Recurrent Squamous Cell Research Articles

Diagnostic dilemma: Overlapping clinical and radiologic features of osteoradionecrosis and recurrent head and neck squamous cell carcinoma.

e18072Background: Definitive chemoradiotherapy (CRT) is the standard of care treatment for locally advanced head and neck squamous cell carcinoma (SCC) but carries the risk of osteoradionecrosis (O...

Nivolumab (nivo) vs investigator’s choice (IC) in patients (pts) with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): Analysis of CheckMate 141 by age.

6028Background: Nivo is the only immunotherapy to significantly improve overall survival (OS) in pts with platinum (plt)–refractory R/M SCCHN. In the randomized, open-label, phase 3 CheckMate 141 t...

EP-1110: PD-L1 expression in recurrent head and neck squamous cell carcinoma

EP-1110: PD-L1 expression in recurrent head and neck squamous cell carcinoma

Prognostic Significance of the Prognostic Nutritional Index in Patients with Recurrent Esophageal Squamous Cell Carcinoma

ABSTRACTThe aim of this study was to evaluate the prognostic impact of the prognostic nutritional index (PNI) in patients with recurrent esophageal squamous cell carcinoma (ESCC). We retrospectively reviewed 76 ESCC patients who developed recurrence after curative subtotal esophagectomy at Nara Medical University Hospital between January 2001 and October 2016. The PNI at ESCC recurrence was calculated as 10 × serum albumin (g/dl) + 0.005 × total lymphocyte count (/mm3). The cutoff value of the PNI was set at 45. Multivariate analysis was performed to identify the prognostic factors. The mean PNI was 44.0 ± 5.8, and 42 (55.3%) patients had a PNI <45 at recurrence. The multivariate analysis identified a low PNI (P = 0.047), multiple recurrence sites (P = 0.002), and no treatment for recurrence (P = 0.034) as independent factors for a short survival time after recurrence. A low PNI was significantly associated with a high performance status score, high C-reactive protein level, and short duration of treatment for recurrence. In conclusion, the PNI at recurrence can predict the survival time in patients with recurrent ESCC.

The prognostic impact of neutrophil to lymphocyte ratio in patients with recurrent or metastatic esophageal squamous cell carcinoma receiving immune checkpoint inhibitors.

69 Background: The study explored the prognostic impacts of clinical parameters including neutrophil to lymphocyte ratio (NLR) in recurrent/metastatic esophageal squamous cell carcinoma (R/M ESCC) patients receiving anti-programmed cell death protein-1 (PD-1)/PD ligand 1 (PD-L1)-based therapy. Methods: Thirty-eight patients were enrolled. Tumor response evaluation was made according to Response Evaluation Criteria in Solid Tumours 1.1, and the clinical benefit response (CBR) was defined as complete response, partial response or stable disease at least 6 months. Clinical factors were analyzed for their impacts on patients' overall survival (OS) and progression-free survival (PFS). Formalin-fixed, paraffin-embedded tissues from 8 patients were analyzed by NanoString nCounter Human PanCancer Immune Profiling (NanoString Technologies, Seattle, WA, US). Results: Twenty-six recurrent and 12 de novo metastatic ESCC patients were enrolled. The response rate is 11.8%, and the CBR rate was 21.1%. The median PFS and OS are 2.7 and 5.5 months, respectively. The CBR group has lower blood white blood cells (WBC) ( P = 0.029), monocytes (p = 0.003), and NLR (p = 0.005). In univariate analysis, WBC, neutrophils, and NLR were statistically associated with PFS; performance status (PS), disease extent, albumin, WBC, neutrophils, and NLR were statistically associated with OS. In multivariate analysis, NLR (p = 0.007) was statistically associated with PFS; PS (p = 0.029) and NLR (p = 0.050) were statistically associated with OS. On examining the immune-related genes in ESCC tissues’ microenvironment, the ratios of mast cells, neutrophils, and macrophages relative to tumor-infiltrating lymphocytes (TILs) have significantly lower in the CBR group than in the non-CBR group. Conclusions: High NLR was associated with inferior prognosis in R/M ESCC patients receiving anti-PD-1/PD-L1-based therapy. The increased ratio of neutrophil to TILs in the ESCC tumor microenvironment of non-CBR patients may suggest a mechanistic role of neutrophils in affecting the efficacy of anti-PD-1/PD-L1 therapy. (Supported by the grant of MOST 105-2314-B-002 -186 -MY3)

Drug Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: Current Status and Future Plans

Drug Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: Current Status and Future Plans

Recurrent anal squamous cell carcinoma in a patient who refuses end colostomy: What to do?

