Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase 2 Trial

Abstract

Background: Pembrolizumab improved survival of patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this phase 2 trial were to determine if pembrolizumab administered to patients with resectable locally advanced, human papillomavirus (HPV)-unrelated HNSCC would be safe, result in pathologic tumor response (pTR), and lower the relapse rate. Methods: Neoadjuvant pembrolizumab (200 mg) was administered 2-3 weeks before surgery. Resection of the primary tumor and involved/at-risk nodes was performed. Post-operative (chemo) radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) were to receive adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10-49%), and pTR-2 (≥50%). Co-primary endpoints were pTR-2 among all patients, and one-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 expression and T-cell infiltration with pTR were assessed, and tumor clonal dynamics were evaluated. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov(NCT02296684), and is ongoing but closed to accrual. Findings: Between June 30, 2015, and March 30, 2018, 36 patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). pTR >10% correlated with baseline tumor PD-L1 expression, immune infiltrate, and IFN-γ pathway activity. Matched sample analysis showed compensatory upregulation of multiple immune inhibitory checkpoints in patients with pTR-0, and confirmed that clonal loss occurred in some patients. The one-year relapse rate among the eighteen patients with high-risk pathology was 16.7% (95%CI: 3.6-41.4%). Conclusions: Among patients with locally advanced, HPV-unrelated HNSCC, neoadjuvant pembrolizumab was safe, and resulted in pTR-1 or pTR-2 in 44% of patients. The one-year relapse rate in patients with high-risk-pathology was lower than historical.

Antitumor immune effects of preoperative sitravatinib and nivolumab in oral cavity cancer: SNOW window-of-opportunity study

“…To date, two phase 2 studies evaluating neoadjuvant anti-PD-1 agents have shown antitumor activity in patients with resectable HNSCC, with clinical to pathological downstaging and PTR rates (defined as a reduction of viable tumor > 50%) ranging from 19% and 22% with one dose of pembrolizumab, to 69% and 40% with two doses of nivolumab, respectively. 18 32 Similar to what occurred in the recurrent/metastatic setting, PD-L1 expression seemed to enrich for responses in the pembrolizumab study, although this correlation was not observed in the nivolumab study. Anti-PD-1/PD-L1-based combinations with other immuno-oncology agents, targeted therapies or chemotherapy are currently being evaluated in the neoadjuvant space of this disease to increase tumor responses.…”

“…Neoadjuvant anti-PD-1 therapy in patients with resectable HNSCC has been investigated in small studies showing promising antitumor activity with an overall safe toxicity profile, leading to ongoing large randomized trials (ie, NCT03765918). 17 18 However, about half of these patients did not respond to neoadjuvant anti-PD-1 therapy, thus, combination strategies using other immuno-oncology agents or targeted therapies such as antiangiogenic agents are under evaluation (NCT04199104 and NCT04675294). 19 20 MET, AXL and VEGF overexpression is associated with early nodal and distant metastasis as well as with mechanisms of resistance to radiation and systemic therapies in HNSCC.…”

Importance of the PD-1/PD-L1 Axis for Malignant Transformation and Risk Assessment of Oral Leukoplakia

“…In some of these patients PD-1 blocking leads to long lasting responses [2]. Recently, the clinical use of checkpoint inhibitors is shifting towards early stages of OSCC treatment with the first results of successful neoadjuvant PD-1 inhibition being published [3,4] and currently evaluated in a large prospective study (KEYNOTE-689 study; NCT03765918).…”

Hypothyroidism in Head and Neck Squamous Cell Carcinoma Patients Receiving Radiotherapy With or Without Immune Checkpoint Inhibitors

“…It can be inferred that a majority of the risk in these patients is derived from radiation treatment effect. Similarly, in a recently published phase 2 study of neo‐adjuvant/adjuvant pembrolizumab in HNSCC treated sequentially with RT followed by PD‐1, the rate of new hypothyroidism was 33% 24 . The development of anti‐thyroid antibodies may have provided some interesting insight as to the mechanisms of thyroid toxicity in RT + PD‐1 treated patients, but were rarely available in our patient cohort limiting this analysis.…”