Jessica Ley

Cisplatin versus Cetuximab Given Concurrently with Definitive Radiation Therapy for Locally Advanced Head and Neck Squamous Cell Carcinoma

Objective: Whether or not cisplatin and cetuximab are similarly effective in improving outcomes when added to radiation therapy (RT) in squamous cell carcinoma of the head and neck is unknown. Methods: Retrospective analysis was performed of patients treated with definitive RT and cisplatin (n = 18) or cetuximab (n = 29). Results: T and N classifications, stage, human papillomavirus status and smoking history were balanced in the two groups; however, patients in the cisplatin group were younger and had a better performance status. Delivery of RT was similar between the two groups. Median follow-up was 23 (4-64) months. Disease-specific survival (DSS) at 3 years was 83% in the cisplatin group and 31% in the cetuximab group. Recurrent disease was more common in the cetuximab group compared with the cisplatin group (17 vs. 4 patients). Propensity score analysis to adjust for differences in patient characteristics which influenced treatment selection showed that DSS was indeed longer with cisplatin than with cetuximab (DSS hazard ratio 0.15, confidence interval 0.033, 0.66; p = 0.012). Conclusions: DSS was superior in the patients given cisplatin with definitive RT compared to cetuximab with definitive RT due to a lower risk of recurrent disease in the cisplatin group. These observations could not be explained by differences between the two groups in the patient and tumor characteristics or in treatment delivery.

A phase 2 trial of induction nab‐paclitaxel and cetuximab given with cisplatin and 5‐fluorouracil followed by concurrent cisplatin and radiation for locally advanced squamous cell carcinoma of the head and neck

Complete response (CR) at the primary tumor site as assessed by clinical examination following induction chemotherapy with PF (cisplatin and 5‐fluorouracil [5‐FU]) is a favorable predictive factor for overall survival and disease control in patients with locally advanced squamous cell carcinoma of the head and neck. In most series, the rate of CR at the primary site after induction PF was 20% to 30%. This study evaluated the efficacy and feasibility of induction nab‐paclitaxel and cetuximab given with PF (ACPF) followed by definitive chemoradiation (CRT) in a phase 2 trial.

Phase I trial of palbociclib, a selective cyclin dependent kinase 4/6 inhibitor, in combination with cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma.

OBJECTIVES To test the safety of the CDK4/6 inhibitor palbociclib with cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS A phase I trial using 3+3 design was performed to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of palbociclib with standard dose weekly cetuximab. Palbociclib was administered orally days 1-21 every 28days: dose level 1 (100mg/d) and 2 (125mg/d; approved monotherapy dose). Pharmacokinetic assessments were performed on cycle 2, day 15. Cyclin D1, p16(INK4a), and Rb protein expression were measured on pre-treatment tumor. Tumor response was assessed using RECIST1.1. RESULTS Nine patients (five p16(INK4a) negative; four positive) were enrolled across dose levels 1 (n=3) and 2 (n=6) and none experienced a DLT. A MTD of palbociclib was not reached. Myelosuppression was the most common adverse event. Six of nine patients had cetuximab-resistant and 4/9 had platin-resistant disease. Disease control (DC) occurred in 89%, including partial response (PR) in two (22%) and stable disease in six (67%) patients. PRs occurred in p16(INK4a) negative HNSCC. Five patients (56%) had measurable decreases in tumor target lesions. In cetuximab-resistant HNSCC, best tumor response was PR in 1 and DC in 5 and median TTP was 112days (range: 28-168). In platin-resistant HNSCC, best tumor response: PR in 1, DC in 3 and median TTP was 112days (range: 28-112). The Cmax and AUC0-24h appeared comparable in patients receiving 125 vs 100mg dose of palbociclib. CONCLUSION This trial, the first to evaluate a CDK4/6 inhibitor in HNSCC, determined that palbociclib 125mg/day on days 1-21 every 28days with cetuximab was safe. Tumor responses were observed, even in cetuximab- or platin-resistant disease.

