A Phase I Trial of Erlotinib and Concurrent Chemoradiotherapy for Stage III and IV (M0) Squamous Cell Carcinoma of the Head and Neck

Abstract

Purpose

Erlotinib, an orally active selective inhibitor of the EGFR tyrosine kinase has synergistic activity with radiation and with cisplatin. The EGFR is overexpressed in the majority of head and neck cancers. The primary objective of this Phase I study was to determine the Maximally Tolerated Dose (MTD) of erlotinib in combination with low-dose daily cisplatin and radiotherapy. We also sought evidence of biological activity of erlotinib alone using serial 18-FDG PET imaging.

Experimental Design

Oral erlotinib was taken daily starting with a 14-day run-in and continued until RT was completed. Low-dose daily cisplatin, 6 mg/m2 IV was given concurrently with standard fractionation RT to a total dose of 66–70 Gy. Dose escalation followed a modified Fibonacci dose escalation design.

Results

Twenty-two patients were enrolled and 18 patients received therapy on protocol. MTD of the combination of erlotinib, cisplatin and radiation therapy was not reached. The recommended phase II dose of erlotinib is 150 mg per day in combination with cisplatin and radiation therapy, the highest dose of erlotinib evaluated in this study. 18F-FDG PET demonstrated evidence for metabolic response to single agent erlotinib. Per PERCIST criteria, the overall metabolic response rate at day 14 was 38.8% (95%CI, 17.3–64.3%). On completion of concurrent chemoradiotherapy, overall response rate derived from tumor measurements based on imaging studies was 83% for all dose levels combined.

Conclusions

Erlotinib in combination with low dose daily cisplatin and radiation therapy is well tolerated and demonstrates evidence of clinical efficacy. The combination should be evaluated further.

Introduction

Forty thousand incident cases of squamous cell carcinoma of the head and neck are diagnosed in the United States each year. Despite standard-of-care platinum-based concurrent chemoradiotherapy (CCR) or surgery plus adjuvant radiotherapy (with or without chemotherapy), the overall survival of patients with local-regionally advanced (stages III–IV, M0) oral squamous cell carcinoma (HNC) remains poor. In particular, patients with human papillomavirus (HPV) negative cancers have a 2-year overall survival of less than 60%(1).

Intergroup Trial 9111 has established high-dose cisplatin concurrently administered with radiation therapy as the standard of care for organ preservation for advanced laryngeal cancer (2). This combination has also been applied as a non-surgical, curative approach to locally advanced cancers arising from other anatomic sites (3–5). A meta-analysis found that cisplatin-based concurrent chemoradiotherapy led to the greatest improvement in overall survival ⁴. However the optimal dose and schedule of cisplatin has not been determined by comparison in clinical trials. Two clinical trials have demonstrated that low-dose daily radiosensitizing cisplatin (6 mg/m² per radiation fraction), administered concurrent with either standard fractionation or hyperfractionation radiation therapy improved local-regional control and overall survival and reduced rates of distant metastases when compared to radiation alone. This dose and schedule of cisplatin was associated with reduced hematological and non-hematological toxicities, and therefore may allow for the safe addition of targeted therapies (6–7).

The Epidermal Growth Factor Receptor (EGFR) and its ligands, EGF and TGF-alpha, play important roles in cell proliferation, motility, adhesion, invasion, survival and angiogenesis (8). Abnormalities of EGFR signal transduction are common in squamous cell carcinomas of the head and neck. Overexpression of EGFR has been demonstrated in the majority (80–100%), and may be related to advanced T stage and presence of nodal disease. EGFR overexpression has also been shown to be a predictor of survival (9–10).

Treatment of tumor cells in vitro with anti-EGFR antibody induces arrest of cells in G₁ with an increase in the cyclin-dependent kinase inhibitor p27kip1 and a decrease in retinoblastoma protein (Rb) phosphorylation (11). Moreover, synergy exists between EGFR inhibition, radiation and chemotherapy. Although not completely understood, these observations may be related to inhibition of multiple growth-promoting signals such as the anti-apoptotic effect of EGFR and EGF-related growth. Additionally, inhibition of cross-talk between the EGFR-signaling and other growth-promoting pathways may heighten sensitivity to the cytotoxic effects of traditional chemotherapeutic agents (12–15).

