Predictors of Outcome With Cetuximab and Paclitaxel for Head and Neck Squamous Cell Carcinoma

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1 The Laryngoscope VC 2016 The American Laryngological, Rhinological and Otological Society, Inc. Predictors of Outcome With Cetuximab and Paclitaxel for Head and Neck Squamous Cell Carcinoma Bruna Pellini Ferreira, MD; Mary Redman, PhD; Kelsey K. Baker, MS; Renato Martins, MD, MPH; Keith D. Eaton, MD, PhD; Laura Quan Man Chow, MD; Christina S. Baik, MD, MPH; Bernardo Goulart, MD, MS; Sylvia Mina Lee, MD; Rafael Santana-Davila, MD; Cristina P. Rodriguez, MD Objectives: Identify predictors of outcome in patients with recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC) treated with weekly cetuximab and paclitaxel (CP). Study Design: Retrospective analysis. Methods: Patients with RMHNSCC treated with CP were identified and patient data was recorded. The Kaplan-Meier method was used to estimate outcomes, and Cox regression analysis was used to examine outcome predictors. Results: Fifty-nine patients initiated CP between January 2007 and June Median age was 56 (range: 39 80) years. The most common primary sites were the oropharynx in 22 (37%) patients, oral cavity in 19 (32%), and larynx in 11 (19%). Eastern Cooperative Oncology Group performance status (ECOG PS) was 0 in seven (12%), 1 in 32 (54%), and 2 in 16 (28%) patients. In 44 (75%) patients, CP was used as a first-line R/M regimen. Median number of cycles was five (range: 1 29). Dose modifications were necessary in 27 (46%) patients. The objective response rate was 47.5%, with 27 (45.8%) partial responses and one (2%) complete response. With a median follow-up of 13.4 months, median progression-free (PFS) and overall survival (OS) were 7.7 and 13.2 months, respectively. On multivariable analysis, an ECOG of 2 of 3 was associated with inferior OS (hazard ratio [HR]: 3.94; P ; 95% confidence interval [CI]: ) and PFS (HR: 7.29; P < 0.01; 95% CI: ) compared to an ECOG 0 of 1. First-line CP administration was associated with superior PFS compared to second line (HR: 2.6; P ; 95% CI: ). Conclusions: CP is well tolerated in this population of patients, with favorable tumor efficacy. First-line use and an ECOG 0 of 1 points appears to confer superior outcomes. Key Words: Cetuximab, paclitaxel, head and neck, squamous cell carcinoma. Level of Evidence: 4. Laryngoscope, 127: , 2017 INTRODUCTION Head and neck squamous cell cancer is the eighth most common cancer in the United States. 1 Most patients (75%) will present with advanced locoregional disease (stage III/IV), often approached with curative intent multimodality therapy. 2,3 Despite progress in the primary treatment by combining chemotherapy, surgery, radiation therapy, and supportive care, the recurrence rates after curative intent treatment range from 30% to 50%. These From the Department of Medicine, University of Central Florida College of Medicine (B.P.F.), Orlando, Florida; the Clinical Research Division, Fred Hutchinson Cancer Research Center (M.R., K.K.B.); and the Department of Medicine, Division of Medical Oncology, University of Washington (R.M., K.D.E., L.Q.M.C., C.S.B., B.G., S.M.L., R.S-D., C.P.R.), Seattle, Washington, U.S.A. Editor s Note: This Manuscript was accepted for publication October 17, Published online as an abstract by Journal of Clinical Oncology in conjunction with 2015 American Society of Clinical Oncology Annual Meeting (May 29 June 2, 2015). J Clin Oncol 2015, 33 (suppl; abstract e Financial Disclosure: The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Dr. Cristina P. Rodriguez, Seattle Cancer Care Alliance, 825 Eastlake Ave. E., Seattle, WA rodrigcr@u.washington.edu DOI: /lary patients have a median survival of 6 months 4 and a 1-year survival rate of only 20%. 3 The epidermal growth factor receptor (EGFR) is almost universally overexpressed among head and neck squamous cell carcinomas and has emerged as a promising therapeutic target. 5,6 EGFR overexpression in squamous cell carcinomas of the head and neck is associated with more aggressive disease biology, increased resistance to chemotherapy and radiotherapy, and poorer prognosis. 5,7 10 Cetuximab, an immunoglobulin G1 monoclonal antibody that binds to extracellular domains of EGFR with high affinity, 5,11,12 has been investigated in both the curative and palliative treatment settings in squamous cell carcinomas of the head and neck. Platinum-based combination regimens have been extensively studied as first-line treatment in patients with recurrent or metastatic head and neck cancer The landmark EXTREME trial, a phase III study in patients with recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC), randomized patients to comparison is cetuximab, platinum and 5- fluorouracil versus platinum and 5-fluorouracil. This study revealed a statistically significant improvement with the addition of cetuximab to chemotherapy. 13 The toxicity of this triplet approach was significant, with 82% 1583