Recurrent anal squamous cell carcinoma in a patient who refuses end colostomy: What to do?

Dramatic response of CTNNB1 and VEGFR-2 mutant temporal bone squamous cell carcinoma to bevacizumab in combination with pemetrexed.

High recurrence rates and poor survival rates for late stage/advanced temporal bone squamous cell carcinoma with the standard treatments continues to be a significant challenge to otolaryngologists. Targeted therapy for temporal bone squamous cell carcinoma after relapse has not been reported. Here we present a 58-year-old man who was diagnosed with recurrent temporal bone squamous cell carcinoma and treated with a regimen developed using whole exome sequencing. Somatic mutations in genes encoding catenin beta 1 and vascular endothelial growth factor receptor 2 were identified in the patient’s tumor sample compared to the normal tissue. The patient was then treated with Bevacizumab in combination with pemetrexed. After two weeks of treatment, tumor volume was reduced by 95% measured by MRI, and the Visual Analogue Scale headache scores went down from 10/10 to 2/10. Our results reveal novel gene mutations of temporal bone squamous cell carcinoma and demonstrate, for the first time, an effective targeted therapy for temporal bone squamous cell carcinoma. The successful treatment regimen of bevacizumab and pemetrexed may provide a new treatment option for treating recurrent temporal bone squamous cell carcinoma that fails to respond to conventional tumor resection, radiotherapy, and/or chemotherapy.

Macrophage type 2 differentiation in a patient with laryngeal squamous cell carcinoma and metastatic prostate adenocarcinoma to the cervical lymph nodes

BackgroundThe tumor microenvironment often polarizes infiltrating macrophages towards a type 2, or M2 phenotype, that is characterized by expression of various cysteine-rich, scavenger receptors, including CD163. The primary function of M2 macrophages is to facilitate wound healing. As such, they are capable of providing metabolic support to a growing tumor, neovascularization, as well as protection from cytotoxic T cells. The tumor microenvironment contains a milieu of secreted factors and vesicles, which in certain circumstances can gain access to lymphatic vessels that drain to local lymph nodes.Case presentationWe report a 59-year-old male with recurrent T4 squamous cell carcinoma (SCC) of the larynx with synchronous prostate adenocarcinoma confined to the prostate and regional pelvic lymph nodes, without metastatic disease. The patient underwent salvage total laryngectomy and bilateral neck dissection with final pathology revealing a recurrent moderately differentiated SCC involving the larynx as well as prostate cancer in draining level 4 cervical lymph nodes bilaterally. CD163 staining was performed on the primary tumor, a negative draining lymph node, and a level four lymph node with a focus of metastatic prostate cancer and compared to benign controls. The negative draining lymph node demonstrated a large CD163 population of cells as did the interface of the focus of prostate cancer and surrounding lymph node. CD163 levels were markedly increased in this patient compared to benign lymph node controls. The macrophage differentiation at the primary tumor in the larynx was strongly CD163 positive supporting an immune permissive environment for tumor growth and metastasis.ConclusionWe describe a unique case of solitary metastatic prostate cancer to cervical lymph nodes in the setting of a laryngeal cancer. These observations suggest that SCC-derived factors drive a tumor-supportive environment in draining lymph nodes dominated by an overwhelming number of CD163+, M2 macrophages. Lymph nodes that are ‘primed’ by SCC differentiation to M2 phenotype may be at higher risk of harboring metastases.

