Response rates and survival to systemic therapy after immune checkpoint inhibitor failure in recurrent/metastatic head and neck squamous cell carcinoma

Highlights

• In head and neck cancer, response rate to systemic therapy after anti-PD1 was 42%.

• The median overall survival to systemic therapy after anti-PD1 was 8.4 months.

• The activity compares favorably to historical controls of second-line therapy.

• Studies on the optimal sequencing of chemotherapy, EGFR, and PD1 inhibitors are needed.

Abstract

Objectives

Prior reports have demonstrated a potential enhancement in overall response rate (ORR) to chemotherapy after exposure to immunotherapy. The goal of this study was to evaluate the ORR and survival to chemotherapy and/or targeted therapy in head and neck squamous cell carcinoma (HNSCC) patients who progressed on immune checkpoint inhibitors (ICI).

Materials and Methods

We retrospectively collected clinical and pathologic data from patients with recurrent/metastatic HNSCC who progressed on ICI and subsequently received chemotherapy or targeted therapy. ORR was assessed by RECIST version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.

Results

A total of 43 patients met criteria for inclusion. The majority were male (91%) and former smokers (60%). Most patients received ICI as first-line (58.14%); the vast majority was platinum exposed (90.7%). The ORR to ICI was 21%. The ORR to systemic therapy before ICI was 47%, and the ORR after ICI failure was 42%. After progression on ICI, the median PFS and OS on the subsequent line of therapy were 4.2 and 8.4 months respectively.

Conclusion

In our cohort of recurrent/metastatic HNSCC patients, the ORR and OS to systemic therapy after progression on ICI were higher than historical controls for second-line or beyond. Further investigations are warranted to better characterize optimal sequencing and combination strategies.

Introduction

Squamous cell carcinoma of the head and neck (HNSCC) is a global health issue, responsible for more than 600,000 cases and 350,000 deaths annually [1], [2]. The overall incidence of HNSCC has been declining over the past decades; however, an increase in specific sites (i.e., oral and oropharyngeal) has been described in recent years, more pronounced in young adults as a result of HPV infection [3], [4], [5]. The majority of HNSCC patients present with locoregionally-advanced disease; nonetheless, most patients will recur despite combined-modality definitive-intent treatment and will succumb as a consequence of disease, highlighting the need for strategies to improve patient outcomes [6], [7].

Platinum-based chemotherapy plus cetuximab was until very recently the standard first-line therapy for patients with recurrent/metastatic HNSCC, achieving median overall survival (OS) of 8–10 months [8], [9]. After progression, single-agent treatment consisting of chemotherapy or the epidermal growth factor receptor (EGFR) inhibitor cetuximab led to overall response rates (ORR) of 5–15% and median OS of around 6 months [9], [10]. Recently, the development of antibodies blocking the programmed death-1 (PD-1) receptor has changed the treatment paradigm for this patient population [11]. Nivolumab and pembrolizumab have been approved by the Food and Drug Administration (FDA) for recurrent/metastatic HNSCC patients previously treated with a platinum-containing regimen based on improved OS compared to single-agent cytotoxic therapy or cetuximab [10], [11], [12], [13]. These agents have demonstrated an ORR of approximately 15%, with median PFS of 2 months and OS of 7.5–8.5 months [10], [12]. While response rate is not high, they are notably durable and patients experience a better quality of live; nevertheless, most patients will not respond and all will eventually progress on ICI, and those with a good performance status, will ultimately receive chemotherapy and/or cetuximab as the next line of treatment.

Improvement in response to chemotherapy has been described following exposure to immunotherapy in multiple cancers. Initially, augmented responses to cytotoxic treatment were noted following vaccine-based immunotherapy in extensive-stage small cell lung cancer and glioblastoma multiforme [14], [15], [16]. Recently, emerging data suggest enhanced responses to chemotherapy following progression on ICI in non-small cell lung cancer (NSCLC) [17], [18], [19], [20]. For illustration, data from our group published by Schvartsman et al. analyzed a cohort of 28 NSCLC patients receiving single-agent chemotherapy following ICI; the confirmed ORR was 29%, which is significantly higher than the 7% ORR to docetaxel in patients without prior exposure to ICI [18], [21]. In the current ever-changing dynamic landscape of oncologic treatments, these data are valuable and can shed light on optimal sequencing strategies.

To the best of our knowledge, however, there is limited data analyzing the outcomes of patients receiving chemotherapy after exposure to ICI in patients with incurable HNSCC [22]. The goal of this study is to evaluate response rates and survival to systemic therapy in second-line or beyond in HNSCC patients who previously progressed on ICI, specifically anti-PD1.