Erlotinib is an orally active potent, selective inhibitor of the EGFR tyrosine kinase. In a phase II trial, single agent erlotinib demonstrated a low response rate (~4%) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). In combination with cisplatin, a response rate of 21% was observed in a phase I/II trial in a similar patient population, and rates of grade 3 and 4 toxicity were minimal. Although the safety and tolerability of combination therapy with erlotinib, cisplatin and radiation has already been investigated in other malignancies this regimen may not be as well tolerated for head and neck primary tumors (16–18).

This trial was designed to evaluate whether the addition of erlotinib to combination chemoradiation (CCR) would produce acceptable toxicities and preliminary evidence of efficacy in patients with locally advanced oral cavity or oropharyngeal cancer. Moreover, the trial aimed to determine the maximum tolerated dose of the combination of daily oral erlotinib in combination with cisplatin and radiation therapy. The pharmacokinetic sampling scheme employed in this trial was designed to measure the erlotinib steady-state concentrations achieved and to ensure that adequate concentrations are sustained during chronic oral administration of erlotinib alone and in combination with standard fractionation external beam radiation therapy with or without low dose daily cisplatin chemotherapy. Finally, the trial evaluated whether a two week window period of erlotinib alone could elicit evidence of a metabolic response on serial ¹⁸F-FDG PET imaging.

Patients and Methods

Patients

Eligibility requirements included a new diagnosis of histologically confirmed AJCC Stage III (T₃N_0-1) or IV (T_1-4N_2-3M₀, T₄N₀M₀) squamous cell carcinoma of the oral cavity or oropharynx. Other criteria included: no prior therapy for the SCCHN; no diagnosis of other malignancy within the prior 3 years; age ≥ 18 years; ECOG PS 0–2; adequate organ and marrow function as denoted by ANC ≥ 1500/mm³, platelets ≥ 100,000/mm³, total bilirubin within institutional upper limit of normal (ULN), transaminases < 2.5x ULN, creatinine within ULN or creatinine clearance ≥ 60 mL/min/1.73 m².

Clinical staging was performed at presentation with a combination of operative direct laryngoscopy, esophagoscopy and bronchoscopy. Moreover, appropriate baseline imaging was obtained (CT scan or MRI chosen per investigator discretion). Baseline evaluations were to be conducted within 1 week prior to start of protocol therapy. Scans and x-rays for eligibility were performed ≤4 weeks prior to the start of therapy.

The protocol was approved by institutional review boards of The Johns Hopkins Hospital in Baltimore, MD and the Louisiana State University Health Sciences Center in New Orleans (LSUHSC). Patients were required to provide written informed consent.

Study Design and Dose Escalation

The principal objective of the study was to determine the Maximally Tolerated Dose (MTD) of erlotinib in combination with low-dose daily cisplatin and radiotherapy. Oral erlotinib was taken daily starting as a 14-day run-in and continued until RT was completed. Erlotonib was allowed to be crushed and placed in a PEG tube. Low-dose daily cisplatin, 6 mg/m² IV, was started together with radiotherapy on day 15 and given for 5 doses each week (Monday-Friday) for a total of 35 doses (thus cumulative cisplatin dose was 210 mgs/m²). The cisplatin was diluted with sodium chloride (0.45%) to a total volume of 100 ml. Cisplatin was administered over 20 minutes, 3 hours prior to radiation therapy. Pre or post-cisplatin hydration was not required. Odansetron 8 mg IV was administered prior to cisplatin. Carboplatin 25 mg/m² IV per day was substituted for cisplatin in the event of persistent elevation of creatinine to > 1.5 mg/dL despite prehydration or for ≥ grade 2 electrolyte wasting.

