuvant settings—in head and neck cancer. Moreover, since response rates to single-agent PD-1 checkpoint blockade are still dismally low, greater efforts are needed to find combination therapies that induce and enhance response, increase the achievement of complete response, and improve the duration of response. In the era after anti–PD-1 antibody approval in squamous cell carcinoma of the head and neck, there is a large new unmet need for the majority of patients who are refractory to or have had disease progression on immunotherapy, and continued strong efforts are needed to improve survival in these patients. ■
DISCLOSURE: Dr. Chow has been a consultant or advisor for Merck and Bristol-Myers Squibb, with honoraria going to her institution.
1. Bauml J, Seiwert TY, Pfister DG, et al: Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: Results from a single-arm, phase II study. J Clin Oncol 35:1542-1549, 2017.
2. U.S. Food and Drug Administration: Pembrolizumab (Keytruda). Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm515627.htm. Accessed July 10, 2017.
3. Chow LQ, Haddad R, Gupta S, et al: Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: Results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol 34:3838-3845, 2016.
4. Mehra R, Seiwert TY, Mahipal A, 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. 2016 ASCO Annual Meeting. Abstract 6012. Presented June 6, 2016.
5. Seiwert TY, Burtness B, Mehra R, et al: Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): An open-label, multicentre, phase 1b trial. Lancet Oncol 17:956-965, 2016.
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12. Hui R, Garon EB, Goldman JW, et al: Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: A phase 1 trial. Ann Oncol 28:874-881, 2017.
13. Chow LQ, Mehra R, Haddad RI, et al: Biomarkers and response to pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma. 2016 ASCO Annual Meeting. Abstract 6010. Presented June 6, 2016.
14. Yearley JH, Gibson C, Yu N, et al: PD-L2 expression in human tumors: Relevance to anti-PD-1 therapy in cancer. Clin Cancer Res 23:3158-3167, 2017.