Phase II Multicenter Study of the Epidermal Growth Factor Receptor Antibody Cetuximab and Cisplatin for Recurrent and Refractory Squamous Ce
http://www.100md.com
《临床肿瘤学》
the Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston
Arlington Cancer Center, Dallas, TX
Department of Oncology, Washington University, St Louis, MO
Winship Cancer Institute, Emory University, Atlanta, GA
Department of Medicine, Section of Hematology and Oncology, Head and Neck Oncology Program, University of Chicago, Chicago, IL
Department of Clinical Affairs, ImClone Systems, Branchburg, NJ
ABSTRACT
PURPOSE: This multicenter phase II study was undertaken to define the efficacy and safety of cetuximab, an antiepidermal growth factor receptor chimeric human and murine monoclonal antibody, administered with cisplatin to patients with refractory metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN).
PATIENTS AND METHODS: One hundred thirty-two patients were to receive two 3-week cycles with cisplatin/paclitaxel or cisplatin/fluorouracil. Patients (n = 30) with a complete or partial response continued standard therapy. Seventy-six patients with stable disease (SD; n = 51) or progressive disease (PD/1; n = 25) received combination therapy with cetuximab (400 mg/m2 intravenously on day 1, then 250 mg/m2/wk) and cisplatin (75 or 100 mg/m2 intravenously on day 1 every 3 weeks). The protocol was subsequently amended to enroll patients who had developed PD within 90 days after platinum-based therapy (PD/2; n = 54).
RESULTS: Five patients (20%) in PD/1, three patients (6%) in PD/2, and nine patients (18%) with SD achieved an objective response. Median duration of response was 4.2, 4.1, and 7.4 months for the PD/1, PD/2, and SD groups, respectively, with median overall survival times of 6.1, 4.3, and 11.7 months. The most common toxicities were anemia, acne-like skin rash, leukopenia, fatigue and malaise, and nausea and vomiting. Seven patients (5%) developed a grade 3 or 4 hypersensitivity reaction to cetuximab.
CONCLUSION: Cetuximab and cisplatin is an active regimen in refractory SCCHN. The relative contribution of cetuximab is better defined in a single-agent trial. Cetuximab did not exacerbate cisplatin toxicity but was associated with skin rash in a majority of patients and occasional serious allergic reactions. Further study of this compound is warranted.
INTRODUCTION
Epidermal growth factor receptor (EGFR) is a 170-kd transmembrane glycoprotein receptor found on cells of epithelial origin.1-3 This glycoprotein is an important growth-regulatory signal transduction element exerting multiple functions through an intrinsic tyrosine kinase activity, which is activated on ligand binding.4-7 EGFR signaling has been associated with the malignant phenotype, inhibition of apoptosis, neoplastic angiogenesis, and enhanced metastatic potential.8 EGFR is overexpressed in squamous cancers of the head and neck,8,9 and increasing surface concentration has been associated with advanced stage and poor prognosis.9-11 In 1983, Kawamoto et al12 first produced monoclonal antibodies that blocked ligand binding preventing activation of the receptor. This approach was found to have antiproliferative effects in vitro, and it was hypothesized that blocking receptor activation would be an effective therapeutic strategy.13 Monoclonal antibodies (M225) directed against this receptor were generated in murine systems12,14 and were shown to have antitumor activity in vitro and in xenograft models.12,14,15 Later, this antibody was chimerized with human immunoglobulin G1 in its constant region to obtain cetuximab16 to increase clinical applicability by reducing the potential for generation of human antimurine antibodies in patients. In a sequence of preclinical studies, cetuximab was found to inhibit the growth of cultured tumor cell lines and repress in vivo growth of xenografts,16,17 augment the activity of doxorubicin18 and cisplatin,17,18 and modulate the response of tumor xenografts after radiation therapy.19
Approximately 40,000 cases of squamous cell carcinoma of the head and neck (SCCHN) were diagnosed in 2003 in the United States.20 Most patients are diagnosed with advanced regional disease, and approximately 40% of these patients will be cured. There have been only modest improvements in survival rates, despite the application of multimodal treatment approaches, with locoregional tumor recurrence the predominant failure pattern.21 The median survival time for patients with recurrent or metastatic disease is 5 to 7 months22,23 and is dismal for patients with refractory disease after first-line chemotherapy.
Shin et al24 conducted a phase IB study of cetuximab, in combination with cisplatin, in patients with recurrent SCCHN to determine the optimal biologic dose (ie, the tumor-saturating dose) and to establish a safety profile for this compound. A loading dose of cetuximab 400 mg/m2 and a weekly maintenance dose of 250 mg/m2 achieved tumor EGFR saturation. Moreover, a surprising observation was that six of nine assessable patients achieved a major response to the cetuximab combination. Three of these patients had experienced treatment failure with prior platinum-containing therapy. An acneiform skin reaction occurred in two patients (17%), and one patient developed a severe allergic reaction precluding further treatment. To confirm and expand on these observations, we designed a subsequent study for patients with recurrent SCCHN. All patients were to be treated with a cisplatin-containing chemotherapy regimen, and those patients failing to achieve disease response or with overt disease progression would proceed to the experimental regimen consisting of cetuximab and cisplatin.
PATIENTS AND METHODS
Patient Eligibility
To be eligible for the trial, patients were required to have the following: pathologically confirmed recurrent squamous cell carcinoma of the oral cavity, pharynx, or larynx considered not curable with conventional treatment; bidimensionally measurable disease; Karnofsky performance score (KPS) of 60; prior total cisplatin exposure 200 mg/m2 at the initiation of the study and 450 mg/m2 after an eligibility amendment (described in Stable and Progressive Disease Cohorts); and neuropathy grade 1 at study entry. Patients were 18 years of age; had adequate hematologic, hepatic, and renal functions; used effective contraception if procreative potential existed; and had sufficient tumor tissue available for immunohistochemical determination of EGFR expression. Exclusion criteria included pregnancy or lactation, prior murine monoclonal antibody therapy or cetuximab therapy, prior surgery or radiation therapy within 2 months of study entry, a history of clinically significant cardiac disease, uncontrolled seizure disorder or other serious neurologic disease, or a previous therapy with an investigational agent within 1 month of study entry. Signed informed consent, in accordance with institutional guidelines, was obtained before treatment.
Stable and Progressive Disease Cohorts
Initially, patients were candidates for this trial at the time of first recurrence after primary therapy or if there was distant metastatic disease. Enrolled patients with a total prior cisplatin exposure of 200 mg/m2 were to receive cisplatin and either paclitaxel or infusional fluorouracil, with regimens repeating at 3-week intervals for two treatment cycles (Fig 1). Patients would then be evaluated for tumor response. Those patients achieving a partial response (PR) or complete response (CR) were not eligible for the experimental regimen. Patients demonstrating stable disease (SD) or progressive disease (PD) were eligible to continue on the study and receive cetuximab in combination with cisplatin at the dose used in the initial treatment regimen (before cetuximab). Because the SD cohort completed accrual ahead of the PD/1 cohort, the protocol was amended in August of 2000 to accrue only patients with documented disease recurrence and tumor progression within 3 months of platinum-based therapy (PD/2). For this group, total prior cisplatin therapy was 450 mg/m2.
Cetuximab was manufactured and supplied by ImClone Systems Inc (Branchburg, NJ) and was administered by intravenous infusion at an initial dose of 400 mg/m2 over 2 hours, followed by weekly doses of 250 mg/m2 over 1 hour. Cisplatin was administered in a 1-hour infusion of 75 or 100 mg/m2 on the first day of each 21-day cycle. Because of the potential for an allergic reaction to cetuximab, patients were medicated with decadron 20 mg and diphenhydramine 50 mg intravenously 30 minutes before the cetuximab infusion and received a 20-mg test dose of cetuximab before the initial dose only, followed by an observation period of 30 minutes for signs of severe infusion reactions. Patients received the remainder of the initial dose after the observation period.