Standard fractionation radiation therapy was delivered daily for 5 days per week starting on day 15 to a total dose of 66–70 Gy in 2 Gy daily fractions over 7 weeks. Either 3D conformal treatment planning or IMRT were used. Clinically positive neck nodes received a dose of 68–70- Gy in 35 fractions, and the clinically uninvolved neck received a total dose of 50 Gy (including N₀ disease).

Dose escalation followed a modified Fibonacci dose escalation design (Table 1). The dose of erlotinib was escalated from a starting dose of 50 mg/day. This dose represented one third the recommended daily dose of single-agent erlotinib in Phase II trials. Patients were treated in successive cohorts of 3 patients. Intra-patient dose escalation was not allowed. All patients in each cohort completed chemoradiation prior to expansion to the next cohort.

Table 1.

Dose Escalation and Study Schema

Dose-Escalation Schedule
Dose Level	Dose
	Erlotinib*	Standard Fraction External Beam Radiation Therapy	Cisplatin (Given on days of radiation administration)	Cohort Size
Level 1	50 mg	70 Gy, 2 Gy per fraction	6 mg/m2/d	3
Level 2	100 mg	“	6 mg/m2/d
Level 3	150 mg	“	6 mg/m2/d

Schema:
Day −28 to −1	Baseline {18F}-FDG PET and CT scan
Day 1 to 14 induction “window”	Single agent, daily oral erlotinib
Day 14	Repeat {18F}-FDG PET and CT scan
Day 15 to 63	Radiation therapy X 7 weeks with concurrent daily low dose cisplatin (6 mg/m2) and daily oral erlotinib
Day 64 (Week 10)	Radiation and cisplatin and erlotinib completed Pharmacokinetic studies completed.
Day 120 (week 18)	Repeat imaging including {18F}-FDG PET and CT scan

^*Doses are stated as exact dose in mg per day.

A Dose Limiting Toxicity (DLT) was defined as the following: grade 3 or 4 neutropenia associated with fever or neutropenia lasting longer than 5 days; grade 3 or 4 thrombocytopenia; any grade 3 or 4 non-hematological toxicity per NCI/CTC criteria with the exception of grade 4 mucositis that resolves to grade 2 or less with a treatment break not to exceed 10 days. Grade 3 diarrhea was dose limiting only if persistent after the initiation of pharmacological anti-diarrheal therapy. Toxicity was graded using NCI Common Toxicity Criteria version 2.0.

The MTD was defined as the dose of erlotinib in combination with cisplatin and radiation therapy in which < 2 of 6 patients experiences a DLT. After the recommended Phase II dose (MTD) was defined, 6 additional patients were enrolled at that dose level.

Dose modifications

Dose adjustments were made for Grade 3 or 4 toxicity. The offending agents could be held for up to 14 days until toxicity resolved to grade 1 or less. Radiation therapy was allowed to continue if erlotinib, the platinum or both were held. If erlotinib was held, RT and platinum could continue at the discretion of the investigator. If platinum held, erlotinib and RT could continue at the discretion of the investigator. If RT held, erlotinib could continue but platinum was held. If the agent causing the toxicity was unknown, then all 3 were held until toxicity resolved to grade 1 or less. The erlotinib was then dose reduced per guidelines. Patients were removed from study if toxicity did not resolve within 14 days or if greater than two dose adjustments were required.

Response evaluation and follow-up

Although response was not the primary endpoint of this trial, patients who completed chemoradiotherapy were evaluable for response. Patients with progressive disease were evaluable if they received at least 30 days of combined modality therapy. Response and progression were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) (19). Disease response was assessed by clinical exam and repeat of baseline imaging on day 15 and day 120 (approximately 12 weeks post completion of RT).