Nab-paclitaxel-based compared to docetaxel-based induction chemotherapy regimens for locally advanced squamous cell carcinoma of the head and neck

We previously reported that nab‐paclitaxel‐based induction chemotherapy (IC) and concurrent chemoradiotherapy resulted in low relapse rates (13%) and excellent survival in head and neck squamous cell carcinoma (HNSCC). We compare the disease‐specific survival (DSS) and overall survival (OS) between patients given nab‐paclitaxel, cisplatin, and fluorouracil with cetuximab (APF‐C) and historical controls given docetaxel, cisplatin, and fluorouracil with cetuximab (TPF‐C). Patients with locally advanced HNSCC were treated with APF‐C (n = 30) or TPF‐C (n = 38). After 3 cycles of IC, patients were scheduled to receive cisplatin concurrent with definitive radiotherapy. T and N classification and smoking history were similar between the two groups and within p16‐positive and p16‐negative subsets. The median duration of follow‐up for living patients in the APF‐C group was 43.5 (range: 30–58) months versus 52 (range: 13–84) months for TPF‐C. The 2‐year DSS for patients treated with APF‐C was 96.7% [95% Confidence Interval (CI): 85.2%, 99.8%] and with TPF‐C was 77.6% (CI: 62.6%, 89.7%) (P = 0.0004). Disease progression that resulted in death was more frequent in the TPF‐C group (39%) compared with the APF‐C group (3%) when adjusted for competing risks of death from other causes (Grays test, P = 0.0004). In p16 positive OPSCC, the 2‐year DSS for APF‐C was 100% and for TPF‐C was 74.6% (CI: 47.4%, 94.6%) (P = 0.0019) and the 2‐year OS for APF‐C was 94.1% (CI: 65.0%, 99.2%) and for TPF‐C was 74.6% (CI: 39.8%, 91.1%) (P = 0.013). In p16 negative HNSCC, the 2‐year DSS for APF‐C was 91.7% (CI: 67.6%, 99.6%) and for TPF‐C was 82.6% (CI: 64.4%, 94.8%) (P = 0.092). A 2‐year DSS and OS were significantly better with a nab‐paclitaxel‐based IC regimen (APF‐C) compared to a docetaxel‐based IC regimen (TPF‐C) in p16‐positive OPSCC.

Risk factors for and pre-medications to prevent cetuximab-induced infusion reactions in patients with squamous cell carcinoma of the head and neck.

OBJECTIVES Cetuximab, a chimeric monoclonal antibody, is the only targeted therapy approved for squamous cell carcinoma of the head and neck (SCCHN). Infusion reactions (IRs) occur in 6-18% of patients pre-medicated with diphenhydramine. Evidence for clinical risk factors for IRs is limited and the benefit of additional pre-medication to prevent IRs is unclear. MATERIALS AND METHODS A retrospective, single institution study of 243 SCCHN patients treated with cetuximab to evaluate potential risk factors for IRs and to assess the efficacy of additional pre-medications (nebulized albuterol and intravenous (IV) corticosteroids and/or H2-blockers) to decrease the risk of IR. RESULTS IR (grades 1-4) and high grade (grades 3-4 only) IR occurred in 47 (19.3%) and 16 (6.6%) patients, respectively. Multivariate analysis identified Caucasian race (OR7.11, p=0.003), medication allergy (OR3.74, p=0.002), and blood eosinophils >3% (OR2.75, p=0.01) independently increased the risk of IR; Caucasian race (OR5.57, p=0.007) and medication allergy (OR4.10, p=0.0007) increased the risk of high grade IR. IR (grades 1-4) and high grade IR occurred in 31.8% and 22.7% pre-medicated with diphenhydramine alone. Univariate analysis identified albuterol, famotidine, and corticosteroids decreased the risk of high grade IR. Furthermore, there was a significant difference between the possible combinations of the pre-medications and the risk of high grade IR by Fisher Exact test (p=0.003) whereby the combination of albuterol, famotidine and corticosteroids was effective in preventing high grade IR. Thirty (64%) of the 47 patients who developed an IR were re-challenged and did not experience a recurrence of an IR. CONCLUSION These data may be used to identify patients at higher risk for cetuximab-induced IR who may be advised to not receive cetuximab or who may benefit from additional pre-medications to decrease the risk of a high grade IR.

RTOG 0522: Huge Investment in Patients and Resources and No Benefit With Addition of Cetuximab to Radiotherapy—Why Did This Occur?