A delay of cetuximab therapy for 2 consecutive weeks was allowed for patients with grade 3 skin toxicity. There was no change in the cetuximab weekly schedule for cisplatin-related toxicity. Patients received hydration fluids and usual antiemetic preparations before the cisplatin administration. Cisplatin dose alterations were implemented for myelosuppression, nephrotoxicity and peripheral neuropathy, excessive vomiting, and ototoxicity. Stable or responding patients who developed grade 2 or 3 neurotoxicity or nephrotoxicity were shifted from cisplatin to carboplatin. The carboplatin dose was calculated according to the Calvert formula with area under the curve of 6. For SD and PD patients achieving SD or a tumor response, the platinum was discontinued after four treatment cycles, and cetuximab was continued weekly until disease progression, protocol noncompliance, intolerable toxicity, or an intercurrent illness that mandated interruption of therapy for more than two consecutive infusions.
Evaluation Criteria
The extent of malignant disease was evaluated in all treated patients before the start of cetuximab treatment and repeated at 6-week intervals. Tumor response was assessed using modified WHO criteria.25 CR was defined as the complete disappearance of all evidence of disease, including disease-related signs and symptoms, lasting at least 4 weeks. PR was defined as a 50% decrease in the sum of the products of the two longest perpendicular diameters of all measured lesions for at least 4 weeks, with no evidence of PD. SD was defined as no significant change in measurable and assessable disease. PD was defined as one or more of the following: a 25% increase in the sum of the products of the two longest perpendicular diameters of measurable lesions, unequivocal growth of existing assessable disease, the certain appearance of a new lesion, or reappearance of old lesions. The objective response rate was the percentage of patients achieving a CR or PR. Disease control was defined as the achievement of CR, PR, or SD. An independent head and neck radiologist confirmed PD status for the patients commencing therapy with cetuximab and cisplatin and verified response status during the course of treatment.
Duration of response was the time from initial response to first evidence of PD. Progression-free survival (PFS) was defined as the time from day 1 of treatment to the first evidence of PD or death within 3 months of the last study treatment administration. Overall survival (OS) was defined as the time from day 1 of treatment to death.
Quality of life (QOL) was assessed using the Functional Assessment of Cancer Therapy–Head and Neck questionnaire.26,27 The patients completed the instrument at study entry, every 6 weeks during therapy, at the time of the post-treatment evaluation, and at one additional follow-up evaluation. Compliance for completing the QOL questionnaires was investigated at each time point.
All patients who received at least one dose of the study medication were evaluated for safety. All clinical adverse events and laboratory abnormalities were graded by the National Cancer Institute Common Toxicity Criteria (version 2).
Statistical Considerations
The study objective was to determine the objective response rate of treatment with cetuximab and cisplatin in patients with recurrent or metastatic SCCHN who experienced treatment failure with cisplatin-based chemotherapy. Gehan's two-stage design, which allowed for early stopping for low activity, was used.28 The targeted response rate for SD and PD/1 patients was 15%. Initially, a total of 19 patients were to be enrolled onto either the SD or PD cohorts. If at least one response was observed, a second group of 30 patients was to be enrolled to allow for estimation of the response rate with an SE of as little as 5%.
The SD cohort completed accrual well ahead of the PD/1 cohort. Therefore, the protocol was amended to enroll only patients with documented disease recurrence and tumor progression within 3 months of platinum-based therapy (PD/2). Using Gehan's method as described earlier, the PD/2 cohort was to enroll a total of 49 patients with documented PD.
Efficacy results were summarized separately by subgroups (SD, PD/1, and PD/2). The response rates and 95% CIs were determined for each subgroup. The distribution of duration of response, PFS, and OS were estimated using the Kaplan-Meier product-limit method.29 A multivariate logistic regression analysis was performed to identify factors predictive of response to treatment. Also, multivariate proportional hazards modeling (Cox regression) was used to find covariates affecting PFS and OS times. QOL data were scored according to the Functional Assessment of Cancer Therapy manual.
Treatment-related adverse events (events that occurred or worsened on or after the first dose through 30 days after the last dose of study treatment) were grouped by Coding Symbols for Thesaurus of Adverse Reaction Terms–preferred term and body systems and summarized by worst grade severity per patient. Toxicities of special interest with cetuximab therapy included hypersensitivity reaction and an acne-like rash.
RESULTS
Patients
August 1999 through September 2001, a total of 187 patients were enrolled onto this study. Of those patients, 56 (30%) discontinued treatment on protocol before receiving cetuximab/cisplatin combination therapy for the following reasons: response to the initial cisplatin-containing regimen (n = 30), early death (n = 8), chemotherapy toxicity (n = 6), withdrawn consent (n = 4), protocol noncompliance (n = 3), PD with poor performance level (n = 2), diagnosis of a second primary tumor (n = 1), abnormal ECG (n = 1), and lost to follow-up (n = 1). One PR patient erroneously received 1 day of cetuximab/cisplatin combination therapy. That patient is included in the analysis of safety but was excluded from the efficacy analyses; 51 SD patients and 79 PD patients (25 PD/1 and 54 PD/2 patients) were evaluated for efficacy.
In summary, 131 patients were to receive cetuximab in combination with cisplatin. There were some differences in pretreatment characteristics between the three cohorts. In particular, patients in the PD/2 cohort had a higher prior cisplatin exposure (Table 1). Of the 131 patients, five with life-threatening hypersensitivity reactions to the first dose of cetuximab did not receive cisplatin. Of the remaining 126 patients, 18 received cisplatin at 100 mg/m2, and the other patients received a lesser dose. There was no statistically significant difference between these subgroups with respect to efficacy or toxicity because the number of patients treated at the higher cisplatin dose level was small. Thus, we report efficacy and toxicity results for the SD, PD/1, and PD/2 patient cohorts.
Efficacy
The investigator assessments of the treatment outcomes and best overall tumor responses are listed in Table 2, and an example of a response is shown in Figure 2. The objective response rate was 18% for the SD cohort and 20% and 6% for the PD/1 and PD/2 groups, respectively. The median duration of response was 7.4 months for the SD cohort, 4.2 months for the PD/1 cohort, and 4.1 months for the PD/2 cohort. The disease control rate was 76% for the SD cohort compared with 64% and 52% for the PD/1 and PD/2 cohorts. In this trial, the response rate trended higher for patients who had PD after two cisplatin-based treatment cycles on protocol (PD/1) than for patients with PD who failed a platinum-containing regimen administered in the community within 3 months of study entry (PD/2), but the numbers were small, and the difference between the two PD cohorts was not statistically significant (Fisher's exact test, P > .10). A multivariate logistic model failed to identify any factor for predicting response to treatment.
Both the PFS and OS times were greater in the SD cohort (4.9 and 11.7 months, respectively) compared with PD/1 (3.0 and 6.1 months, respectively) and PD/2 cohorts (2.0 and 4.3 months, respectively; Figs 3 and 4). A multivariate Cox regression analysis showed that, in this trial, for the PD cohorts, severity of rash was a predictor of PFS (Fig 5).
Table 3 lists the response rate and 1-year survival rates of patients by age, sex, KPS, prior paclitaxel therapy, and worst grade rash. Pretreatment KPS and severity of rash (Figs 6 and 7) were predictors of OS. There were no apparent trends found in the analysis of the Functional Assessment of Cancer Therapy–General and Functional Assessment of Cancer Therapy–Head and Neck results. A formal review and analysis is underway and will be reported separately.