2 of patients experiencing grade 3 or higher toxicity. Such an approach is often difficult to apply to a patient population wherein comorbidity is overrepresented. Hitt et al. 2 reported the results of a phase-ii study of cetuximab and paclitaxel in the first-line treatment of RMHNSCC. The observed overall response rate was 54% (95% CI, 39% 69%), with a median progression-free survival (PFS) of 4.2 months and a median overall survival (OS) of 8.1 months. 2 Three other European retrospective studies have reported results with this regimen after platinumbased therapy failure; the response rate ranged from 38% to 55%, with a median OS of 7.6 to 10.0 months. 3,4,14 Our group has adopted the combination of cetuximab and paclitaxel (CP) as first-line treatment for patients with RMHNSCC who are deemed unsuitable for platinum-based regimens due to platinum refractory disease (i.e., recurrence within 6 months after platinum-based curative intent chemoradiation, or progression after a platinum-containing regimen in the R/M setting, and/or comorbidity). The aim of this retrospective study was to determine predictors for outcomes in patients with RMHNSCC who were treated with weekly CP. MATERIALS AND METHODS Patients We retrospectively reviewed patient records to identify those with histologically confirmed recurrent and/or metastatic HNSCC who were treated with weekly CP at our institution between January 2007 and June Patients were known to be either platinum refractory or deemed poor candidates for a platinumcontaining regimen. Data on patient demographics, tumor characteristics, treatment related toxicities, and response were collected. The study was reviewed and approved by the institutional review board. Treatment Cetuximab and paclitaxel was given in a 28-day cycle, with paclitaxel administered weekly at a dose of 90 mg/m 2 over 1 hour on days 1, 8, and 15 of each cycle. Cetuximab administered at a loading dose of 400 mg/m 2 during a 2-hour infusion, followed by a weekly 1-hour infusion of 250 mg/m 2 on days 1, 8, 15, and 22 of the treatment cycle. Patients received intravenous premedication before each course of chemotherapy, which consisted of 20 mg of dexamethasone, 50 mg of ranitidine, and 8 mg of ondansetron. All patients were required to have adequate hematological and hepatic function before treatment. Patient s clinical response to treatment was evaluated every 4 weeks by the treating clinician, and radiographically using computerized tomography imaging every 8 weeks. Antitumor activity was retrospectively evaluated accordingly to the Response Evaluation Criteria in Solid Tumor criteria 16 via the review of historical imaging results. Statistical Design The response rate was estimated as the proportion of patients who achieved a complete or a partial response from the total number of patients who received at least one cycle of CP. Overall survival (OS) was defined as the time from the date of first administration of CP to the date of death from any cause. Progression-free survival was calculated from the date of first CP administration to the date of disease progression or death. TABLE I. Patient Demographics and Clinical Characteristics. Characteristics N % Median age, years [range] 56 [39 80] Sex Male Female Race White Black 5 9 Hispanic 1 2 American Indian 2 3 Asian 5 9 Unknown 2 3 Site of primary tumor Oropharynx Oral cavity Larynx Cutaneous 3 5 Hypopharynx 2 3 Maxillary sinus 1 2 Unknown 1 2 P16 Status (oropharynx only) Negative 5 22 Positive 5 22 Unknown ECOG performance status Unknown Reason for treating with CP regimen Progression within 6 months of cisplatin Ongoing infection Advanced age Declining PS and/or comorbidity CP 5 cetuximab and paclitaxel; ECOG 5 Eastern Cooperative Oncology Group; PS 5 performance status. If progression or death had not occurred before the last contact, data were censored at the time of the last follow-up assessment. Survival distributions were estimated by the Kaplan-Meier method. Multivariable Cox regression analysis was used to examine outcome predictors. All analysis were performed with SAS 9.4 (SAS Institute Inc., Cary, NC). RESULTS Patient Characteristics Between January 2007 and June 2014, 59 patients with RMHNSCC were treated at the University of Washington/Seattle Cancer Care Alliance, Seattle, Washington, with a combination of CP. Patient characteristics at baseline are summarized in Table I. The population mostly consisted of men (42 patients, 71.19%) of white 1584