For investigative purposes only, baseline ¹⁸F-FDG PET was performed within 28 days pre-therapy and on day 14 of study treatment, prior to initiation of CCR. All PET readings were performed by the same designated study radiologist to prevent interpretation variability. Assessment of metabolic response to 14 days of single agent erlotinib and to the entire treatment algorithm was performed via serial ¹⁸F-FDG PET at baseline, day 14 and day 120, performed and interpreted per PERRECIST criteria (20). Patients were fasting for at least 4–6 hours and had serum glucose < 200 mg/dL. Baseline and repeat PET were obtained within 50–70 min of tracer injection. Follow-up scan was performed within 15 min of baseline injection time. The region of interest was the measurable target lesion in the primary tumor with maximal 3.0-cm diameter volume SUV [Lesion 1-SUVmax(3cm)] on the baseline scan. Lesion 1-SUVmax(3cm) was adjusted to lean body mass [Lesion 1-SUV-LBMmax(3cm)] and normalized to the average liver SUV-LBMmax(3cm). A metabolic response was defined as a 30% or greater change in adjusted Lesion 1-SUV-LBMmax(3cm) when values from day 14 and day 120 were compared to the baseline values. A modified radical neck dissection was planned for patients with initial presentation that demonstrated N2a or greater neck involvement at presentation. A biopsy at the primary site was performed if recurrence was suspected.

Pharmacokinetic sampling and analysis

Whole blood samples were collected on days 1 and 2 and then weekly for 10 weeks before drug administration. Plasma was separated by centrifugation and frozen at −70°C until analysis. Plasma concentrations of erlotinib 1(range 0 to 10,000 ng/mL ) and OSI-420 (1 to 1000 ng/mL), the major active metabolite, were measured using a validated reversed-phase high-performance liquid chromatography assay with tandem mass spectrometry detection (21). Quality control samples were assayed with each analytic run and were within 15% of the nominal concentration.

Erlotinib pretreatment trough concentration (C_min) was evaluable if the sample was collected 18 to 30 hours after drug dose and the patient was compliant (e.g., 80% of drug administration during sampling interval). C_min at steady state (C_ss,min) was determined as the average of the pretreatment erlotinib and OSI-420 concentrations on days 8 and 15 (when administered alone) and on days 22, 29, 36, 43, 207, 57, and 64 (when administered in combination with radiation with or without cisplatin). The C_ss,min ratio of metabolite to erlotinib was calculated.

Statistical Analysis

Toxicity, responses, and pharmacokinetics were summarized using descriptive statistics. A Wilcoxon matched pairs signed-rank test was used to compare C_ss,min when administered alone versus in combination with radiation with or without cisplatin. A Kruskal-Wallis analysis of variance by ranks was used to compare the differencesin dose-normalized C_ss,min as a function of dose level and to correlate pharmacokinetic and pharmacodynamic endpoints. Statistical tests were performed using JMP Statistical Discovery software, version 4.0.4 (SAS Institute, Cary, NC, USA).

Results

Patients

Twenty-two patients were enrolled and 18 patients received therapy on protocol. Four patients were excluded due to screening failure (n=2); disease progression prior to treatment initiation (n=1); and withdrawal of consent (n=1). The baseline characteristics of the 18 patients who received therapy are shown in Table 2. Median age was 56 (range 42–66), and the majority were Caucasian males.

Table 2.

Treated Patient Characteristics

Patients	N=18
Gender
Female	3
Male	15
Age Range	42–66 yrs
Median	55
Mean	58
Disease Site
Oral Cavity	2
Oropharynx	16
Stage
III	0
IV	18
ECOG Performance Status
0	13
1	5

Three patients were withdrawn from protocol therapy. One patient experienced grade 3 pneumonitis (n=1). This patient also had a possible pulmonary infection. The relationship to erlotinib was deemed possible and patient was removed from study before completing CCR. Two other patients were withdrawn from protocol without experiencing DLT. One patient was, diagnosed with Fanconi’s anemia (n=1), and another had a diagnosis of metastatic disease by PET on day 14. These three patients were subsequently replaced on study.