Safety and Treatment Duration
All 131 patients receiving cetuximab were reported in the safety analysis. Of the 10 patients who experienced hypersensitivity reactions to their first dose of cetuximab, five discontinued cetuximab treatment after this initial dose, including three patients with grade 4 anaphylactic shock. Those patients recovered. The median duration of treatment with cetuximab was 12 weeks (range, 1 to 77 weeks). Sixteen patients (12%) continued on cetuximab beyond 6 months, and of these patients, five patients (4%) were treated for more than a year. The median duration of treatment with cisplatin and cetuximab was also 12 weeks (range, 1 to 20 weeks). Three patients started cetuximab treatment with carboplatin, 13 patients switched from cisplatin to carboplatin during the treatment phase, and 46 patients continued on cetuximab after cisplatin was discontinued. Of the eight patients who discontinued the study because of an adverse event, six had a major hypersensitivity reaction, one had fatigue, and one had aspiration pneumonia.
Dose reduction of cetuximab was uncommon. Dose delays of at least 1 week occurred in one third of the patients. Most treatment-related delays of cetuximab dosing were a result of folliculitis or paronychial infection. Cisplatin was delayed mostly for myelosuppression, hematologic toxicity, and/or nephrotoxicity. Twelve patients died on study (all unrelated to treatment).
The most common nonhematologic toxicity generally associated with cetuximab was rash, which was often described as acne-like and occurred in 70% of patients, including five patients with severe cases (Table 4). Median time to the first onset of rash was 2 weeks, with 80% of the rashes occurring during the first 3-week cycle of treatment. Median duration of rash was 4 weeks, and most resolved with no sequelae.
The most common grade 3 and 4 cisplatin toxicities were myelosuppression and nephrotoxicity. The most common hematologic toxicity was anemia, which occurred in 92% of patients. One patient was hospitalized for acute kidney failure and sepsis, and another patient was hospitalized for kidney failure and neutropenic fever. There was no apparent adverse interaction between cetuximab and cisplatin. None of the 28 deaths on study or within 30 days of the last dose of cetuximab was judged to be treatment related.
Pharmacokinetics
Mean cetuximab concentrations before every third dose ranged from 41.421 to 55.111 μg/mL (through dose 27). In addition, the data showed relatively consistent levels of cetuximab before every third dose, suggesting that the concentrations of cetuximab remained at a constant level throughout therapy.
DISCUSSION
In this phase II study, we identified patients with recurrent and refractory SCCHN for treatment with cisplatin and cetuximab. Cetuximab is a chimeric human/murine monoclonal antibody directed against EGFR. Cetuximab was combined with cisplatin because of a compelling preclinical literature indicating that therapeutic efficacy would be greater in combination with cytotoxic agents or radiation therapy.17-19 Shin et al24 had previously demonstrated in a phase IB study that six of nine assessable patients with recurrent SCCHN achieved major responses to this combination. This study was designed to extend those observations.
In the first phase of the protocol, patients with disease considered stable after two cycles of cisplatin-based chemotherapy then proceeded to the experimental regimen. Of 51 SD patients, nine (18%) achieved a major tumor response, with 39 patients (76%) considered to achieve some measure of disease control. Median OS time for the SD patients was an impressive 11.7 months. Seventy-nine patients identified as having PD after first-line cisplatin-based chemotherapy were studied. PD/1 consisted of 25 assessable patients, with five (20%) achieving partial disease remission and another 11 (44%) observed to have SD. In contrast, 54 patients (PD/2) entered the study after the amendment. These were PD patients with a clear demonstration of disease progression after chemotherapy administered within 90 days before treatment. In this group, only three patients (6%) achieved PR, and another 25 patients (46%) had SD. In aggregate, 10% of PD patients achieved partial disease regression. The discrepancy in response rates between PD/1 and PD/2 did not exceed confidence limits. However, there were clinical differences between these groups. Notably, median exposure to cisplatin before the experimental regimen was greater in PD/2 patients compared with PD/1 patients (200 v 150 mg/m2, respectively). The median time from prior therapy to the experimental treatment program was 3.9 weeks for PD/1 (range, 2.7 to 6.9 weeks) and 5.1 weeks for PD/2 (range, 2.5 to 25 weeks). Fifteen PD/2 patients (28%) started cetuximab and cisplatin 7 weeks or more after first-line chemotherapy. Because the prognosis for such patients is poor, any delay in starting the experimental program may have allowed for further disease progression, despite similarity in performance status and other baseline patient demographics. Thus, prospects for a tumor response in the PD/2 cohort may have been compromised. There also was a trend favoring survival for PD/1 patients compared with PD/2 patients (median survival time, 6.1 v 4.3 months, respectively).
There is no indication that cisplatin-based toxicity was exacerbated in combination with cetuximab. Five percent of patients had serious or life-threatening hypersensitivity responses after administration of the chimeric monoclonal antibody, leading to discontinuation of treatment. Moreover, 70% of patients suffered an acneiform or folliculitis-like rash attributed to cetuximab. A review of selected clinical toxicities, as presented in Table 4, otherwise seems to reflect the clinical course of patients declining with advanced SCCHN and of expected cisplatin-related effects.
Our data are comparable to those of Baselga et al30 who treated 96 patients with refractory SCCHN who were similar to our PD/2 cohort. An overall response rate of 14.6% was observed. Trigo et al.31 have recently reported that single-agent cetuximab, at the schedule used in our study, achieved PRs in 12.5% of patients with platinum-refractory SCCHN. This would suggest that the activity observed in our trial is related to the effects of cetuximab and not the cetuximab and cisplatin combination. Burtness et al32 conducted a double-blind, randomized, phase III trial comparing cisplatin as a single agent with cisplatin and cetuximab in patients with recurrent SCCHN. Tumor response was significantly higher after the experimental drug combination compared with the single agent (23.6% v 9.8%, respectively), and there was a trend toward better 2-year OS (15.6% v 9.2%, respectively). Furthermore, in a potential landmark study, Bonner et al33 reported the results of a phase III, prospectively randomized comparison of definitive radiotherapy with or without cetuximab. Patients were treatment na?ve, and the experimental arm consisted of concomitant cetuximab administered weekly with radiotherapy. Three-year OS was superior with the combination compared with radiotherapy alone (57% v 44%, respectively).
Cohen et al,34 from the University of Chicago, conducted a phase II trial of the small-molecule tyrosine kinase inhibitor gefitinib in patients with recurrent or metastatic SCCHN. Of 47 assessable patients, responses were observed in 10.6%. Performance status and development of a skin rash were strong predictors of a tumor response and OS. The compound was generally well tolerated. Treatment was not associated with a change in EGFR or phosphorylated extracellular signal-regulated kinase expression in 10 patients.
Treatment-related skin rash may represent a pharmacodynamic surrogate indicator for the activity of cetuximab or gefitinib because the phenomenon is likely intimately related to the mechanism of action of these EGFR inhibitors. Saltz et al35 described a strong statistical association between the appearance of skin rash and improved survival in solid tumor patients treated in phase II cetuximab studies of varying malignancies. Soulieres et al36 also reported this association in a phase II study of erlotinib in SCCHN. The consistency of the observation suggests that skin rash may be an important clinical marker for treatment efficacy relating to the underlying mechanism of action. Notably, there were no other clinical or pathologic features predictive of a favorable response. Further investigations directed toward the elucidation of this phenomenon are indicated.
Our study was undertaken to characterize the activity of cetuximab with cisplatin in patients with advanced and refractory SCCHN. A sequence of studies strongly indicates that cetuximab is an active compound and that targeted therapy will be further investigated as a component of primary therapy for SCCHN patients. To better understand the biology of EGFR inhibitors and to improve patient selection, future trials will emphasize correlative molecular studies.
