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Journal of Clinical Oncology, Vol 25, No 16 (June 1), 2007: pp. 2178-2183 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.6547 Phase I/II Trial of Erlotinib and Cisplatin in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: A Princess Margaret Hospital Phase II Consortium and National Cancer Institute of Canada Clinical Trials Group Study
From the Princess Margaret Hospital Phase II Consortium, Toronto; National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada; and the National Cancer Institute, Bethesda, MD Address reprint requests to Lillian L. Siu, MD, Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Ave, Suite 5-718, Toronto, Ontario, Canada M5G 2M9; e-mail: lillian.siu{at}uhn.on.ca
Purpose: To determine the phase II dose and objective response rate of erlotinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, in combination with cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC). Patients and Methods: HNSCC patients with no prior chemotherapy and measurable disease were treated in three escalating-dose cohorts of daily continuous oral (PO) erlotinib and intermittent intravenous (IV) cisplatin given every 21 days. The recommended phase II dose (RPTD) was then evaluated in a two-stage trial with a primary end point of objective response rate. Results: A total of 51 patients were enrolled. The RPTD was identified as erlotinib 100 mg PO daily and cisplatin 75 mg/m2 IV every 21 days. Forty-five patients were treated at the RPTD, of which 44 and 43 were eligible for toxicity and efficacy evaluations, respectively. The intention-to-treat response rate was 21%, with one complete and eight partial responses (95% CI, 10% to 36%), and disease stabilization was achieved in 21 patients (49%; 95% CI, 33% to 65%). Median progression-free survival was 3.3 months (95% CI, 2.7 to 4.8 months) and median overall survival was 7.9 (95% CI, 5.6 to 9.5) months. The combination was well tolerated, with minimal grade 3 or higher toxicity. Subgroup analysis suggested that patients who developed higher grade skin rashes during cycle 1 had better survival outcomes (P = .034). Conclusion: This schedule of erlotinib and cisplatin has a favorable toxicity profile and has antitumor activity in HNSCC comparable to standard combination chemotherapy regimens.
Large randomized clinical trials that spanned the last decade evaluating combination chemotherapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) have demonstrated little progress; median survival remains only 6 to 8 months.1,2 Although conventional cytotoxic combinations produce objective responses in approximately 25% to 30% of patients, they often cause significant toxicity, and their effects on the quality of life in this population have not been well studied.2,3 Intensification of chemotherapeutic regimens, such as the use of high-dose paclitaxel in combination with cisplatin and growth factor support in the Eastern Cooperative Oncology Group study E1393, has led to excessive toxicity and failed to improve survival outcome.4 Such observations have motivated oncologists to continue to seek novel treatments to improve disease control and palliation for these patients. Multiple lines of evidence support targeting epidermal growth factor receptor (EGFR) as a therapeutic strategy in HNSCC. EGFR is expressed in 80% to 100% of HNSCC, and elevated levels of EGFR and transforming growth factor mRNA have been detected in both tumors and histologically normal mucosa from patients with HNSCC, when compared with control normal mucosa.5 Clinicopathologic associations between EGFR overexpression and poorer prognosis have also been reported.6-8 Current therapeutic strategies targeting EGFR that have found clinical utility include monoclonal antibodies and small molecule tyrosine kinase inhibitors. Erlotinib hydrochloride (erlotinib; N-(3-ethynyphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine; formerly CP-358,774, OSI-774; Tarceva; OSI Pharmaceuticals, Melville, NY) is an orally available, potent, reversible, and selective inhibitor of the EGFR tyrosine kinase. In a large, multicenter phase II study of single-agent erlotinib administered on a continuous schedule of 150 mg once daily, partial responses and disease stabilization were observed, respectively, in 4% and 38% of patients with refractory HNSCC.9 Cisplatin is the cytotoxic agent with the greatest single-agent activity in