Phase III Randomized, Placebo-Controlled Trial of Docetaxel With or Without Gefitinib in Recurrent or Metastatic Head and Neck Cancer: An Eastern Cooperative Oncology Group Trial

Abstract

Purpose

We hypothesized that the addition of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, to docetaxel would enhance therapeutic efficacy in squamous cell carcinoma of the head and neck (SCCHN).

Patients and Methods

Patients with recurrent or metastatic SCCHN with Eastern Cooperative Oncology Group (ECOG) performance status of 2, or patients with ECOG performance status of 0 to 2 but were previously treated with chemotherapy, were randomly assigned to receive weekly docetaxel plus either placebo (arm A) or gefitinib 250 mg/d, orally (arm B) until disease progression. At the time of progression, patients in the placebo arm could receive single-agent gefitinib. EGFR, c-MET, and KRAS mutations and polymorphisms in drug metabolizing enzymes and transporters were evaluated by pyrosequencing.

Results

Two hundred seventy patients were enrolled before the study was closed early at interim analysis (arm A, n = 136; arm B, n = 134). Median overall survival was 6.0 months in arm A versus 7.3 months in arm B (hazard ratio, 0.93; 95% CI, 0.72 to 1.21; P = .60). An unplanned subset analysis showed that gefitinib improved survival in patients younger than 65 years (median 7.6 v 5.2 months; P = .04). Also, there was a trend for improved survival in patients with c-MET wild-type (5.7 v 3.6 months; P = .09) regardless of treatment. Grade 3/4 toxicities were comparable between the two arms except that grade 3/4 diarrhea was more common with docetaxel/gefitinib. Of 18 eligible patients who received gefitinib after disease progression in arm A, one patient had a partial response.

Conclusion

The addition of gefitinib to docetaxel was well tolerated but did not improve outcomes in poor prognosis but otherwise unselected patients with SCCHN.

INTRODUCTION

Approximately 52,000 new instances of head and neck cancer are diagnosed annually in the United States.¹ Although locally advanced squamous cell carcinoma of the head and neck (SCCHN) is potentially curable with combined-modality therapy, recurrent or metastatic (R/M) disease carries a poor prognosis. Patients with disease progression after first-line therapy for R/M SCCHN or early recurrence after potentially curative chemoradiotherapy have a particularly poor outcome. Performance status (PS) is a strong predictor of survival in SCCHN.² There are limited data on therapeutic outcomes in patients with compromised PS.³ A number of single agents have activity in previously treated patients with R/M SCCHN, including the taxanes and methotrexate, however, there is no standard treatment. Weekly docetaxel was active in a phase II trial in the first-line treatment of R/M SCCHN with a reported a response rate of 42% and median overall survival (OS) of 11.3 months.⁴ A phase II randomized study of weekly docetaxel versus methotrexate showed higher response rates for docetaxel but comparable survival rates.⁵

Epidermal growth factor receptor (EGFR) inhibitors have antitumor activity and tolerable toxicity profiles in SCCHN. Cetuximab, a monoclonal antibody against EGFR, has demonstrated efficacy in the management of SCCHN.⁶ A randomized Eastern Cooperative Oncology Group (ECOG) study (E5397) in R/M SCCHN showed that adding cetuximab to cisplatin improves objective response rate but not overall survival.⁷ In contrast, a larger phase III trial conducted by Vermorken et al⁸ showed that adding cetuximab to platinum/fluorouracil prolongs survival in first-line treatment of R/M SCCHN.

Gefitinib, an oral quinazoline, is a highly selective EGFR-tyrosine kinase inhibitor (TKI). Its common adverse effects included rash, diarrhea, and elevated transaminases. Gefitinib resulted in single-agent response rates in phase II trials in R/M SCCHN of 1% to 11%.^9–11 A phase III trial showed that gefitinib at doses of 250 mg or 500 mg was not superior to methotrexate.³ EGFR-TKIs can potentiate the effect of chemotherapy in a manner that may be tumor type– and schedule-dependent. The combination of docetaxel with gefitinib is supported by preclinical observations in SCCHN models. Simultaneous administration or sequencing gefitinib after chemotherapy was optimal in the laboratory.^12–14