Appendix
The following investigators participated in this study: Lisle Nabell, University of Alabama Birmingham, AL; Roy Herbst, M.D. Anderson Cancer Center, Houston, TX; Rosemary Fiore, Monmouth Hematology/Oncology, Long Branch, NJ; Roger Cohen, University of Virginia, Charlottesville, VA; George Simon, University of Colorado Denver, CO; Fairooz Kabbinavar, University of California, Los Angeles Medical Center, Los Angeles, CA; Anne-Marie Maddox, University of Arkansas, Little Rock, AR; David Quinn, University of Southern California Norris Cancer Center, Los Angeles, CA; Amy Law, New England Medical Center, Boston, MA; Daniel Berg, University of Iowa, Iowa City, IA; Stephen Malamud, Beth Israel Medical Center, New York, NY; Hamid Rezazadeh, University of Wisconsin, Wausau, WI; William Schmidt, Trident Palmetto Hematology/Oncology, Charleston, SC; Stephen Grund, Albany Medical College, Albany, NY; Luis Fayad, Nevada Cancer Center, Las Vegas, NV; N. Simon Tchekmedyian, Pacific Shores Medical, Long Beach, CA; Lawrence Garbo, Capital District Hematology/Oncology, Albany, NY; Ross Siemers, Hubert Humphrey Cancer Center, Robbinsdale, MN; Matthew Arquette (deceased), Washington University, St Louis, MO; Francisco Gonzalez, University of South Carolina, Columbia, SC; Billy Clowney, Santee Hematology/Oncology, Sumter, SC; Roger Keresztes, Presbyterian Cornell Medical Center, New York, NY; Alan Kramer, San Francisco Oncology, San Francisco, CA; Paul Rosenberg Sacramento Center for Hematology, Sacramento, CA; Thomas Cartwright Ocala Oncology Center, Ocala, FL; Karel Dicke, Arlington Cancer Center, Arlington, TX; Michael Schwartz, Mount Sinai Medical Center, Miami Beach, FL; Lowell Hart, Florida Cancer Specialists, Ft Meyers, FL; Arthur Rosenberg, Bendheim Cancer Center, Greenwich, CT; Everett Vokes, University of Chicago, Chicago, IL; Michael Castine, Medical Oncology LLC, Baton Rouge, LA; John Eckardt, St Johns Mercy Medical Center, Washington, MO; Barbara Murphy, Vanderbilt Cancer Center, Nashville, TN; Steven William, Corso Gibbs Cancer Center, Spartanburg, SC; Donald Fleming, Louisville, KY; John Hamm Norton Health Care, Louisville, KY; George Simon, Denver Health Medical Center, Denver, CO; Lisle Nabell, University of Alabama at Birmingham, Birmingham, AL; and Madeline Kane, Denver Veterans Administration Medical Center, Denver, CO.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, the following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank Gloria Riojas for secretarial work.
NOTES
Deceased.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Ullrich A, Schlessinger J: Signal transduction by receptors with tyrosine kinase activity. Cell 61:203-212, 1990
Thompson DM, Gill GN: The EGF receptor: Structure, regulation and potential role in malignancy. Cancer Surv 4:767-788, 1985
Schlessinger J: The epidermal growth factor receptor as a multifunctional allosteric protein. Biochemistry 27:3119-3123, 1988
Yarden Y, Sliwkowski M: Untangling the ErbB signalling network. Nat Rev Mol Cell Bio 2:127-137, 2001
Olayioye M, Neve R, Lane H, et al: The ErbB signaling network: Receptor heterodimerization in development and cancer. EMBO J 19:3159-3167, 2000
Schlessinger J: Cell signaling by receptor tyrosine kinases. Cell 103:211-225, 2000
Mendelsohn J, Baselga J: The EGF receptor family as targets for cancer therapy. Oncogene 19:6550-6565, 2000
Santini J, Formento JL, Francoual M, et al: Characterization, quantification, and potential clinical value of the epidermal growth factor receptor in head and neck squamous cell carcinomas. Head Neck 13:132-139, 1991
Salomon DS, Brandt R, Ciardiello F, et al: Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19:183-232, 1995
Grandis JR, Melhem MF, Gooding WE, et al: Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 90:824-832, 1998
Ang KK, Berkey BA, Tu X, et al: Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 62:7350-7356, 2002
Kawamoto T, Sato JD, Le A, et al: Growth stimulation of A431 cells by epidermal growth factor: Identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci USA 80:1337-1341, 1983
Mendelsohn J: Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 20:1S-13S, 2002 (suppl 2)
Sato JD, Kawamoto T, Le AD, et al: Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med 1:511-529, 1983
Masui H, Kawamoto T, Sato JD, et al: Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 44:1002-1007, 1984
Goldstein NI, Prewett M, Zuklys K, et al: Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1:1311-1318, 1995
Fan Z, Baselga J, Masui H, et al: Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 53:4637-4642, 1993
Baselga J, Norton L, Masui H, et al: Antitumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies. J Natl Cancer Inst 85:1327-1333, 1993
Huang SM, Bock JM, Harari PM: Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 59:1935-1940, 1999
Jemal A, Murray T, Samuels A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5-26, 2003
Forastiere A, Koch W, Trotti A, et al: Head and neck cancer. N Engl J Med 345:1890-1900, 2001
Forastiere AA, Metch B, Schuller DE, et al: Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: A Southwest Oncology Group study. J Clin Oncol 10:1245-1251, 1992
Lu C, Kies M: Systemic therapy for recurrent and metastatic diseases, in Harrison LR, Sessions RB, Hong WK (eds): Head and Neck Cancer (ed 2). Philadelphia, PA, Lippincott Williams & Wilkins, 2003, pp 919-925
Shin DM, Donato NJ, Perez-Soler R, et al: Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer. Clin Cancer Res 7:1204-1213, 2001
WHO: World Health Organization Handbook for Reporting Results for Cancer Treatment. Geneva, Switzerland, WHO, 1979
Cella DF, Tulsky DS, Gray G, et al: The Functional Assessment of Cancer Therapy scale: Development and validation of the general measure. J Clin Oncol 11:570-579, 1993
List MA, D'Antonio LL, Cella DF, et al: The Performance Status Scale for Head and Neck Cancer Patients and the Functional Assessment of Cancer Therapy-Head and Neck Scale: A study of utility and validity. Cancer 77:2294-2301, 1996
Gehan EA: The determination of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent. J Chronic Dis 13:346-353, 1961
Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958
Baselga J, Trigo J, Bourhis J, et al: Cetuximab (C225) plus cisplatin/carboplatin is active in patients (pts) with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) progressing on a same dose and schedule platinum-based regimen. Proc Am Soc Clin Oncol 21:226a, 2002 (abstr 900)
Trigo J, Hitt P, Koralewski E, et al: Cetuximab monotherapy is active in patients (pts) with platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SSCH): Results of a phase II study. J Clin Oncol 22:488s, 2004 (suppl; abstr 5502)
Burtness B, Li Y, Flood W, et al: Phase III trial comparing cisplatin (C) + placebo (P) to C + anti-epidermal growth factor antibody (EGF-R) C225 in patients (pts) with metastatic/recurrent head and neck cancer (HNC). Proc Am Soc Clin Oncol 21:226a, 2002 (abstr 901)
Bonner JA, Harari PM, Giralt J, et al: Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab. J Clin Oncol 22:489a, 2004 (suppl; abstr 5507)
Cohen E, Rosen F, Stadler W, et al: Phase II trial of ZD 1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 21:1980-1987, 2003
Saltz L, Kies M, Abbruzzese J, et al: The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies. Proc Am Soc Clin Oncol 22:204a, 2003 (abstr 817)
Soulieres D, Senzer NN, Vokes EE, et al: Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 22:77-85, 2004(Roy S. Herbst, Matthew Ar)
Arlington Cancer Center, Dallas, TX
Department of Oncology, Washington University, St Louis, MO
Winship Cancer Institute, Emory University, Atlanta, GA
Department of Medicine, Section of Hematology and Oncology, Head and Neck Oncology Program, University of Chicago, Chicago, IL
Department of Clinical Affairs, ImClone Systems, Branchburg, NJ
ABSTRACT
PURPOSE: This multicenter phase II study was undertaken to define the efficacy and safety of cetuximab, an antiepidermal growth factor receptor chimeric human and murine monoclonal antibody, administered with cisplatin to patients with refractory metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN).