HNSCC.10 In vivo, erlotinib combined with cisplatin produced additive antitumor effects without increased toxicity.11 Based on the rationale provided by these observations, a phase I/II trial to evaluate a combination of erlotinib and cisplatin in recurrent or metastatic HNSCC was undertaken. The primary objective of the phase I component was to determine the recommended phase II dose (RPTD) of this combination. The primary objective of the phase II component was to elucidate the efficacy and toxicity of this combination in this population. Secondary objectives included measurements of stable disease rates, duration of responses, progression-free survival (PFS), overall survival (OS), pharmacokinetic profile of erlotinib administered with cisplatin, and pharmacodynamic effects of erlotinib in tumor and skin samples. The latter results are reported separately in a companion article.12
Eligibility Patients with histologically or cytologically confirmed diagnosis of recurrent or metastatic HNSCC from any of the primary sites were candidates for this trial. Patients may have had prior induction or concurrent chemotherapy delivered as part of their primary treatment but must have completed primary therapy at least 6 months before study entry. EGFR overexpression was not an inclusion criterion for this study, but all patients must have archival or fresh tumor specimens available and assessable for determination of expression of the EGFR by immunohistochemistry. Other eligibility criteria included age 18 years or older; Eastern Cooperative Oncology Group performance status 0 to 2; ability to swallow tablets, or presence of a silicone-based gastrostomy or jejunostomy feeding tube whereby tablets could be dissolved and administered; measurable disease by Response Evaluation Criteria in Solid Tumors Group criteria13; adequate hematopoietic (absolute neutrophil count  1.5 x 109/L and platelet count 100 x 109/L), hepatic (AST and ALT levels  2.5x the upper normal limit and bilirubin 1.25x the upper limit of normal), and renal functions (serum creatinine within normal limits or measured creatinine clearance 60 mL/min); and no prior therapy with EGFR-targeting agents. This trial was approved by the research ethics boards of the participating institutions, and all patients gave written informed consent in accordance with the federal and institutional guidelines before study treatment.
Drug Administration
Phase I and Phase II Components
For the phase II component, P0 and P1 were set at .2 and .4 respectively, with
Pretreatment and Follow-Up Studies
Pharmacokinetic Sampling and Assay
Statistical Analysis and Sample Size Determination
Phase I Component During the phase I component of this trial, three assessable patients were enrolled onto each of three dose levels. DLT was not encountered in dose levels 1 and 2. Two of three patients in dose level 3 encountered DLT, with grade 4 neutropenia in one patient and grade 3 fatigue in another patient. Hence, dose level 3 was deemed to be the maximally administered dose. Although normally the dose level immediately below would be expanded, a decision was made by study investigators to expand dose level 1 (ie, erlotinib 100 mg PO daily and cisplatin 75 mg/m2 IV every 3 weeks). Interestingly, two of three patients treated at dose level 1 achieved partial responses, whereas no objective responses were seen in dose levels 2 and 3. Hence, even though the sample sizes were small, the decision to expand dose level 1 was made due to its favorable therapeutic index. An additional three assessable patients were treated at the expanded dose level 1; one of these three patients developed grade 3 creatinine elevation deemed to be dose-limiting, but no other DLT was seen. Hence, dose level 1 with DLT occurring in one of six assessable patients, was determined to be the RPTD.
Phase II Component
Safety Table 2 lists the most frequently observed adverse events considered possibly, probably, or definitely related to study therapy for the 44 patients treated in the phase II cohort at RPTD. Overall, the combination of erlotinib and cisplatin was well tolerated. The most frequent grade 1 to 2 toxicities encountered, based on percentage of cycles delivered, were rash (68%), hypomagnesemia (51%), anemia (29%), fatigue (23%), lymphopenia (23%), and dry skin (21%). Adverse events of grade 3 or worse were rare; the most frequent were fatigue and lymphopenia, seen in 3% of treatment cycles.