Clinical data with docetaxel plus gefitinib have been reported in many cancers, including phase II data with cisplatin/docetaxel plus gefitinib in SCCHN.¹⁵ The combination of erlotinib and docetaxel resulted in significant toxicities in a phase I trial in patients with SCCHN necessitating reduction of the erlotinib dose to 50 mg daily.¹⁶ This prompted us to study gefitinib as the EGFR-TKI of choice. Our hypothesis was that the addition of gefitinib to docetaxel will be synergistic and improve the outcome of previously treated and/or compromised performance status patients with recurrent or metastatic SCCHN.

PATIENTS AND METHODS

Patient Selection

Eligible patients were at least 18 years old with R/M SCCHN considered incurable with locoregional therapies; adequate hematologic and liver function test parameters; and measurable or nonmeasurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST)¹⁷; PS 2, if previously untreated (including prior chemotherapy as part of potentially curative therapy > 6 months); or PS 0 to 2, if previously treated for R/M disease or prior chemotherapy as part of potentially curative therapy within 6 months of study enrollment. Any number of prior regimens was permitted except prior treatment with an EGFR inhibitor or docetaxel. Prior paclitaxel was allowed, if disease did not progress while receiving paclitaxel. Patients with peripheral neuropathy of grade 2 or worse, unstable comorbid disease, or hypercalcemia were excluded. Female patients of childbearing potential could not be pregnant or breastfeeding. Patients with major tumor-related hemorrhagic events in the previous 3 months, on therapeutic anticoagulation, or with tumors that invaded major vessels were also excluded. All patients signed informed consent and the protocol was approved by the respective institutional review boards.

Treatment Plan

Docetaxel was administered as a 60-minute infusion at a dose of 35 mg/m² on days 1, 8, and 15 of a 28-day cycle. Placebo (arm A) or gefitinib (Iressa, AstraZeneca, Wilmington, DE; arm B) at a dose of 250 mg (one tablet) was administered orally each day starting on day 1 and continuing for days 1 to 28 of each cycle. Premedication with dexamethasone was given for a total of three doses: 4 mg orally 12 hours before docetaxel, 4 mg intravenously or orally 30 to 60 minutes before docetaxel, and 4 mg orally 12 hours after docetaxel. Docetaxel plus placebo/gefitinib treatment continued until disease progression. Patients assigned to arm A had the option of unblinding at disease progression and registering (step 2) to receive single-agent gefitinib 250 mg once daily until disease progression. This option was eliminated in September 2007. Docetaxel and gefitinib dose modifications were applied for hematologic and nonhematologic toxicities according to protocol-specified criteria. Gefitinib and matching placebo were provided by AstraZeneca (Wilmington, DE) and distributed by the Pharmaceutical Management Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis of the National Cancer Institute.

Patient Assessments and Monitoring

Patients were evaluated by computed tomography of the chest and abdomen and computed tomography or magnetic resonance imaging of the neck at baseline, within 4 weeks of registration, and after every 2 cycles (8 weeks). Bone scan was performed at baseline and then as clinically indicated. Objective response was evaluated using RECIST version 1.0.¹⁷ Complete blood counts were obtained on days 1 and 8 and serum chemistry tests were administered on day 1 of each cycle. All toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0.

Genotyping and Mutation Analyses

Genotyping studies were performed to identify biomarkers that would correlate with treatment. Genomic DNA was extracted from whole blood or paraffin-embedded tumor blocks for analyses of single nucleotide polymorphisms (SNPs) or mutations, respectively, using standard extraction procedures. SNPs in CYP3A4, CYP3A5, ABCB1, EGFR Q787, and ABCG2 genes, as well as mutations in EGFR exons 18 to 21^18–21; c-MET exons 2, 14, 15, and the tyrosine kinase domain^22–26; and KRAS exons 12 and 13^27–29 were analyzed by pyrosequencing. EGFRvIII was analyzed by polymerase chain reaction–amplifying-specific regions of the EGFR gene and visualizing samples on a 2% agarose-ethidium bromide gel for the absence or presence of mutant EGFR.¹⁹