Abstract 2713: The mutational landscape of recurrent and nonrecurrent human papillomavirus-associated head and neck squamous cell carcinoma

Abstract Background: Despite the better prognosis for human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) compared to HPV-negative HNSCC, 10% to 25% of HPV-associated cases recur within 3 years of completing therapy. We sought to compare the mutational profiles of primary tumors among recurrent and non-recurrent HPV-associated HNSCC. We hypothesized that the mutational profile of primary tumors from recurrent cases resembles that of HPV-negative HNSCC. Methods: Sequencing was performed on DNA extracted from the primary tumors of p16-positive recurrent and non-recurrent HNSCC cases utilizing a high-coverage (&amp;gt;500X), CLIA-certified, 262 multiplexed gene sequencing panel (i.e., UW OncoPlex). Primary tumors from 11 recurrent and 13 non-recurrent cases were included in our sample. Mutational differences between the primary tumors of recurrent and non-recurrent tumors were evaluated. Results: 88% of patients were male with a mean (standard deviation; SD) age of 60.3 (11) years. Among the recurrent cases, 100% arose from the oropharynx. Among the non-recurrent cases, 77% arose from the oropharynx with the remainder originating from the oral cavity, nasal cavity, and larynx. 83% of patients presented with stage III or higher disease, and the median survival time was 21 months and 19 months among the recurrent and non-recurrent cases, respectively. The mean (SD) number of somatic nucleotide variants per tumor among the recurrent cases was 16.4 (12.2) compared to 4.3 (1.5) among non-recurrent cases (p &amp;lt; 0.05). The ratio of nonsynonymous to synonymous variants among primary tumors of recurrent cases was 2 vs 5 among the non-recurrent cases (p = 0.224). Among primary tumors of recurrent cases, 17% of variants included indels, splice site, and nonsense mutations vs 14% of variants among the non-recurrent cases. The mean (SD) number of tumor suppressor mutations per tumor was 1.2 (1.3) among recurrent cases vs 1.0 (1.0) among non-recurrent cases (p = 0.81). Interestingly, the mean (SD) number of mutations in DNA damage response (DDR) genes among the primary tumors of recurrent cases was 2.7 (2.4) compared to 0.7 (1.2) mutations per tumor among non-recurrent cases (p = 0.07). Conclusion: We observed a greater mutational burden among the primary tumors of recurrent HPV-associated HNSCC compared to non-recurrent HNSCC. Moreover, among the primary tumors of recurrent cases, there were more mutations in DNA damage response genes coupled and relatively fewer deleterious mutations compared to non-recurrent cases. Dysregulation of DDR genes may select for advantageous mutations via genomic instability. Alternatively, gain of function of DDR genes may promote treatment resistance. Future work aims to further characterize mutational differences between the primary tumors of HPV-associated recurrent and non-recurrent HNSCC and evaluate mechanisms promoting treatment resistance. Citation Format: Richard A. Harbison, Mark Kubik, Eric Q. Konnick, Seok-Geun Lee, Michael Kao, Michael Mason, Thomas Yu, Chang Xu, Daniel Faden, Colin C. Pritchard, Cristina P. Rodriguez, Chu Chen, Justin Guinney, Umamaheswar Duvvuri, Eduardo Mendez. The mutational landscape of recurrent and nonrecurrent human papillomavirus-associated head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2713. doi:10.1158/1538-7445.AM2017-2713

Abstract 5012: Mouse-human co-clinical trials demonstrate superior efficacy with combinational approach of BKM120 and erbitux over BKM120 monotherapy in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M-SCCHN)