Efficacy Efficacy data for the phase II cohort are summarized in Table 3. A total of 238 treatment cycles (median, 4; range, 1 to 15) were administered to 44 patients. Nine patients achieved an objective tumor response, confirmed by independent radiology review. One patient had a complete response and remained on study treatment for 15 cycles before disease progression. Eight patients had partial responses lasting seven to 12 cycles. The objective response rate, by intention-to-treat status, was nine of 43 (21%; 95% CI, 10% to 36%). Twenty-one patients achieved disease stabilization, two of whom had unconfirmed partial responses. The rate of stable disease was 21 of 43 (49%; 95% CI, 33% to 65%) by intention-to-treat status. Nine patients had disease progression as their best response on study.
All patients who discontinued study treatment did so because of disease progression or death except one patient who withdrew consent (after 2 weeks) and two patients who discontinued study treatment due to adverse events (after 2 and 14.9 weeks, respectively). Median PFS was 3.3 months (95% CI, 2.7 to 4.8 months), and the 6-month PFS rate was 20.6% (95% CI, 11.2% to 38.0%; Fig 1A). All but four patients (one withdrew consent at 2 weeks, one was lost to follow-up with brain metastases at 1 month, and two are alive at 15.8 and 18.5 months, respectively) are known to have died. Median OS was 7.9 months (95% CI, 5.6 to 9.5 months), 6-month OS rate was 61.0% (95% CI, 47.7% to 77.9%), and 12-month OS rate was 19.5% (95% CI, 10.5% to 36.3%; Fig 1B).
Subgroup Analysis When analyzed as a function of rash severity in cycle 1, the median survival durations of patients with no rash, grade 1 rash, and grade 2 rash were 4.2, 7.9, and 9.2 months, respectively (P = .034). No patients developed skin rashes of grade 3 or worse intensity. Figure 1C illustrates the Kaplan-Meier curves of survival as stratified by grade of skin rash in cycle 1.
Pharmacokinetic Analysis
The RPTD derived from the dose-finding component of this study was erlotinib 100 mg PO daily and cisplatin 75 mg/m2 IV every 3 weeks. Objective tumor responses were seen in nine of 39 assessable patients, which included one complete and eight partial responses. Two additional patients had unconfirmed partial responses that were counted as stable disease. The study's preset criterion, which was calculated based on a P0 of .2 and P1 of .4, specified that this regimen would be considered for additional evaluation if 11 or more objective responses were observed out of 37 assessable patients. With this fairly ambitious threshold, the efficacy outcome of this study did not fulfill its preset criterion. However, the expectation to obtain response rates near 40% with a targeted agent plus platinum combination in recurrent or metastatic HNSCC is likely unrealistic. The results of this study are consistent with those published in the literature. Table 5 summarizes the results of antitumor activity of EGFR inhibitors with or without platinum in patients with recurrent or metastatic HNSCC.9,16-20 Single-agent EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, exhibit objective response rates in the range of 1% to 10%, and disease stabilization rates of 33% to 47%.9,19,20 PFS ranged from 1.8 to 3.4 months and median survival ranged from 5.5 to 8.1 months. Patients in these studies typically were heavily pretreated, with 59% to 85% having had prior exposure to chemotherapy. The combination of the anti-EGFR monoclonal antibody, cetuximab, with cisplatin has been evaluated in both platinum-sensitive and platinum-refractory recurrent or metastatic HNSCC populations.