PATIENTS AND METHODS: One hundred thirty-two patients were to receive two 3-week cycles with cisplatin/paclitaxel or cisplatin/fluorouracil. Patients (n = 30) with a complete or partial response continued standard therapy. Seventy-six patients with stable disease (SD; n = 51) or progressive disease (PD/1; n = 25) received combination therapy with cetuximab (400 mg/m2 intravenously on day 1, then 250 mg/m2/wk) and cisplatin (75 or 100 mg/m2 intravenously on day 1 every 3 weeks). The protocol was subsequently amended to enroll patients who had developed PD within 90 days after platinum-based therapy (PD/2; n = 54).
RESULTS: Five patients (20%) in PD/1, three patients (6%) in PD/2, and nine patients (18%) with SD achieved an objective response. Median duration of response was 4.2, 4.1, and 7.4 months for the PD/1, PD/2, and SD groups, respectively, with median overall survival times of 6.1, 4.3, and 11.7 months. The most common toxicities were anemia, acne-like skin rash, leukopenia, fatigue and malaise, and nausea and vomiting. Seven patients (5%) developed a grade 3 or 4 hypersensitivity reaction to cetuximab.
CONCLUSION: Cetuximab and cisplatin is an active regimen in refractory SCCHN. The relative contribution of cetuximab is better defined in a single-agent trial. Cetuximab did not exacerbate cisplatin toxicity but was associated with skin rash in a majority of patients and occasional serious allergic reactions. Further study of this compound is warranted.
INTRODUCTION
Epidermal growth factor receptor (EGFR) is a 170-kd transmembrane glycoprotein receptor found on cells of epithelial origin.1-3 This glycoprotein is an important growth-regulatory signal transduction element exerting multiple functions through an intrinsic tyrosine kinase activity, which is activated on ligand binding.4-7 EGFR signaling has been associated with the malignant phenotype, inhibition of apoptosis, neoplastic angiogenesis, and enhanced metastatic potential.8 EGFR is overexpressed in squamous cancers of the head and neck,8,9 and increasing surface concentration has been associated with advanced stage and poor prognosis.9-11 In 1983, Kawamoto et al12 first produced monoclonal antibodies that blocked ligand binding preventing activation of the receptor. This approach was found to have antiproliferative effects in vitro, and it was hypothesized that blocking receptor activation would be an effective therapeutic strategy.13 Monoclonal antibodies (M225) directed against this receptor were generated in murine systems12,14 and were shown to have antitumor activity in vitro and in xenograft models.12,14,15 Later, this antibody was chimerized with human immunoglobulin G1 in its constant region to obtain cetuximab16 to increase clinical applicability by reducing the potential for generation of human antimurine antibodies in patients. In a sequence of preclinical studies, cetuximab was found to inhibit the growth of cultured tumor cell lines and repress in vivo growth of xenografts,16,17 augment the activity of doxorubicin18 and cisplatin,17,18 and modulate the response of tumor xenografts after radiation therapy.19
Approximately 40,000 cases of squamous cell carcinoma of the head and neck (SCCHN) were diagnosed in 2003 in the United States.20 Most patients are diagnosed with advanced regional disease, and approximately 40% of these patients will be cured. There have been only modest improvements in survival rates, despite the application of multimodal treatment approaches, with locoregional tumor recurrence the predominant failure pattern.21 The median survival time for patients with recurrent or metastatic disease is 5 to 7 months22,23 and is dismal for patients with refractory disease after first-line chemotherapy.
Shin et al24 conducted a phase IB study of cetuximab, in combination with cisplatin, in patients with recurrent SCCHN to determine the optimal biologic dose (ie, the tumor-saturating dose) and to establish a safety profile for this compound. A loading dose of cetuximab 400 mg/m2 and a weekly maintenance dose of 250 mg/m2 achieved tumor EGFR saturation. Moreover, a surprising observation was that six of nine assessable patients achieved a major response to the cetuximab combination. Three of these patients had experienced treatment failure with prior platinum-containing therapy. An acneiform skin reaction occurred in two patients (17%), and one patient developed a severe allergic reaction precluding further treatment. To confirm and expand on these observations, we designed a subsequent study for patients with recurrent SCCHN. All patients were to be treated with a cisplatin-containing chemotherapy regimen, and those patients failing to achieve disease response or with overt disease progression would proceed to the experimental regimen consisting of cetuximab and cisplatin.
PATIENTS AND METHODS
Patient Eligibility
To be eligible for the trial, patients were required to have the following: pathologically confirmed recurrent squamous cell carcinoma of the oral cavity, pharynx, or larynx considered not curable with conventional treatment; bidimensionally measurable disease; Karnofsky performance score (KPS) of 60; prior total cisplatin exposure 200 mg/m2 at the initiation of the study and 450 mg/m2 after an eligibility amendment (described in Stable and Progressive Disease Cohorts); and neuropathy grade 1 at study entry. Patients were 18 years of age; had adequate hematologic, hepatic, and renal functions; used effective contraception if procreative potential existed; and had sufficient tumor tissue available for immunohistochemical determination of EGFR expression. Exclusion criteria included pregnancy or lactation, prior murine monoclonal antibody therapy or cetuximab therapy, prior surgery or radiation therapy within 2 months of study entry, a history of clinically significant cardiac disease, uncontrolled seizure disorder or other serious neurologic disease, or a previous therapy with an investigational agent within 1 month of study entry. Signed informed consent, in accordance with institutional guidelines, was obtained before treatment.
Stable and Progressive Disease Cohorts
Initially, patients were candidates for this trial at the time of first recurrence after primary therapy or if there was distant metastatic disease. Enrolled patients with a total prior cisplatin exposure of 200 mg/m2 were to receive cisplatin and either paclitaxel or infusional fluorouracil, with regimens repeating at 3-week intervals for two treatment cycles (Fig 1). Patients would then be evaluated for tumor response. Those patients achieving a partial response (PR) or complete response (CR) were not eligible for the experimental regimen. Patients demonstrating stable disease (SD) or progressive disease (PD) were eligible to continue on the study and receive cetuximab in combination with cisplatin at the dose used in the initial treatment regimen (before cetuximab). Because the SD cohort completed accrual ahead of the PD/1 cohort, the protocol was amended in August of 2000 to accrue only patients with documented disease recurrence and tumor progression within 3 months of platinum-based therapy (PD/2). For this group, total prior cisplatin therapy was 450 mg/m2.
Cetuximab was manufactured and supplied by ImClone Systems Inc (Branchburg, NJ) and was administered by intravenous infusion at an initial dose of 400 mg/m2 over 2 hours, followed by weekly doses of 250 mg/m2 over 1 hour. Cisplatin was administered in a 1-hour infusion of 75 or 100 mg/m2 on the first day of each 21-day cycle. Because of the potential for an allergic reaction to cetuximab, patients were medicated with decadron 20 mg and diphenhydramine 50 mg intravenously 30 minutes before the cetuximab infusion and received a 20-mg test dose of cetuximab before the initial dose only, followed by an observation period of 30 minutes for signs of severe infusion reactions. Patients received the remainder of the initial dose after the observation period.