3 TABLE II. Treatment Summary. N (n 5 59) % Curative intent Surgery Neck dissection Radiotherapy Concurrent chemoradiotherapy Previous chemotherapy Platinum Cetuximab 8 14 Erlotinib (on a clinical trial) 7 13 Docetaxel 2 3 Number of prior chemotherapy regimens for recurrent/metastatic disease Number of cetuximab and paclitaxel cycles Median [range] 4.98 [1 29] ethnicity (43 patients, 74.14%) with a median age of 56 years (range, years) at treatment initiation. The three most common locations of the primary tumor were the oropharynx (22 patients, 37.29%), the oral cavity (19 patients, 32.20%), and the larynx (11 patients, 18.64%). Prior to treatment initiation, 24 (40.68%) patients had both metastatic and locoregional recurrent disease. Recurrent disease was locoregional only in 20 (33.90%) patients and distant only in 15 (25.42%) patients As shown in Table II, 52 patients (88.14%) were initially treated with a curative intent. Of those, 21 (35.59%) patients underwent surgical resection of the primary site, and 22 (37.29%) underwent neck dissection. Forty-nine patients (83%) underwent radiation therapy, and 40 (68%) received systemic therapy concurrent with radiation. Cisplatin was administered concurrent with radiation in 33 (56%) patients, and seven (12%) received cetuximab concurrent with radiation. Among the 33 patients receiving cisplatin concurrent with radiation therapy, 24 received cisplatin as a single agent; one patient received cisplatin, docetaxel, and cetuximab; one patient received cisplatin and docetaxel; and seven patients received cisplatin and erlotinib in the context of a clinical trial. The clinicianstated reasons for treating patients with CP were as follows: progression within 6 months of cisplatin in 29 (49%) patients, ongoing infection in four (7%) patients, advanced age in three (5%) patients, and declining performance status and/or comorbidity in 23 (39%) patients. Most of these patients had received CP in a first-line setting. CP was used as first-line regimen for recurrent/metastatic disease in 44 (74.58%) patients. Fifteen (25.42%) patients had received one prior line of chemotherapy prior to CP. Toxicity Given the retrospective nature of our study, we were unable to formally grade subjective toxicities. We retrospectively graded the hematologic and metabolic toxicities using Common Terminology Criteria for Adverse Advents (CTCAE) version 4.0 (National Cancer Institute; National Institutes of Health, Bethesda, MD). The main toxicity was rash, which occurred in 34 (57.63%) patients. Dose reductions were necessary in 27 (45.76%) patients, and 13 required unplanned hospitalizations. Eleven (18.64%) patients required one unplanned hospitalization and two (3.39%) were hospitalized twice. Reasons for hospitalizations are described in Table III. The second most common toxicity was neuropathy, which was documented as present in 13 (22%) patients. Neuropathy was the stated reason for treatment discontinuation in one patient. Diarrhea was reported in five (8.5%) patients, and two of these patients required intravenous hydration. Fatigue was reported in two (3%) patients, who discontinued CP due to this adverse event. With regard to myelosuppression, three (5%) patients developed neutropenia. Neutropenia was grade 1 in one patient and grade 3 in two patients. Grade 1 anemia was noted in one patient. One patient developed grade 1 thrombocytopenia. Hypomagnesemia was observed in three (5.08%) patients, and was grade 1 in one patient and grade 2 in two patients. Adverse effects are summarized in Table III. TABLE III. Summary of Adverse Events. N % Rash Neuropathy Hypersensitivity reaction 3 5 Diarrhea 5 8 Fatigue 2 3 Neutropenia 3 5 Grade Grade Anemia (grade 1) 1 2 Thrombocytopenia (grade 1) 1 2 Hypomagnesemia 3 5 Grade Grade Dose reductions Patients requiring hospitalization Number of hospitalizations Causes of hospitalization Bleeding from tracheostomy site 1 2 Dyspnea 1 2 Fever 3 5 Hypersensitivity reaction to paclitaxel 1 2 Nausea and/or vomiting 2 3 PEG tube infection 1 2 Seizure 1 2 Tachyarrhythmia 3 5 Weakness 2 4 PEG 5 percutaneous endoscopic gastrostomy. 1585

4 TABLE IV. Outcome Summary. N % Extent of first recurrence Locoregional only Metastatic Both metastatic and locoregional Extent of most recent recurrence Locoregional only Metastatic Both metastatic and locoregional Best response Complete response 1 2 Partial response Stable disease Disease progression 9 15 Not assessed 4 7 Efficacy With a median follow-up of 13.4 months (95% confidence interval [CI]: ), the objective response rate (ORR) was 47.5%, with one complete response (1.69%) and 27 partial responses (45.76%). Eighteen (30.51%) patients had stable disease and nine (15.25%) had disease progression (Table IV). The median number of cycles given was 4.98 (range: 1 29). Median PFS and OS were 7.7 months and 13.2 months, respectively (Figs. 1 and 2). Patients who received CP as first-line in the recurrent and/or metastatic setting had a median PFS and an OS of 7.7 and 13.2 months, respectively. Among patients who received CP as second-line therapy for R/M disease, we observed a median PFS and OS of 5.8 and 11.6 months, respectively. Of note, eight patients received prior cetuximab therapy (in the setting of curative intent treatment). The median interval between curative intent cetuximab and CP treatment was 22 months (range 10 32). The best responses noted in these patients were a partial Fig. 2. Overall survival (months). [Color figure can be viewed in the online issue, which is available at response in three patients, stable disease in three, and progressive disease in two. Two patients previously had received docetaxel (one in the curative intent setting 18 months prior CP; another in the