In the studies that evaluated this combination among patients with platinum-refractory disease,17,18 objective response rates and disease stabilization rates generally were approximately 6% to 20% and 44% to 53%, respectively. PFS durations varied from 2.0 to 3.0 months and median survival varied from 4.3 to 6.1 months. These results are remarkably similar to those obtained using single-agent tyrosine kinase inhibitors. Burtness et al16 presented the only phase III data of cetuximab plus cisplatin versus placebo plus cisplatin in patients with platinum-sensitive recurrent or metastatic HNSCC. In that study, the addition of cetuximab to cisplatin significantly increased objective response rate, but did not significantly improve PFS and OS. Results from our phase II study of erlotinib plus cisplatin are highly concordant with those derived from the cetuximab plus cisplatin arm of the randomized phase III trial, with response rates of 21% v 26%, PFS of 3.3 v 4.2 months, and median survival of 7.9 v 9.2 months, respectively. It is unlikely that the combination of erlotinib and cisplatin will yield improved survival outcomes compared with cisplatin alone, given the results of the phase III trial evaluating cetuximab plus cisplatin.16 However, among patients who are symptomatic (in whom it is important to achieve rapid tumor shrinkage or disease stabilization), the erlotinib plus cisplatin combination offers a disease control rate of 70%, with minimal adverse effects. When compared against standard regimens using infusional fluorouracil or higher dose cisplatin (100 mg/m2), the combination of erlotinib and cisplatin (75 mg/m2) may obviate the need for prolonged continuous intravenous infusions or overnight admissions for hydration. The therapeutic index of the erlotinib and cisplatin combination in the current study compares favorably to standard cytotoxic platinum-based doublets, especially with respect to its efficacy outcomes and its low incidences of grade 3 or worse adverse events.2 Similar to previous studies with EGFR inhibitors,9,16,17,20 our study showed in subgroup analysis that the development of skin rash correlated with survival outcomes in this patient population, and not with tumor response. The early development of skin rash, along with pharmacodynamic markers in tumor and skin biopsies, reported in our companion article,12 require additional validation of their predictive roles in clinical outcome. The concurrent administration schedule of erlotinib and cisplatin in this study is a subject worthy of discussion. Preclinically in head and neck tumor xenografts, regardless of the dosing sequence (ie, erlotinib before cisplatin, cisplatin before erlotinib, or concurrent delivery of both agents), no differences in antitumor activity or toxicity was seen.11 Clinical studies of concurrent administration of erlotinib and platinum-based chemotherapy in advanced non–small-cell lung cancer have failed to demonstrate benefits in response rates or survival compared with chemotherapy alone.21,22 Whether this lack of benefits is due to negative pharmacologic or molecular interactions is uncertain, although speculations about the potential mechanisms have been raised.23 Equally unclear is the relevance of this finding to the combination of EGFR tyrosine kinase inhibitors and platinum-based chemotherapy in other disease sites, such as HNSCC. Although the lack of survival advantage with cetuximab plus cisplatin versus placebo plus cisplatin in the randomized trial by Burtness et al16 raised similar concerns, this study was not powered to detect OS differences as its primary end point. In conclusion, even though this trial did not meet its preset criterion for additional development of the erlotinib plus cisplatin combination in recurrent or metastatic HNSCC, this regimen was well tolerated and convenient in its delivery.
Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. Employment: N/A Leadership: N/A Consultant: Denis Soulioeres, Hoffman-La Roche Inc Stock: N/A Honoraria: Denis Soulieres, Hoffman-La Roche Inc Research Funds: Denis Soulieres, Hoffman-La Roche Inc Testimony: N/A Other: N/A
Conception and design: Lillian L. Siu, Janet Dancey, Eric Winquist Administrative support: Lillian L. Siu, Janet Dancey, Elizabeth A. Eisenhauer Provision of study materials or patients: Lillian L. Siu, Denis Soulieres, Eric X. Chen, Soo F. Chin, Luc Harvey, Eric Winquist Collection and assembly of data: Gregory R. Pond, Peggy Francis, Meri Klein Data analysis and interpretation: Lillian L. Siu, Gregory R. Pond, Wenjiang Zhang, Eric Winquist Manuscript writing: Lillian L. Siu, Eric Winquist Final approval of manuscript: Lillian L. Siu, Denis Soulieres, Eric X. Chen, Gregory R. Pond, Soo F. Chin, Peggy Francis, Luc Harvey, Meri Klein, Wenjiang Zhang, Janet Dancey, Elizabeth A. Eisenhauer, Eric Winquist