Abstract Background: To investigate clinical activity, safety and biomarkers of a pan-PI3K inhibitor BKM120 in R/M-SCCHN and identify optimal combinational strategies by conducting mouse co-clinical trials mirroring the ongoing clinical study. Methods: Patients with R/M-SCCHN were eligible if they had progressed on platinum-based chemotherapy, and were treated with BKM120 100mg/day. The primary endpoint was disease control rate (DCR) at 8 weeks. Secondary endpoints included response rate (RR), progression-free survival rate (PFS), overall survival (OS) and safety. Patient-derived xenografts (PDXs) with genomic annotations were established directly from patients for evaluation of novel drug combinations and biomarkers. Based on the integrated clinical and preclinical data, study protocol had been revised to combine BKM120 and erbitux to explore whether erbitux increases the efficacy of BKM120 in R/M-SCCHN. Results: A total of 52 patients were enrolled. Patient characteristics included median age (55 years; range, 31-82); male (84.6%); ECOG performance status 0/1/2 (13.5%/73%/13.5%); locoregional/metastatic/both (30.8%/30.8%/38.4%); oral cavity/oropharynx/larynx primary (36.5%/30.8%/13.5%); prior chemotherapy regimens 1/≥2 (40%/60%). Seven patients were not evaluable due to rapid progression or withdrawal. DCR at 8 weeks was 60% (27/45) and RR was 2.2% (1/45) in BKM120 monotherapy. Median PFS and OS were 8.0 (95% CI, 5.3-9.5) and 30.7 weeks (95% CI, 11.8-26.6). After protocol revision, 11 patients were treated with BKM120 and erbitux after progression to BKM120. In combination phase, PR was observed in 18.1% (2/11) and SD was 45.5% (5/11) in patients who failed to BKM120. Toxicities were not increased in combination phase. In seven established PDXs, we tested BKM120 alone or in combination with erbitux. All PDXs showed strong resistance to single-agent BKM120, whereas three PDXs (3/7, 42.8%) demonstrated strong synergistic inhibition of tumor growth to combined BKM120 and erbitux, compared with single agent (vs. BKM120, P&amp;lt;0.01; vs. Erbitux, P&amp;lt;0.01), which resembled the responses of corresponding patients. We found several genetic alterations in F2 tumors including EGFR fusion, HRAS mutation (G12D), MYC amplification, KRAS mutation (G13D), and EGFR amplification. Interestingly, two PDXs with RAS mutations demonstrated synergistic effect of BKM120 and erbitux. Conclusions: Combining BKM120 and Erbitux would be effective treatment strategies with manageable toxicity in R/M-SCCHN based on strong rationale of co-clinical trial with PDXs (NCT01527877). Citation Format: Han Na Kang, Mi Ran Yun, Kyoung Ho Pyo, Myung-Ju Ahn, Jong-Mu Sun, Sun Min Lim, Soonmyung Paik, Byoung Chul Cho, Hye Ryun Kim. Mouse-human co-clinical trials demonstrate superior efficacy with combinational approach of BKM120 and erbitux over BKM120 monotherapy in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M-SCCHN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5012. doi:10.1158/1538-7445.AM2017-5012

Abstract 1681A: Overcoming pd1 targeting antibody resistance using combination strategies

Abstract PD-1 targeting antibodies (nivolumab, pembrolizumab) are now approved in various tumor types either as second line treatment (locally advanced or metastatic urothelial carcinoma, advanced renal cell carcinoma, recurrent or metastatic head and neck squamous cell carcinoma, classical Hodgkin lymphoma) or even as first line therapy (metastatic melanoma, metastatic non-small cell lung cancer). Despite an increase in response rate as well as survival, there is still issue with resistance to PD-1 targeting therapies. Selection biomarkers as well as response biomarkers are still under intensive research. In addition, combination strategies are needed to increase response rate and overcome resistance. Combination strategies were therefore tested in one well characterized syngeneic mouse model, i.e. EMT-6 breast carcinoma. The model is known to be highly sensitive to CTLA-4 targeting antibody (optimum tumor to control ratio (T/C) of 3%), a moderate responder to PD-1 targeting treatment (best T/C of 54%) and a well immune infiltrated tumor. Antibodies targeting co-stimulatory receptor such as OX40, GITR and 4-1BB as well as co-inhibitory receptor such as Tim3 were combined to anti-PD-1 antibody. In all cases, combination arm produces better therapeutic activity when compared to single treatment alone. Moreover, both strategies, meaning combination of two antibodies targeting co-inhibitory receptors (PD-1 + Tim3) and combination targeting one co-inhibitory (i.e. PD-1) and one co-stimulatory receptors (OX40, GITR or 4-1BB) worked. Detailed results will be presented including response rate, immune infiltrates and cytokines profiles in order to rationally choose the best therapeutic treatment. Citation Format: Jean-François Mirjolet, Maxime Ramelet, Damien France. Overcoming pd1 targeting antibody resistance using combination strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1681A. doi:10.1158/1538-7445.AM2017-1681A

Clonal repopulation dynamics in recurrent human papillomavirus-associated head and neck cancer.