R/M setting 7 months prior CP); both had stable disease with the CP regimen. Using Cox multivariable analysis, an ECOG of 2 or 3 was associated with an inferior OS (hazard ratio [HR]: 3.94; 95% CI: ; P ) and PFS (HR: 7.29; 95% CI: ; P < 0.01) compared to Eastern Cooperative Oncology Group (ECOG) 0 (Tables V and VI). There were no statistically significant differences in OS or PFS when comparing the different primary tumor locations. In addition, we observed no association between OS or PFS with the development of a CP-related rash. Forty-four patients had not previously received chemotherapy for the treatment of R/M disease. First-line CP administration was associated with superior PFS compared to second-line (HR: 2.6; P ; 95% CI: TABLE V. Cox Regression: Overall Survival. Parameter Hazard Ratio P value [95% CI] Fig. 1. Progression-free survival (months). [Color figure can be viewed in the online issue, which is available at Primary site Hypopharynx Reference Oral cavity [ ] Oropharynx [ ] Rash Absent Reference Present [ ] ECOG status 0 Reference [ ]] 2 or [ ] Prior treatment No Reference Yes [ ] CI 5 confidence interval; ECOG 5 Eastern Cooperative Oncology Group. 1586

5 TABLE VI. Cox Regression-Progression-Free Survival. Parameter Hazard Ratio P Value [95% CI] Primary site Hypopharynx Reference Oral cavity [ ] Oropharynx [ ] Rash Absent Reference Present [ ] ECOG Status 0 Reference [ ] 2 or <0.01 [ ] Prior treatment No Reference Yes [ ] CI 5 confidence interval; ECOG 5 Eastern Cooperative Oncology Group ); however, no statistical difference was noted in terms of OS (HR: 1.32; P ; 95% CI: ). DISCUSSION Our article discusses a large retrospectively studied North American cohort, and our findings are consistent with prior observations 2 4,14 that CP is an active regimen (ORR: 47.5%) in this disease. We observed a median PFS (7.7 months) and OS (13.2 months) that appear longer than previously published studies. 3,4,14 Possible explanations for this include the fact that most of our patients (74.58%) received CP as first-line therapy for R/M disease. It is increasingly recognized that the cyclin-dependent kinase-4 inhibitor (p16)1 population has an improved prognosis even in the recurrent metastatic setting. We could only identify a small population of p161 patients in our cohort, and perhaps inadvertent inclusion of p161 patients in our oropharynx cohort resulted in more favorable PFS and OS compared to previous observations. In addition, we are a large tertiary referral institution; therefore, selection bias in our population cannot be discounted. Our experience suggests that the CP regimen is feasible in this patient population, for which comorbidity often is overrepresented and systemic therapeutic options is limited. It must be noted that our patients were treated in a tertiary hospital, high-volume setting in a dedicated head and neck cancer service capable of maximizing supportive care when necessary. The toxicity profile and unplanned hospitalization rate may not necessarily be reproducible in other clinical settings. We recognize the limitations of a small singleinstitution retrospective series. Our adverse events were not prospectively collected and graded according to CTCAE criteria. The timing of response evaluation, which we generally repeat after every two cycles, was not mandated to occur every 8 weeks; therefore, it could impact our progression-free survival observation. Furthermore, the efficacy, tolerance, and cost of paclitaxel and cetuximab given sequentially as single agents, rather than as a doublet, are unknown and impossible to determine by comparison to published historical cohorts treated with single agents. Despite published literature on efficacy outcomes in smaller patient numbers, both prospective and retrospective, there is little data on what clinical factors predict for superior outcomes with CP. The weekly administration and use of a monoclonal antibody make this a relatively higher-cost regimen; thus, the need to identify patients most likely to benefit. On multivariable analysis, factors predicting for superior outcome with the CP regimen were its use as first-line therapy for R/M disease in ECOG 0 patients. The observation that fitter patients do better with systemic therapy in the recurrent metastatic setting has been described extensively. 5,13,14,17 Among squamous cell carcinomas, it is well established that treatment-naive patients have higher response rates to systemic agents, and that heavily pretreated patients are less likely to experience benefit from systemic treatment. 18,19 Our results support these intuitive predictors and are factors that we consider during treatment planning. CONCLUSION The CP regimen has not previously been compared prospectively with platinum-based single agent or doublet chemotherapy regimens, and its superiority over a potentially less costly regimen remains unproven. Nonetheless, this active and well tolerated regimen should be considered in the therapeutic armamentarium for RMHNSCC. 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