A delay of cetuximab therapy for 2 consecutive weeks was allowed for patients with grade 3 skin toxicity. There was no change in the cetuximab weekly schedule for cisplatin-related toxicity. Patients received hydration fluids and usual antiemetic preparations before the cisplatin administration. Cisplatin dose alterations were implemented for myelosuppression, nephrotoxicity and peripheral neuropathy, excessive vomiting, and ototoxicity. Stable or responding patients who developed grade 2 or 3 neurotoxicity or nephrotoxicity were shifted from cisplatin to carboplatin. The carboplatin dose was calculated according to the Calvert formula with area under the curve of 6. For SD and PD patients achieving SD or a tumor response, the platinum was discontinued after four treatment cycles, and cetuximab was continued weekly until disease progression, protocol noncompliance, intolerable toxicity, or an intercurrent illness that mandated interruption of therapy for more than two consecutive infusions.
Evaluation Criteria
The extent of malignant disease was evaluated in all treated patients before the start of cetuximab treatment and repeated at 6-week intervals. Tumor response was assessed using modified WHO criteria.25 CR was defined as the complete disappearance of all evidence of disease, including disease-related signs and symptoms, lasting at least 4 weeks. PR was defined as a 50% decrease in the sum of the products of the two longest perpendicular diameters of all measured lesions for at least 4 weeks, with no evidence of PD. SD was defined as no significant change in measurable and assessable disease. PD was defined as one or more of the following: a 25% increase in the sum of the products of the two longest perpendicular diameters of measurable lesions, unequivocal growth of existing assessable disease, the certain appearance of a new lesion, or reappearance of old lesions. The objective response rate was the percentage of patients achieving a CR or PR. Disease control was defined as the achievement of CR, PR, or SD. An independent head and neck radiologist confirmed PD status for the patients commencing therapy with cetuximab and cisplatin and verified response status during the course of treatment.
Duration of response was the time from initial response to first evidence of PD. Progression-free survival (PFS) was defined as the time from day 1 of treatment to the first evidence of PD or death within 3 months of the last study treatment administration. Overall survival (OS) was defined as the time from day 1 of treatment to death.
Quality of life (QOL) was assessed using the Functional Assessment of Cancer Therapy–Head and Neck questionnaire.26,27 The patients completed the instrument at study entry, every 6 weeks during therapy, at the time of the post-treatment evaluation, and at one additional follow-up evaluation. Compliance for completing the QOL questionnaires was investigated at each time point.
All patients who received at least one dose of the study medication were evaluated for safety. All clinical adverse events and laboratory abnormalities were graded by the National Cancer Institute Common Toxicity Criteria (version 2).
Statistical Considerations
The study objective was to determine the objective response rate of treatment with cetuximab and cisplatin in patients with recurrent or metastatic SCCHN who experienced treatment failure with cisplatin-based chemotherapy. Gehan's two-stage design, which allowed for early stopping for low activity, was used.28 The targeted response rate for SD and PD/1 patients was 15%. Initially, a total of 19 patients were to be enrolled onto either the SD or PD cohorts. If at least one response was observed, a second group of 30 patients was to be enrolled to allow for estimation of the response rate with an SE of as little as 5%.
The SD cohort completed accrual well ahead of the PD/1 cohort. Therefore, the protocol was amended to enroll only patients with documented disease recurrence and tumor progression within 3 months of platinum-based therapy (PD/2). Using Gehan's method as described earlier, the PD/2 cohort was to enroll a total of 49 patients with documented PD.
Efficacy results were summarized separately by subgroups (SD, PD/1, and PD/2). The response rates and 95% CIs were determined for each subgroup. The distribution of duration of response, PFS, and OS were estimated using the Kaplan-Meier product-limit method.29 A multivariate logistic regression analysis was performed to identify factors predictive of response to treatment. Also, multivariate proportional hazards modeling (Cox regression) was used to find covariates affecting PFS and OS times. QOL data were scored according to the Functional Assessment of Cancer Therapy manual.
Treatment-related adverse events (events that occurred or worsened on or after the first dose through 30 days after the last dose of study treatment) were grouped by Coding Symbols for Thesaurus of Adverse Reaction Terms–preferred term and body systems and summarized by worst grade severity per patient. Toxicities of special interest with cetuximab therapy included hypersensitivity reaction and an acne-like rash.
RESULTS
Patients
August 1999 through September 2001, a total of 187 patients were enrolled onto this study. Of those patients, 56 (30%) discontinued treatment on protocol before receiving cetuximab/cisplatin combination therapy for the following reasons: response to the initial cisplatin-containing regimen (n = 30), early death (n = 8), chemotherapy toxicity (n = 6), withdrawn consent (n = 4), protocol noncompliance (n = 3), PD with poor performance level (n = 2), diagnosis of a second primary tumor (n = 1), abnormal ECG (n = 1), and lost to follow-up (n = 1). One PR patient erroneously received 1 day of cetuximab/cisplatin combination therapy. That patient is included in the analysis of safety but was excluded from the efficacy analyses; 51 SD patients and 79 PD patients (25 PD/1 and 54 PD/2 patients) were evaluated for efficacy.
In summary, 131 patients were to receive cetuximab in combination with cisplatin. There were some differences in pretreatment characteristics between the three cohorts. In particular, patients in the PD/2 cohort had a higher prior cisplatin exposure (Table 1). Of the 131 patients, five with life-threatening hypersensitivity reactions to the first dose of cetuximab did not receive cisplatin. Of the remaining 126 patients, 18 received cisplatin at 100 mg/m2, and the other patients received a lesser dose. There was no statistically significant difference between these subgroups with respect to efficacy or toxicity because the number of patients treated at the higher cisplatin dose level was small. Thus, we report efficacy and toxicity results for the SD, PD/1, and PD/2 patient cohorts.
Efficacy
The investigator assessments of the treatment outcomes and best overall tumor responses are listed in Table 2, and an example of a response is shown in Figure 2. The objective response rate was 18% for the SD cohort and 20% and 6% for the PD/1 and PD/2 groups, respectively. The median duration of response was 7.4 months for the SD cohort, 4.2 months for the PD/1 cohort, and 4.1 months for the PD/2 cohort. The disease control rate was 76% for the SD cohort compared with 64% and 52% for the PD/1 and PD/2 cohorts. In this trial, the response rate trended higher for patients who had PD after two cisplatin-based treatment cycles on protocol (PD/1) than for patients with PD who failed a platinum-containing regimen administered in the community within 3 months of study entry (PD/2), but the numbers were small, and the difference between the two PD cohorts was not statistically significant (Fisher's exact test, P > .10). A multivariate logistic model failed to identify any factor for predicting response to treatment.
Both the PFS and OS times were greater in the SD cohort (4.9 and 11.7 months, respectively) compared with PD/1 (3.0 and 6.1 months, respectively) and PD/2 cohorts (2.0 and 4.3 months, respectively; Figs 3 and 4). A multivariate Cox regression analysis showed that, in this trial, for the PD cohorts, severity of rash was a predictor of PFS (Fig 5).
Table 3 lists the response rate and 1-year survival rates of patients by age, sex, KPS, prior paclitaxel therapy, and worst grade rash. Pretreatment KPS and severity of rash (Figs 6 and 7) were predictors of OS. There were no apparent trends found in the analysis of the Functional Assessment of Cancer Therapy–General and Functional Assessment of Cancer Therapy–Head and Neck results. A formal review and analysis is underway and will be reported separately.