e17517 Background: Despite the better prognosis for human papillomavirus (HPV)-associated head and neck cancer (HNC) relative to HPV-negative HNC, 10 to 25% of HPV-associated cases recur within 3 years of completing therapy. We sought to investigate clonal repopulation dynamics in recurrent HPV-related oropharyngeal squamous cell carcinoma (OPSCC). Methods: Deep sequencing ( &gt; 500X) using a CLIA-certified, targeted 262-gene multiplexed assay was performed on DNA extracted from 11 pairs of matched FFPE-preserved primary and subsequent recurrent p16-positive OPSCC samples including two pairs from the University of Washington and nine from the University of Pittsburgh. Results: 82% of patients were male with a median (IQR) age of 62 (15) years. Nine of eleven patients presented with advanced stage disease. Five were initially treated with surgery and concurrent chemoradiation, two with surgery, and four with concurrent chemoradiation. Median (IQR) time to recurrence was 10 (10.5) months. Four patients reported a history of tobacco use. The mean (SD) number of somatic nucleotide variants (SNVs) per tumor was 16.4 (12.2). 42% of SNVs occurred in the primary alone while 28% were unique to recurrences. 28% of SNVs were shared between primary-recurrent pairs. Three patients with distant or regional recurrences had different mutational profiles between the primary and recurrence suggesting repopulation by an early-appearing clone vs sampling error. One patient developed two local recurrences with conserved mutations in addition to de novo mutations in each subsequent recurrence suggesting repopulation by early and late evolving clones. Genes with a substantial functional impact that were frequently mutated in primary tumors include IDH2 and FBXW7. Recurrently mutated genes found in recurrent tumors include TET3, PIK3CA, STK11, and HDAC4. Conclusions: In thistargeted exome sequencing study of matched primary-recurrent OPSCC tumor pairs, we observed clonal repopulation with both transmitted and de novo mutations. Intriguingly, we noted a predilection for mutations involving genes regulating metabolism including IDH2 among primary tumors which has potential implications for precision medicine approaches.

Timing of percutaneous endoscopic gastrostomy (PEG) tube placement as supportive care in HNSCC patients (Pts) receiving concurrent chemoradiotherapy (CRT).

e17571 Background: Concurrent CRT with curative intent is the standard of care treatment for Pts with locally advanced or local recurrent head and neck squamous cell carcinoma (HNSCC). The CRT is associated with significant toxicities including nausea/vomiting, dysphagia and/or odynophagia, which prevent Pts from tolerating oral hydration and nutrition intakes. Treatment frequently leads to weight loss, renal injury and unexpected emergent care or hospitalizations along with therapy interruptions. This study is to determine the timing of PEG tube placement and its impact on the safety and tolerability from HNSCC patients receiving CRT. Methods: We retrospectively reviewed 413 electronic medical records (EMR), of which 335 of HNSCC Pts who had complete EMR during CRT period were included in this study. 127 of these 335 Pts (38%) required no PEG tube placement, 208 (62%) required PEG placement. The timing of PEG placement has been observed as two groups: 1) 109 Pts had PEG tube placement before initiation of CRT (Prophylactic Group PG); 2) 89 Pts had PEG tube during CRT period in reaction to a serious toxicity event (Reactive Group_RG). Logistic regressions were used to estimate the effect of PEG timing on Emergency Department (ED) visits, hospitalization, and experiencing treatment interruptions. Results: Our study showed that patients in PG demonstrated 43% less likely on their visiting ED or 42% less likely for hospitalization than Pts of RG with an odds ratio (OR) at 0.396 (95% CI: 0.165~0.952, p = 0.038) for PG over RG from toxicity-related therapy interruptions. Pts in PG also showed an OR at 0.40 from improving hypoalbuminemia over RG Pts (95% CI: 0.16~0.64, p = 0.001) which associated with 23% of chance of maintaining pre-CRT body mass index (BMI) for Pts in PG over those in RG. Conclusions: We observed the prophylactic PEG tube placement prevented unexpected ER visits and hospitalizations through reducing the risk of malnutrition and dehydration, which improved Pts in PG through the CRT with less therapy interruptions and preserved BMI, especially for those Pts of older age, pre-therapy dysphagia, hypoalbuminemia and receiving cisplatin in CRT.

Nivolumab (Nivo) vs investigator’s choice (IC) in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): Efficacy and safety in CheckMate 141 by prior cetuximab use.