Supported by Clinical Trial Contract from the US National Cancer Institute (N01-CM-17107). Presented in part at the 15th Annual National Cancer Institute-European Organisation for Research and Treatment of Cancer-American Association for Cancer Research Symposium on Molecular Targets in Cancer Therapy, November 17-21, 2003, Boston, MA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. 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 2. Gibson MK, Li Y, Murphy B, et al: Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): An intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 23:3562-3567, 2005 3. Cohen EE, Lingen MW, Vokes EE: The expanding role of systemic therapy in head and neck cancer. J Clin Oncol 22:1743-1752, 2004 4. Forastiere AA, Leong T, Rowinsky E, et al: Phase III comparison of high-dose paclitaxel + cisplatin + granulocyte colony-stimulating factor versus low-dose paclitaxel + cisplatin in advanced head and neck cancer: Eastern Cooperative Oncology Group Study E1393. J Clin Oncol 19:1088-1095, 2001 5. Grandis JR, Tweardy DJ: Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 53:3579-3584, 1993 6. 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 7. Hitt R, Ciruelos E, Amador ML, et al: Prognostic value of the epidermal growth factor receptor (EGRF) and p53 in advanced head and neck squamous cell carcinoma patients treated with induction chemotherapy. Eur J Cancer 41:453-460, 2005[CrossRef][Medline] 8. Pomerantz RG, Grandis JR: The epidermal growth factor receptor signaling network in head and neck carcinogenesis and implications for targeted therapy. Semin Oncol 31:734-743, 2004[CrossRef][Medline] 9. 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 10. Jacobs C, Lyman G, Velez-Garcia E, et al: A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 10:257-263, 1992[Medline] 11. Pollack VA, Savage DM, Baker DA, et al: Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: Dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther 291:739-748, 1999 12. Agulnik M, da Cunha-Santos G, Hedley D, et al: Predictive and pharmacodynamic biomarker studies in tumor and skin tissue samples of patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated by erlotinib. J Clin Oncol 25:10.1200/JCO.2006.07.6554 13. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 14. Zhang W, Siu LL, Moore MJ, et al: Simultaneous determination of OSI-774 and its major metabolite OSI-420 in human plasma by using HPLC with UV detection. J Chromatogr B Analyt Technol Biomed Life Sci 814:143-147, 2005[Medline] 15. Hidalgo M, Siu LL, Nemunaitis J, et al: Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267-3279, 2001 16. Burtness B, Goldwasser MA, Flood W, et al: Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 23:8646-8654, 2005 17. Baselga J, Trigo JM, Bourhis J, et al: Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 23:5568-5577, 2005 18. Herbst RS, Arquette M, Shin DM, et al: Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol 23:5578-5587, 2005 19. Cohen EE, Kane MA, List MA, et al: Phase II trial of gefitinib 250 mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res 11:8418-8424, 2005 20. Cohen EE, Rosen F, Stadler WM, et al: Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 21:1980-1987, 2003 21. Herbst RS, Prager D, Hermann R, et al: TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 23:5892-5899, 2005 22. Gatzemeier U, Pluzanska A, Szczesna A, et al: Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC). J Clin Oncol 22:619s, 2004 (suppl; abstr 7010) 23. Piperdi B, Ling Y-H, Kroog G, et al: Schedule-dependent interaction between epidermal growth factor inhibitors (EGFRI) and G2/M blocking chemotherapeutic agents (G2/MB) on human NSCLC cell lines in vitro. J Clin Oncol 22:623s, 2004 (suppl; abstr 7028) Submitted May 31, 2006; accepted August 28, 2006. Related Editorial
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
= .10, ß = .10. In the first stage, 17 patients assessable for response would be enrolled, and accrual would proceed to the second stage only if four or more objective responses were observed. This group would include the six patients treated at the RPTD in the phase I portion. In the second stage, 20 additional patients assessable for response would be enrolled, and the regimen would be considered of interest for additional evaluation if at least 11 objective responses were observed out of the total phase II sample size of 37 assessable patients. 