Safety Experience: Dose Escalation

One of three patients at dose level 1 (50 mg erlotinib) experienced grade 3 neutropenia and fever and therefore the first cohort was expanded to 6. No dose limiting toxicity was noted in the 3 additional patients. A total of 5 patients were enrolled on dose level 2, erlotinib 100 mg/day. Two were removed from protocol therapy, one due to grade 3 pneumonitis with an attribution of possibly related to erlotinib. One was removed due to a diagnosis of Fanconi’s anemia. Three patients completed this dose level without dose limiting toxicity. Three patients at the third dose level of erlotinib 150 mg/day had grade 3 anorexia and 1 patient demonstrated grade 3 radiation dermatitis. However, these toxicities were not attributed to the investigational drug. This cohort was then expanded to 9 patients. In the expanded cohort, 1 patient experienced grade 3 neutropenia, 1 experienced grade 3 anorexia. However, these toxicities were not considered dose limiting. Grade 3/4 toxicities attributed to the addition of erlotinib to CCR include lymphopenia, diarrhea, rash and pneumonitis.

One patient in dose level 1 required an 8 day treatment break for grade 4 mucositis. Otherwise, no treatment breaks greater than 3 days occurred. The details of the RT from the LSU site are not known due to destruction of patient records in Hurricane Katrina. See Table 3 for Grade 3/4 toxicities.

Table 3.

Grade 3/4 Toxicities

	Grade 3/4 Toxicity N=patients	DoseLevel (erlotinib dose mg)
Nausea	2	50
Anorexia	2	50
	2	100
	7	150
Xerostomia	1	50
	1	100
	1	150
Pneumonitis	1	100
Diarrhea	1	100
Lymphopenia	4	50
	4	100
	7	150
Mucositis	2	50
	2	100
	5	150
Radiation dermatitis	2	150
Rash	3	150

Response Evaluation

A total of 18 patients were evaluable for response assessment at the completion of combined modality treatment. The average time to clinical response determination was 119 days (range 64–194 days). Best overall response is summarized in Table 4.

Table 4.

Best Overall Response

Dose Level	Best Overall Response (N=number of patients)
1	CR 3
	SD 2
	PD 1
2	CR 1
	PR 2
3	CR 4
	PR 5

Thus, overall response rate derived from tumor measurements based on imaging studies was 83% for all dose levels combined. Response evaluation took place at an average of 83 days post CCR (range 64–194 days).

Pharmacokinetic Evaluation

Plasma pharmacokinetic studies were performed on specimens from 16 patients. One patient was removed from evaluation due to non-compliance. Trough values were obtained 65% of the time. There was no difference in erlotinib C_ss,min (p=0.30), OSI-420 C_ss,min (p=0.20), or the C_ss,min ratio of OSI-410:erlotinib (p=0.30) when erlotinib was administered alone or combination with radiation and cisplatin (see Table 5). Additionally, there was no difference in dose-normalized C_ss,min as a function of dose level for erlotinib (p=0.14) or OSI-410 (p=0.23)or in the ratio of OSI-410:erlotinib (p=0.07) with increasing ratios with increasing erlotinib dose.

Table 5.

Plasma exposure to erlotinib during the course of chemoradiation

	Erlotinib Css,min (ng/mL)	OSI-420 Css,min (ng/mL)	OSI-420 : Erlotinib Css,min ratio
50 mg Alone	563.2 ± 238.9 (4)	39.5 ± 20.9 (4)	0.07 ± 0.01 (4)
50 mg Combination	808.7 ± 536.4 (4)	61.8 ± 45.5 (4)	0.08 ± 0.01 (4)
100 mg Alone	489.9, 542.8 (2)	30.6, 59.4 (2)	0.08, 0.12 (2)
100 mg Combination	299.2 (1)	25.0 (1)	0.09 (1)
150 mg Alone	741.9 ± 469.6 (7)	67.8 ± 53.7 (7)	0.09 ± 0.03 (7)
150 mg Combination	949.3 ± 756.2 (9)	101.3 ± 90.9 (9)	0.10 ± 0.03 (9)

^*Values are expressed as mean ± standard deviation (n) or as individual concentrations if n <2. C_ss,min = average steady-state trough plasma concentration.