TO THEEDITOR: Angetal 1 recentlypresentedRadiationTherapy Oncology Group 0522 (RTOG 0522; Radiation Therapy and Cisplatin With or Without Cetuximab in Treating Patients With Stage III or Stage IV Head and Neck Cancer), a large randomized phase III trial of 940 patients with locally advanced head and neck squamous cell carcinoma (HNSCC) that tested whether the addition of cetuximab to cisplatin and accelerated radiation therapy (RT) improved progression-free survival (PFS) compared with cisplatin and radiation (CRT) alone. 1 It did not. Survival, locoregional failure, and distant metastases end points were not significantly different between the two groups. However, cetuximab plus CRT versus CRT resulted in more interruptions in RT, more treatment-relatedgrade5adverseevents(death),andmoregrade3 to 4 radiation mucositis, rash, fatigue, anorexia, and hypokalemia. These results are extremely disappointing. Should we be surprised? Let us look at prior data that led to the development of RTOG 0522. The rationale for performing RTOG 0522includedphaseIIItrialsshowingimprovedoverallsurvival(OS) with the addition of cetuximab to RT in patients with curable HNSCC 2 andimprovedOSwiththeadditionofcetuximabtochemotherapy in patients with incurable HNSCC. 3 Importantly, one small

A prospective trial comparing FDG-PET/CT and CT to assess tumor response to cetuximab in patients with incurable squamous cell carcinoma of the head and neck

Computed tomography (CT), the standard method to assess tumor response to cetuximab in incurable squamous cell carcinoma of the head and neck (SCCHN), performs poorly as judged by the disparity between high disease control rate (46%) and short time to progression (TTP) (70 days). F‐18 fluorodeoxyglucose positron emission tomography (FDG‐PET)/CT is an alternative method to assess tumor response. The primary objective of this prospective trial was to evaluate the metabolic response of target lesions, assessed as the change in maximum standardized uptake value (SUVmax) on FDG‐PET/CT before and after 8 weeks (cycle 1) of cetuximab. Secondary objectives were to compare tumor response by CT (RECIST 1.0) and FDG‐PET/CT (EORTC criteria) following cycle 1, and determine TTP with continued cetuximab administration in patients with disease control by CT after cycle 1 but stratified for disease control or progression by FDG‐PET/CT. Among 27 patients, the mean percent change of SUVmax of target lesions after cycle 1 was −21% (range: +72% to −81%); by FDG‐PET/CT, partial response (PR)/stable disease (SD) occurred in 15 patients (56%) and progression in 12 (44%), whereas by CT, PR/SD occurred in 20 (74%) and progression in 7 (26%). FDG‐PET/CT and CT assessments were discordant in 14 patients (P = 0.0029) and had low agreement (κ = 0.30; 95% confidence interval [CI]: 0.12, 0.48). With disease control by CT after cycle 1, median TTP was 166 days (CI: 86, 217) if the FDG‐PET/CT showed disease control and 105 days (CI: 66, 159) if the FDG‐PET/CT showed progression (P < 0.0001). Median TTP of the seven patients whose post cycle 1 CT showed progression compared to the 12 whose FDG‐PET/CT showed progression were similar (53 [CI: 49, 56] vs. 61 [CI: 50, 105] days, respectively). FDG‐PET/CT may be better than CT in assessing benefit of cetuximab in incurable SCCHN.

Metastasis occurring eleven years after diagnosis of human papilloma virus-related oropharyngeal squamous cell carcinoma

Human papilloma virus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) is associated with a favourable prognosis, although approximately 20–25% of patients ultimately develop recurrent cancer. Most disease recurrence events appear within 3 years; however, long-term follow-up of reported studies are limited, and the risk of late recurrence is unknown. We present a case report of a patient who developed distant metastases of HPV-related SCC 11 years after initial diagnosis and treatment of HPV-related OPSCC. Late disease recurrence may occur after initial diagnosis of HPV-related OPSCC. This observation has implications on the appropriate duration of follow-up and surveillance of these patients.

nab-Paclitaxel, cisplatin, and 5-fluorouracil followed by concurrent cisplatin and radiation for head and neck squamous cell carcinoma