6020 Background: In CheckMate 141, nivo resulted in significantly prolonged overall survival (OS), favorable safety, and stable quality of life vs IC in patients (pts) with platinum-refractory (PR) R/M SCCHN. Cetuximab, a formal trial stratification factor, permits exploratory subgroup assessment. Outcomes by prior cetuximab use are described. Methods: CheckMate 141 was a randomized, open-label, phase 3 trial (NCT02105636) in which pts (N = 361) with PR R/M SCCHN were randomized 2:1 and stratified by prior cetuximab use to nivo 3 mg/kg every 2 weeks or IC of methotrexate, docetaxel, or cetuximab. The primary endpoint was OS; additional endpoints were progression-free survival (PFS), objective response rate (ORR), and safety. A multivariate analysis will explore influence of additional factors. Results: Nivo improved OS vs IC regardless of prior cetuximab, and improvement was greater in pts without prior cetuximab (Table). Median OS was longer for nivo vs IC in pts with PD-L1 expression ≥ 1% regardless of prior cetuximab, and in pts with PD-L1 expression &lt; 1% without prior cetuximab. Among pts with PD-L1 expression ≥ 1%, ORR was higher with nivo vs IC with/without prior cetuximab. PFS was similar regardless of prior cetuximab. Grade 3–4 treatment-related adverse event rates for nivo vs IC were 11.7% vs 40.9% with prior cetuximab and 15.4% vs 26.7% without prior cetuximab. Conclusions: OS and ORR improved with nivo vs IC regardless of prior cetuximab use, and the magnitude of benefit was greater in pts without prior cetuximab exposure. These results support the use of nivo for R/M SCCHN regardless of prior cetuximab use. Clinical trial information: NCT02105636. [Table: see text]

Phase II study of afatinib in recurrent and/or metastatic esophageal squamous cell carcinoma (R/M ESCC) (KCSG HN14-18).

4051 Background: Afatinib, an irreversible pan-ErbB kinase inhibitor showed anti-tumor activity against esophageal cancer in phase I trial. In this multicenter, open-label, single arm phase II study, we aimed to evaluate the activity and safety of afatinib in R/M ESCC. Methods: Patients (pts) who had ECOG PS 0-2 and had progressed on platinum-based chemotherapy for R/M ESCC were enrolled. Pts were treated with afatinib 40mg/day until disease progression, unacceptable toxicity, or patient’s refusal. Primary endpoint was objective response rate (ORR) per RECIST 1.1. The estimated sample size was 49, using a two-stage minimax design to evaluate incremental response rate from 5 to 15%. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety profile. Additionally, we try to identify biomarker to predict efficacy of afatinib with target capture sequencing and gene expression profile as exploratory endpoints. Results: In a total of 49 enrolled pts (median age 60; range 44 -84), ORR and DCR were 14.3 % and 73.3%, respectively. With a median follow-up of 6.6 months, median PFS and OS was 3.4 months (95% CI 2.2-4.6) and 6.6 months (95% CI 5.2-8.0). Median treatment duration and duration of response were 2.8 months (range, 0.4-15.3) and 7.1 months (range, 2.5-13.9), respectively. Dose reduction and interruption occurred in 19 (38.8%) and 15 (30.6 %) pts. Treatment-related adverse events (TRAE) occurred in 33 pts (67.3%) with most common TRAEs being diarrhea (n=22, 44.9%) and acneiform rash (n=12, 24.5%). G3-4 TRAEs were rare, occurring in 7 pts (14.3 %). Conclusions: Afatinib demonstrated modest efficacy with manageable toxicity in platinum-resistant R/M ESCC patients. Given the modest response rate, identification of predictive biomarkers is essential for further clinical investigation of afatinib in R/M ESCC. Those biomarkers are being analyzed and will be presented in the conference (NCT02353936). Clinical trial information: NCT02353936. [Table: see text]

Phase III randomized trial of chemotherapy with or without bevacizumab (B) in patients (pts) with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Survival analysis of E1305, an ECOG-ACRIN Cancer Research Group trial.