Safety and Treatment Duration
All 131 patients receiving cetuximab were reported in the safety analysis. Of the 10 patients who experienced hypersensitivity reactions to their first dose of cetuximab, five discontinued cetuximab treatment after this initial dose, including three patients with grade 4 anaphylactic shock. Those patients recovered. The median duration of treatment with cetuximab was 12 weeks (range, 1 to 77 weeks). Sixteen patients (12%) continued on cetuximab beyond 6 months, and of these patients, five patients (4%) were treated for more than a year. The median duration of treatment with cisplatin and cetuximab was also 12 weeks (range, 1 to 20 weeks). Three patients started cetuximab treatment with carboplatin, 13 patients switched from cisplatin to carboplatin during the treatment phase, and 46 patients continued on cetuximab after cisplatin was discontinued. Of the eight patients who discontinued the study because of an adverse event, six had a major hypersensitivity reaction, one had fatigue, and one had aspiration pneumonia.
Dose reduction of cetuximab was uncommon. Dose delays of at least 1 week occurred in one third of the patients. Most treatment-related delays of cetuximab dosing were a result of folliculitis or paronychial infection. Cisplatin was delayed mostly for myelosuppression, hematologic toxicity, and/or nephrotoxicity. Twelve patients died on study (all unrelated to treatment).
The most common nonhematologic toxicity generally associated with cetuximab was rash, which was often described as acne-like and occurred in 70% of patients, including five patients with severe cases (Table 4). Median time to the first onset of rash was 2 weeks, with 80% of the rashes occurring during the first 3-week cycle of treatment. Median duration of rash was 4 weeks, and most resolved with no sequelae.
The most common grade 3 and 4 cisplatin toxicities were myelosuppression and nephrotoxicity. The most common hematologic toxicity was anemia, which occurred in 92% of patients. One patient was hospitalized for acute kidney failure and sepsis, and another patient was hospitalized for kidney failure and neutropenic fever. There was no apparent adverse interaction between cetuximab and cisplatin. None of the 28 deaths on study or within 30 days of the last dose of cetuximab was judged to be treatment related.
Pharmacokinetics
Mean cetuximab concentrations before every third dose ranged from 41.421 to 55.111 μg/mL (through dose 27). In addition, the data showed relatively consistent levels of cetuximab before every third dose, suggesting that the concentrations of cetuximab remained at a constant level throughout therapy.
DISCUSSION
In this phase II study, we identified patients with recurrent and refractory SCCHN for treatment with cisplatin and cetuximab. Cetuximab is a chimeric human/murine monoclonal antibody directed against EGFR. Cetuximab was combined with cisplatin because of a compelling preclinical literature indicating that therapeutic efficacy would be greater in combination with cytotoxic agents or radiation therapy.17-19 Shin et al24 had previously demonstrated in a phase IB study that six of nine assessable patients with recurrent SCCHN achieved major responses to this combination. This study was designed to extend those observations.
In the first phase of the protocol, patients with disease considered stable after two cycles of cisplatin-based chemotherapy then proceeded to the experimental regimen. Of 51 SD patients, nine (18%) achieved a major tumor response, with 39 patients (76%) considered to achieve some measure of disease control. Median OS time for the SD patients was an impressive 11.7 months. Seventy-nine patients identified as having PD after first-line cisplatin-based chemotherapy were studied. PD/1 consisted of 25 assessable patients, with five (20%) achieving partial disease remission and another 11 (44%) observed to have SD. In contrast, 54 patients (PD/2) entered the study after the amendment. These were PD patients with a clear demonstration of disease progression after chemotherapy administered within 90 days before treatment. In this group, only three patients (6%) achieved PR, and another 25 patients (46%) had SD. In aggregate, 10% of PD patients achieved partial disease regression. The discrepancy in response rates between PD/1 and PD/2 did not exceed confidence limits. However, there were clinical differences between these groups. Notably, median exposure to cisplatin before the experimental regimen was greater in PD/2 patients compared with PD/1 patients (200 v 150 mg/m2, respectively). The median time from prior therapy to the experimental treatment program was 3.9 weeks for PD/1 (range, 2.7 to 6.9 weeks) and 5.1 weeks for PD/2 (range, 2.5 to 25 weeks). Fifteen PD/2 patients (28%) started cetuximab and cisplatin 7 weeks or more after first-line chemotherapy. Because the prognosis for such patients is poor, any delay in starting the experimental program may have allowed for further disease progression, despite similarity in performance status and other baseline patient demographics. Thus, prospects for a tumor response in the PD/2 cohort may have been compromised. There also was a trend favoring survival for PD/1 patients compared with PD/2 patients (median survival time, 6.1 v 4.3 months, respectively).
There is no indication that cisplatin-based toxicity was exacerbated in combination with cetuximab. Five percent of patients had serious or life-threatening hypersensitivity responses after administration of the chimeric monoclonal antibody, leading to discontinuation of treatment. Moreover, 70% of patients suffered an acneiform or folliculitis-like rash attributed to cetuximab. A review of selected clinical toxicities, as presented in Table 4, otherwise seems to reflect the clinical course of patients declining with advanced SCCHN and of expected cisplatin-related effects.
Our data are comparable to those of Baselga et al30 who treated 96 patients with refractory SCCHN who were similar to our PD/2 cohort. An overall response rate of 14.6% was observed. Trigo et al.31 have recently reported that single-agent cetuximab, at the schedule used in our study, achieved PRs in 12.5% of patients with platinum-refractory SCCHN. This would suggest that the activity observed in our trial is related to the effects of cetuximab and not the cetuximab and cisplatin combination. Burtness et al32 conducted a double-blind, randomized, phase III trial comparing cisplatin as a single agent with cisplatin and cetuximab in patients with recurrent SCCHN. Tumor response was significantly higher after the experimental drug combination compared with the single agent (23.6% v 9.8%, respectively), and there was a trend toward better 2-year OS (15.6% v 9.2%, respectively). Furthermore, in a potential landmark study, Bonner et al33 reported the results of a phase III, prospectively randomized comparison of definitive radiotherapy with or without cetuximab. Patients were treatment na?ve, and the experimental arm consisted of concomitant cetuximab administered weekly with radiotherapy. Three-year OS was superior with the combination compared with radiotherapy alone (57% v 44%, respectively).
Cohen et al,34 from the University of Chicago, conducted a phase II trial of the small-molecule tyrosine kinase inhibitor gefitinib in patients with recurrent or metastatic SCCHN. Of 47 assessable patients, responses were observed in 10.6%. Performance status and development of a skin rash were strong predictors of a tumor response and OS. The compound was generally well tolerated. Treatment was not associated with a change in EGFR or phosphorylated extracellular signal-regulated kinase expression in 10 patients.
Treatment-related skin rash may represent a pharmacodynamic surrogate indicator for the activity of cetuximab or gefitinib because the phenomenon is likely intimately related to the mechanism of action of these EGFR inhibitors. Saltz et al35 described a strong statistical association between the appearance of skin rash and improved survival in solid tumor patients treated in phase II cetuximab studies of varying malignancies. Soulieres et al36 also reported this association in a phase II study of erlotinib in SCCHN. The consistency of the observation suggests that skin rash may be an important clinical marker for treatment efficacy relating to the underlying mechanism of action. Notably, there were no other clinical or pathologic features predictive of a favorable response. Further investigations directed toward the elucidation of this phenomenon are indicated.
Our study was undertaken to characterize the activity of cetuximab with cisplatin in patients with advanced and refractory SCCHN. A sequence of studies strongly indicates that cetuximab is an active compound and that targeted therapy will be further investigated as a component of primary therapy for SCCHN patients. To better understand the biology of EGFR inhibitors and to improve patient selection, future trials will emphasize correlative molecular studies.