OBJECTIVES We previously reported the efficacy of nab-paclitaxel added to cisplatin, 5-FU, and cetuximab (APF-C) followed by concurrent high dose bolus cisplatin and radiation therapy (CRT) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). In this phase II trial, we determined the efficacy of APF (without cetuximab) followed by CRT in similar patients. MATERIALS AND METHODS Eligible patients had stage III-IV oropharynx (OP), larynx, or hypopharynx SCC and adequate organ function and performance status. T1 tumors were excluded. Patients were treated with three cycles of APF followed by CRT. Efficacy endpoints included two-year disease-specific survival (DSS), progression-free survival (PFS), overall survival (OS), and relapse rate. RESULTS Thirty patients were enrolled. Most patients were smokers (77%) with bulky T3/4 (73%) and N2/3 (83%) tumors. Analyses were stratified for human papilloma virus (HPV) status: HPV-related OPSCC (n=17; 57%) and HPV-unrelated HNSCC (n=13; 43%). With a minimum follow-up of 21months, relapse occurred in 1 (3%) patient. Two-year DSS was 94% in HPV-related OPSCC and 100% in HPV-unrelated HNSCC. Two-year PFS was 94% in HPV-related OPSCC and 100% in HPV-unrelated HNSCC. Two-year OS was 94% in HPV-related OPSCC and 92% in HPV-unrelated HNSCC. Causes of death were relapse (1), treatment-related mortality (1), and co-morbidity (1). Two patients with HPV-unrelated HNSCC treated with APF declined CRT and remained free of relapse at 36 and 28months of follow-up. CONCLUSION This phase II trial demonstrated favorable two-year DSS, PFS, and OS and a low relapse rate in HPV-unrelated HNSCC and HPV-related OPSCC treated with APF followed by CRT.

Pazopanib plus cetuximab in recurrent or metastatic head and neck squamous cell carcinoma: an open-label, phase 1b and expansion study

BACKGROUND Angiogenesis is a hallmark of head and neck squamous cell carcinoma (HNSCC), and a mechanism of resistance to EGFR inhibition. We investigated the safety and potential activity of pazopanib, an angiogenesis inhibitor, plus cetuximab, an EGFR inhibitor, in patients with recurrent or metastatic HNSCC. METHODS We did an open-label, single-centre, dose-escalation phase 1b trial using a standard 3 + 3 design, followed by an expansion cohort phase. Eligible participants were patients with histologically or cytologically confirmed recurrent or metastatic HNSCC, aged at least 18 years, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and an Eastern Cooperative Oncology Group performance status of 0-1. During dose escalation, pazopanib oral suspension was administered daily in 8-week cycles at doses of 200 mg/day, 400 mg/day, 600 mg/day, or 800 mg/day, with cetuximab given intravenously once per week (400 mg/m2 first dose and 250 mg/m2 in consecutive cycles). The primary endpoint was to determine the maximum tolerated dose or recommended phase 2 dose of pazopanib in combination with cetuximab. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov, number NCT01716416, and it is ongoing but closed to accrual. FINDINGS Between June 5, 2013, and April 4, 2017, we enrolled 22 patients into the phase 1b, dose-escalation phase of the trial. A maximum tolerated dose of pazopanib in combination with cetuximab was not reached. Single dose-limiting toxic events (all grade 3) during dose escalation occurred with pazopanib 400 mg/day (neutropenia with infection), 600 mg/day (proteinuria), and 800 mg/day (fatigue). The established recommended phase 2 dose for the combination was 800 mg/day of pazopanib during cycles of 8 weeks each, plus cetuximab 400 mg/m2 on day 1 of cycle 1, then cetuximab 250 mg/m2 weekly. A further nine patients were enrolled into the expansion cohort and treated with the established recommended phase 2 dose. The most common (grade 3-4) adverse events for all patients were hypertension (ten [32%] of 31), lymphocyte count decrease (seven [23%]), and dysphagia (seven [23%]). There were no treatment-related deaths. 11 (35%; 95% CI 19·2-54·6) of 31 patients achieved an overall response, as assessed by the investigator; two (6%) had a complete response and nine (29%) a partial response. Tumour responses were also observed in six (55%) of 11 patients with platinum-naive and cetuximab-naive disease, three (25%) of 12 patients with cetuximab-resistant disease, and five (28%) of 18 patients with platinum-resistant disease. INTERPRETATION Pazopanib oral suspension at a dose of 800 mg/day was feasible to administer in combination with standard weekly cetuximab for patients with recurrent or metastatic HNSCC. Encouraging preliminary antitumour activity was observed with this combination therapy and warrants further validation in randomised trials. FUNDING GlaxoSmithKline and Novartis.