6000 Background: The addition of B, an anti-VEGF monoclonal antibody, to chemotherapy has improved outcomes in several solid tumors. Pemetrexed plus B showed promising efficacy in R/M SCCHN (Argiris et al. JCO 2011). E1305 was designed to evaluate the addition of B to a platinum doublet in R/M SCCHN. Methods: B-eligible pts with performance status 0-1, not having received chemotherapy for R/M SCCHN (prior chemotherapy for locally advanced disease allowed ≥ 4 months) and without factors predisposing to bleeding (history of bleeding due to SCCHN, anticoagulation, central cavitary lung metastasis, carotid invasion) were randomized to: A) one of 4 regimens (investigator's choice) given every 3 weeks: A1, cisplatin (C) 100 mg/m2, 5-FU 1000 mg/m2/day x 4 days; A2, carboplatin (Cb) AUC 6, 5-FU 1000 mg/m2/day x 4 days; A3, C 75 mg/m2, docetaxel (D) 75 mg/m2; A4, Cb AUC 6, D 75 mg/m2, or B) the same regimen (B1, B2, B3, B4) plus B 15 mg/Kg IV, every 3 weeks, until progression. Chemotherapy could be stopped after 6 cycles after maximum response. All pts received prophylactic antibiotics. The primary endpoint was overall survival (OS). Control median OS of 8.5 months (mo) was projected; the addition of B was hypothesized to increase median OS to 11.5 mo with a hazard ratio (HR) of 0.74. Results: 403 pts were randomized (200 in arm A; 203 in arm B). Baseline characteristics were well balanced. 38% in arm A/42% in arm B had an oropharyngeal primary; 87% received C or Cb plus D. With a median follow-up of 23.1 mo, median OS was 11 mo in arm A and 12.6 mo in arm B; HR 0.84 (95% CI 0.67-1.05), p = 0.13. The 1-, 2-, 3-, and 4-year OS were 46% vs 51%, 18% vs 26%, 8% vs 16%, 6% vs 13%, in arm A vs B, respectively. Median PFS was 4.4 mo in arm A and 6.1 mo in arm B (HR 0.71, 95% CI 0.58-0.87; p = 0.0012). Objective response rate was 25% in arm A vs 36% in arm B (p = 0.013). Grade 3-5 bleeding occurred in 3.5% in arm A vs 7.7% in arm B (p = 0.08). Conclusions: B added to a standard platinum doublet improved response rate and PFS but not OS in first-line treatment of R/M SCCHN. The control arm in this study performed better than expected. Clinical trial information: NCT00588770.

A retrospective cohort study of PD-L1 expression in recurrent and/or metastatic squamous cell carcinoma of the head and neck (SUPREME-HN).

6040 Background: Patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) have a poor prognosis. Targeting the PD-1/PD-L1 axis has resulted in clinically meaningful antitumor activity and improved overall survival (OS) in R/M HNSCC patients. Tumoral PD-L1 expression correlates with response to blocking PD-1/PD-L1 antibodies. We investigated the prognostic value of PD-L1 expression in R/M HNSCC patients. Methods: Archival tumor samples from R/M HNSCC patients diagnosed between March 2011 and June 2015 at 12 institutions in 6 countries were stained for PD-L1 and clinic-demographic data were abstracted from medical records. Tumoral PD-L1 protein expression was assessed with the validated Ventana SP263 assay and scored as high (≥25% of tumor cells [TC]) or low/negative ( &lt; 25% of TC). Extracted data included demographic and tumor characteristics, treatment patterns, and clinical outcomes. Descriptive analyses were conducted and survival estimated by the Kaplan-Meier method. OS was defined from the diagnosis index date of R/M disease to time of death. Results: As ofSeptember 26, 2016 (interim analysis), data were available for 143 patients of whom 138 were eligible for analysis. Median age was 62.0 years (range, 28.0−88.0), 76.8% were male, and 84.0% were white. PD-L1 protein expression was high in 43 patients (31.2%), low/negative in 91 (65.9%), and unknown in 4 (2.9%). Median OS (8.2 vs. 8.8 months; P = 0.94) and progression-free survival (PFS) from the start of first-line (6.0 vs. 5.6 months; P = 0.29) or second-line therapy (7.1 vs. 1.8 months; P = 0.11) did not significantly differ between PD-L1 high and low/negative patients, respectively. There were no significant differences in OS based on PD-L1 status within subgroups defined by age, race, tobacco or alcohol use, primary tumor site, performance status, metastatic disease at diagnosis, or treatment with platinum-based chemotherapy. Conclusions: Interim analyses indicate that PD-L1 status is not associated with OS or PFS in R/M HNSCC patients.

Randomized, double-blind, placebo-controlled, phase II trial of first-line platinum/docetaxel with or without erlotinib (E) in patients (pts) with recurrent and/or metastatic (R/M) head and neck squamous cell carcinomas (HNSCCs).