Appendix
The following investigators participated in this study: Lisle Nabell, University of Alabama Birmingham, AL; Roy Herbst, M.D. Anderson Cancer Center, Houston, TX; Rosemary Fiore, Monmouth Hematology/Oncology, Long Branch, NJ; Roger Cohen, University of Virginia, Charlottesville, VA; George Simon, University of Colorado Denver, CO; Fairooz Kabbinavar, University of California, Los Angeles Medical Center, Los Angeles, CA; Anne-Marie Maddox, University of Arkansas, Little Rock, AR; David Quinn, University of Southern California Norris Cancer Center, Los Angeles, CA; Amy Law, New England Medical Center, Boston, MA; Daniel Berg, University of Iowa, Iowa City, IA; Stephen Malamud, Beth Israel Medical Center, New York, NY; Hamid Rezazadeh, University of Wisconsin, Wausau, WI; William Schmidt, Trident Palmetto Hematology/Oncology, Charleston, SC; Stephen Grund, Albany Medical College, Albany, NY; Luis Fayad, Nevada Cancer Center, Las Vegas, NV; N. Simon Tchekmedyian, Pacific Shores Medical, Long Beach, CA; Lawrence Garbo, Capital District Hematology/Oncology, Albany, NY; Ross Siemers, Hubert Humphrey Cancer Center, Robbinsdale, MN; Matthew Arquette (deceased), Washington University, St Louis, MO; Francisco Gonzalez, University of South Carolina, Columbia, SC; Billy Clowney, Santee Hematology/Oncology, Sumter, SC; Roger Keresztes, Presbyterian Cornell Medical Center, New York, NY; Alan Kramer, San Francisco Oncology, San Francisco, CA; Paul Rosenberg Sacramento Center for Hematology, Sacramento, CA; Thomas Cartwright Ocala Oncology Center, Ocala, FL; Karel Dicke, Arlington Cancer Center, Arlington, TX; Michael Schwartz, Mount Sinai Medical Center, Miami Beach, FL; Lowell Hart, Florida Cancer Specialists, Ft Meyers, FL; Arthur Rosenberg, Bendheim Cancer Center, Greenwich, CT; Everett Vokes, University of Chicago, Chicago, IL; Michael Castine, Medical Oncology LLC, Baton Rouge, LA; John Eckardt, St Johns Mercy Medical Center, Washington, MO; Barbara Murphy, Vanderbilt Cancer Center, Nashville, TN; Steven William, Corso Gibbs Cancer Center, Spartanburg, SC; Donald Fleming, Louisville, KY; John Hamm Norton Health Care, Louisville, KY; George Simon, Denver Health Medical Center, Denver, CO; Lisle Nabell, University of Alabama at Birmingham, Birmingham, AL; and Madeline Kane, Denver Veterans Administration Medical Center, Denver, CO.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, the following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank Gloria Riojas for secretarial work.
NOTES
Deceased.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Ullrich A, Schlessinger J: Signal transduction by receptors with tyrosine kinase activity. Cell 61:203-212, 1990
Thompson DM, Gill GN: The EGF receptor: Structure, regulation and potential role in malignancy. Cancer Surv 4:767-788, 1985
Schlessinger J: The epidermal growth factor receptor as a multifunctional allosteric protein. Biochemistry 27:3119-3123, 1988
Yarden Y, Sliwkowski M: Untangling the ErbB signalling network. Nat Rev Mol Cell Bio 2:127-137, 2001
Olayioye M, Neve R, Lane H, et al: The ErbB signaling network: Receptor heterodimerization in development and cancer. EMBO J 19:3159-3167, 2000
Schlessinger J: Cell signaling by receptor tyrosine kinases. Cell 103:211-225, 2000
Mendelsohn J, Baselga J: The EGF receptor family as targets for cancer therapy. Oncogene 19:6550-6565, 2000
Santini J, Formento JL, Francoual M, et al: Characterization, quantification, and potential clinical value of the epidermal growth factor receptor in head and neck squamous cell carcinomas. Head Neck 13:132-139, 1991
Salomon DS, Brandt R, Ciardiello F, et al: Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19:183-232, 1995
Grandis JR, Melhem MF, Gooding WE, et al: Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 90:824-832, 1998
Ang KK, Berkey BA, Tu X, et al: Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 62:7350-7356, 2002
Kawamoto T, Sato JD, Le A, et al: Growth stimulation of A431 cells by epidermal growth factor: Identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci USA 80:1337-1341, 1983
Mendelsohn J: Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 20:1S-13S, 2002 (suppl 2)
Sato JD, Kawamoto T, Le AD, et al: Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med 1:511-529, 1983
Masui H, Kawamoto T, Sato JD, et al: Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 44:1002-1007, 1984
Goldstein NI, Prewett M, Zuklys K, et al: Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1:1311-1318, 1995
Fan Z, Baselga J, Masui H, et al: Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 53:4637-4642, 1993
Baselga J, Norton L, Masui H, et al: Antitumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies. J Natl Cancer Inst 85:1327-1333, 1993
Huang SM, Bock JM, Harari PM: Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 59:1935-1940, 1999
Jemal A, Murray T, Samuels A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5-26, 2003
Forastiere A, Koch W, Trotti A, et al: Head and neck cancer. N Engl J Med 345:1890-1900, 2001
Forastiere AA, Metch B, Schuller DE, et al: Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: A Southwest Oncology Group study. J Clin Oncol 10:1245-1251, 1992
Lu C, Kies M: Systemic therapy for recurrent and metastatic diseases, in Harrison LR, Sessions RB, Hong WK (eds): Head and Neck Cancer (ed 2). Philadelphia, PA, Lippincott Williams & Wilkins, 2003, pp 919-925
Shin DM, Donato NJ, Perez-Soler R, et al: Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer. Clin Cancer Res 7:1204-1213, 2001
WHO: World Health Organization Handbook for Reporting Results for Cancer Treatment. Geneva, Switzerland, WHO, 1979
Cella DF, Tulsky DS, Gray G, et al: The Functional Assessment of Cancer Therapy scale: Development and validation of the general measure. J Clin Oncol 11:570-579, 1993
List MA, D'Antonio LL, Cella DF, et al: The Performance Status Scale for Head and Neck Cancer Patients and the Functional Assessment of Cancer Therapy-Head and Neck Scale: A study of utility and validity. Cancer 77:2294-2301, 1996
Gehan EA: The determination of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent. J Chronic Dis 13:346-353, 1961
Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958
Baselga J, Trigo J, Bourhis J, et al: Cetuximab (C225) plus cisplatin/carboplatin is active in patients (pts) with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) progressing on a same dose and schedule platinum-based regimen. Proc Am Soc Clin Oncol 21:226a, 2002 (abstr 900)
Trigo J, Hitt P, Koralewski E, et al: Cetuximab monotherapy is active in patients (pts) with platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SSCH): Results of a phase II study. J Clin Oncol 22:488s, 2004 (suppl; abstr 5502)
Burtness B, Li Y, Flood W, et al: Phase III trial comparing cisplatin (C) + placebo (P) to C + anti-epidermal growth factor antibody (EGF-R) C225 in patients (pts) with metastatic/recurrent head and neck cancer (HNC). Proc Am Soc Clin Oncol 21:226a, 2002 (abstr 901)
Bonner JA, Harari PM, Giralt J, et al: Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab. J Clin Oncol 22:489a, 2004 (suppl; abstr 5507)
Cohen E, Rosen F, Stadler W, et al: Phase II trial of ZD 1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 21:1980-1987, 2003
Saltz L, Kies M, Abbruzzese J, et al: The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies. Proc Am Soc Clin Oncol 22:204a, 2003 (abstr 817)
Soulieres D, Senzer NN, Vokes EE, et al: Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 22:77-85, 2004(Roy S. Herbst, Matthew Ar)