Pharmacokinetic-pharmacodynamic Correlations

No correlation was observed between clinical responses (Table 1) and pharmacokinetic parameters (erlotinib C_ss,min (p=0.55), OSI-410 C_ss,min (p=0.71), or the C_ss,min ratio of OSI-410:erlotinib (p=0.71).

A summary of the baseline, day 14 and day 120 findings for the primary tumor on ¹⁸F-FDG PET are shown in Table 6, stratified by erlotinib dose level. Scans for two patients at dose level 2 on day 120 were not performed per patient request. There was evidence for metabolic response to single agent erlotinib. Per PERCIST criteria, the overall metabolic response rate at day 14 was 38.8% (95%CI, 17.3–64.3%). Median percent reduction in SUVmax of the primary tumor at day 14 appeared greater at the second and third dose levels, but differences were non-significant (median 6.8 vs. 28.7 vs. 21.8, k-wallis p=0.41, dose levels 1, 2, and 3, respectively). All but two evaluable patients had a metabolic response to treatment at the day 120 evaluation, with the majority (7 of 10) of the patients at the highest dose level having no SUV uptake over background at this time point.

Table 6.

Percent change in adjusted SUV-LBM (3cm), by treatment group

Dose Level	SUV-LBM (3cm) Adjusted Value
	Baseline	Day 14	% Changea	Day 120	% Changea
1
	7.25	6.0	−17.2	1.83	−82.1
	3.92	2.6	−33.7	1.27	−67.6
	7.2	7.46	3.6	2.04	−71.7
	7.13	7.55	5.9	2.08	−70.8
2
	8.46	3.85	−54.5	--	--
	11.92	6.25	−47.6	--	--
	8.17	7.65	−6.4	1.0	−87.8
	10.25	9.25	−9.8	4.29	−58.1
3
	6.53	5.2	−20.4	2.72	−58.3
	3.38	2.33	−31.1	2.39	−29.3
	4.67	4.8	2.8	4.3	−7.9
	12.35	9.47	−23.3	1.0	−91.9
	10.43	9.53	−8.6	1.0	−90.4
	3.94	3.82	−12	1.0	−74.6
	7.64	5.25	−31.3	1.0	−86.9
	9.0	1.0	−88.9	1.0	−88.9
	8.44	5.0	−40.8	1.0	−88.2
	5.82	5.15	−11.5	1.0	−82.8

^aCompared to baseline

Discussion

Based on this Phase I investigation, the combination of standard fractionation RT, low dose daily cisplatin and daily erlotinib is well tolerated. MTD was not reached. The recommended phase II dose of erlotinib is 150 mg per day in combination with cisplatin and radiation therapy, the highest dose of erlotinib evaluated in this study. Importantly, while 1 patient demonstrated Grade 3 rash, overall skin toxicity (including radiation dermatitis) and mucositis were consistent with historical controls that used concurrent RT and platinum. Additionally, only two patients had treatment breaks and one of these breaks was due to non-study related issues again demonstrating the tolerability of the regimen. Only 1 patient had a break due to mucositis. Pill diaries and pharmacokinetic assessment demonstrated good compliance with the daily dosing of the erlotinib. Our pharmacokinetic data demonstrated that cisplatin and RT did not affect steady state levels of erlotinib and is consistent with previously published data (18).

Previous investigations of EGFR inhibitors in combination with RT or chemoRT have been reported. Cetuximab concurrent with RT demonstrated clinical benefit but some limitations. Bonner et. al. demonstrated the superior clinical outcomes of radiation therapy plus EGFR inhibition (cetuximab) versus radiation therapy alone in locally advanced HNC (22). The combination of radiation and cetuximab has been associated with grade 3 and 4 skin reactions. Moreover, cetuximab has been associated with potentially life-threatening infusion reactions, with a higher rate in some parts of the United States. The superiority of this regimen over cisplatin-based CCR has not yet been demonstrated. It remains unclear whether toxicity of the combination of cisplatin and EGFR inhibition is acceptable. In fact, a Phase II trial of concurrent cetuximab 400 mg/m2 weeks 1 and then 250 mg/m2 weekly, cisplatin 100 mg/m2 weeks 1 and 4 and concomitant boost RT (1.8 Gy/d for total 70 Gy) for locally advanced head and neck cancer closed early due to significant adverse events (23). While further investigation of the safety profile of that combination is needed, the study did demonstrate a 3 year overall survival rate of 76% and a 3-year progression free survival of 56%(23).