6017 Background: In a single-arm, phase 2 study, we previously demonstrated that in pts with R/M HNSCC, cisplatin, docetaxel and E improved progression-free survival (PFS) compared to historical data (Kim et al., ASCO 2006). Herein, we evaluated this regimen in a single center, randomized, phase 2 trial. Methods: Pts with R/M HNSCC, with a performance status (PS) 0-2, were randomized (1:1) to receive up to 6 cycles of first-line chemotherapy with cisplatin 75 mg/m2 (or carboplatin AUC 6) and docetaxel 75 mg/m2 i.v. on day 1 every 21 days, plus placebo (P) vs. E 150 mg p.o. daily, followed by maintenance P or E until disease progression. The primary endpoint was PFS. With 120 pts, the study had 80% power to detect an improvement in median PFS from 3.0 to 4.9 months with a two-sided type I error rate of 0.1. Results: From 05/2010 to 07/2015, 120 pts were randomized to the P (N = 60) or E (N = 60) groups. All pts but one initiated treatment and were eligible for evaluation of the primary endpoint – 92 males; median age 62 years; 52 oropharynx, 40 oral cavity, 19 larynx, 8 hypopharynx cancer pts; 86 current/former smokers; 43 with recurrence within 6 months of completion of local treatment; 27 with prior exposure to EGFR inhibitors. Median PFS was 4.4 vs. 6.1 months for the P and E groups, respectively (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.42-0.95 months, p = 0.026). Response rates were 44% vs. 56% for P vs. E (p = 0.21). Median overall survival (OS) for P- and E-treated pts was 13.7 vs. 17.0 months (HR = 0.67, 95% CI 0.43-1.04, p = 0.07). Benefits from E on PFS and OS were more pronounced in pts with oropharyngeal tumors (p≤0.05 for interaction). In the E group, first-cycle rash grade 2-4 (34% pts) was associated with longer OS (HR = 0.40, p = 0.02). E-treated pts experienced a higher incidence of grade 3-4 adverse events (33.9 vs. 53.3%), including diarrhea (3 vs.17%), dehydration (5 vs. 15%), nausea (5 vs. 14%), rash (0 vs. 12%). Conclusions: This study met its primary endpoint. Addition of E to first-line platinum/docetaxel improved PFS and OS. This regimen may warrant further evaluation in randomized, phase 3 trials. Clinical trial information: NCT01064479.

Cost-effectiveness of nivolumab for treatment of platinum-resistant recurrent or metastatic squamous cell carcinoma of the head and neck.

6026 Background: The Checkmate 141 randomized trial found that patients with platinum-refractory, recurrent or metastatic (R/M) squamous-cell carcinoma of the head and neck (SCCHN) treated with nivolumab had significantly longer overall survival than those treated with standard, single-agent therapy. However, nivolumab is more expensive than standard treatment. We conducted a cost-effectiveness analysis of nivolumab for the treatment of R/M SCCHN. Methods: We constructed a Markov model to simulate treatment with nivolumab or other single-agent therapy (docetaxel, cetuximab, or methotrexate) for patients with R/M SCCHN. Transition probabilities including disease progression, survival, and toxicity were derived from clinical trial data, while costs (in 2016 US dollars) and health utilities were estimated from the literature. Incremental cost-effectiveness ratios (ICERs), expressed as dollar per quality-adjusted life-year (QALY), were calculated with values less than $100,000/QALY considered cost-effective from a healthcare payer perspective. We conducted one-way and probabilistic sensitivity analyses to examine model uncertainty. Results: Our base-case model found that treatment with nivolumab increased overall cost by $59,000 and improved effectiveness by 0.2443 QALYs compared to single-agent therapy, leading to an ICER of $241,100/QALY. In sensitivity analyses, the model was most sensitive to the cost of nivolumab and assumptions about survival. Nivolumab would become cost-effective if the cost per cycle decreased from $13,432 to $5,716. If we assumed that all patients alive at the end of the Checkmate 141 trial were cured of their disease then nivolumab was still not considered cost-effective (ICER $160,000/QALY). Probabilistic sensitivity analysis also demonstrated relative stability of the cost-effectiveness model and found that treatment with nivolumab was cost-effective 0% of the time at a willingness-to-pay threshold of $100,000/QALY. Conclusions: While nivolumab significantly improves overall survival, at the current cost it would not be considered a cost-effective treatment option for patients with R/M SCCHN.