Our regimen also demonstrates similar response rates to other Phase I investigations of TKI based therapy in HNC. Chen et. al. treated 23 patients with locally advanced HNC with a gefitinib plus radiation or gefitinib plus radiation and weekly cisplatin. The most common acute grade 3–4 toxicity for gefitinib plus radiotherapy alone was mucositis but the prevalence was consistent with RT alone. Clinical complete response rate was 91% (24). In a small Phase I trial of gefitinib with paclitaxel and RT, investigators noted prolonged stomatitis (beyond expected for RT alone) and a response rate of 70%. In our study, EGFR inhibition did not increase the rate of grade 3–4 mucositis over CCR alone and compares favorably to others studies of EGFR inhibition plus CCR (25). Our overall response rate of 83% is consistent with prior reports of EGFR inhibition plus CCR as noted above. While Worden et. al. did not evaluate TKI based therapy, this CCR-based study did concentrate on oropharyngeal tumors, which provided the mainstay of our study population. Worden demonstrated CCR of 92% but this trial was designed to evaluate response rate and the majority were HPV positive (26). A phase II trial of the regimen would need to be done in order to determine whether responses to this regimen compare favorably to those as noted above.

Thus, investigation of alternate methods of EGFR inhibition proves to be potentially important. Ultimately, further questions will need to be addressed: 1) can the addition of EGFR inhibition to the backbone of chemotherapy and RT improve clinical outcomes 2) do certain head and neck cancer populations benefit more than others (ex: Human Papillomavirus positive versus negative tumors). While these questions are outside the scope of this investigation, they provide a rational basis for why a well-tolerated, easily administered EGFR inhibitor should be evaluated for curative therapy of locally advanced HNC. The low dose daily cisplatin regimen proved attractive for this investigation as Jeremic et. al. demonstrated its tolerability as well as the oral dosing of erlotinib Moreover, the drug can be crushed and placed in a gastrostomy tube if necessary. Given the need to identify efficacious, well-tolerated novel regimens, we performed this Phase I trial of RT in combination with erlotinib and daily low dose cisplatin.

The potential for ¹⁸F-FDG-PET to evaluate evidence of clinical response was preliminarily explored in this study. Interestingly, several patients demonstrated significant decrease in FDG avidity from baseline on the day 14 PET. While this did not correlate with any pharmacodynamic data, future studies should further evaluate biomarkers for response to erlotinib. In summary, this Phase I evaluation demonstrated that the combination is well-tolerated. Evidence of biological effect of single agent erlotinib was observed as early as 14 days after initiation of the drug. Future investigation will evaluate efficacy of this combination of agents. It remains unclear whether the addition of erlotinib to CCR improves on the efficacy of CCR (cisplatin-based) alone. However, prospective evaluations are warranted.

Statement of Translational Relevance.

This study evaluates the addition of an EGFR inhibitor to the traditional concurrent chemoradiotherapy (CCR) backbone of head and neck cancer (HNC) therapy. Given the overexpression of the EGFR in a majority of HNC, this regimen potentially builds on the efficacy of CCR alone. Additionally, imaging of response to concurrent chemoradiotherapy per RECIST criteria proves challenging in both pre-treatment and post-treatment HNC and molecularly targeted agents may not elicit traditional measurable responses but rather stable disease and progression free survival. This study demonstrates the tolerability of erlotinib with traditional CCR. Moreover, the 14 day run-in period of erlotinib demonstrated evidence of single agent activity and the potential for ¹⁸F-FDG-PET to evaluate evidence of clinical response and its role as a potential biomarker for response or clinical benefit.