Statistical Design and Analysis

This was a double blind, placebo-controlled phase III randomized trial. Patients were randomly assigned equally to docetaxel/placebo (arm A) and docetaxel/gefitinib (arm B). Randomization was done using permuted blocks within strata, with dynamic balancing within main institutions and their affiliate networks, with stratification by prior chemotherapy status (treated/untreated), PS (0, 1, or 2), weight loss in the last 6 months (< 5% v ≥ 5%), and prior cetuximab (yes v no). The study was designed to detect an improvement in median OS from 6 months in the control arm to 8.4 months in the experimental arm. A total accrual of 314 eligible patients and total information of 286 deaths were needed to attain 80% power with 2.5% type I error, using a one-sided log-rank test. To allow for up to 5% of the patients to be ineligible, a total of 330 patients were to be accrued. The trial was monitored according to principles of group-sequential methods using a one-sided O'Brien-Fleming³⁰ upper boundary. Interim analyses were scheduled beginning at 25% of full information, then semiannually with stopping rules in favor of the null and alternative hypotheses based on repeated CI³¹ on the hazard ratio (HR), using the O'Brien-Fleming boundary. In November 2008, the ECOG Data Monitoring Committee recommended study closure to accrual because it was unlikely that the primary end point would be reached.

The analysis of efficacy outcomes excluded ineligible patients, whereas the toxicity summary included all patients who received treatment. OS was defined as the time from registration to death from any cause or censored at the time of last contact. Time-to-progression (TTP) was defined as time from registration to evidence of disease progression or censored at the last disease evaluation. Categorical data were summarized by frequency and percentage. Exact binomial confidence intervals were estimated for response rates.³² Wilcoxon rank sum and Fisher's exact tests were used to compare continuous and categoric variables, respectively, between groups. The survival data were analyzed using the Kaplan-Meier³³ method and the significance was tested by log-rank tests. Cox's proportional hazards models³⁴ were used to estimate HR and evaluate interaction effects. All P values are two-sided. A level of 5% was considered statistically significant. SNPs were investigated in blood samples and efficacy was compared by genotype (variant v nonvariant, including wild-type and heterozygote) for each polymorphism. Mutations were examined in tumor samples and efficacy was compared by mutation status (wild-type v mutation, including heterozygote and variant). Because the analysis of correlatives was exploratory, no statistical adjustment was performed for multiple comparisons.

RESULTS

From August 2004 to November 2008, a total of 270 patients (136 in arm A; 134 in arm B) were enrolled onto the study, of whom 239 were eligible (117 in arm A; 122 in arm B; Fig 1). Fifteen patients (seven in arm A; eight in arm B) never started their assigned treatment.

Fig 1.

CONSORT diagram representing enrollment and outcomes of patients in the docetaxel/placebo (arm A) or docetaxel/gefitinib (arm B) treatment group. RECIST, Response Evaluation Criteria in Solid Tumors.

Twenty-four patients initially assigned to docetaxel plus placebo were registered to step 2 following disease progression; of those patients, 22 were eligible and four patients never started gefitinib. A total of six patients received cetuximab after study treatment completion and before documented disease progression per study criteria (four patients in arm A; two in arm B).

Patient Characteristics and Treatment Delivery

Table 1 provides baseline patient demographics and disease characteristics for eligible patients (N = 239). Except for the prior biologic/targeted therapy status, there were no statistically significant imbalances between the two arms. The median number of treatment cycles received was two (range, 0 to 10) and two (range, 0 to 18) for arms A and B, respectively. Appendix Table A1 (online-only) presents the reasons for treatment discontinuation, the most common of which was progressive disease. Although a similar number of gefitinib cycles was administered to younger and elderly patients (median, two), a higher proportion of the elderly required gefitinib dose interruptions in arm B (72% v 41%; P < .001) but not placebo in arm A (47% v 46%; P = 1.00). No significant association between docetaxel dose modifications and treatment arm was observed for either younger patients or older patients.

Table 1.

Patient Characteristics, Disease Status, and Prior Treatment (N = 239)

Characteristic	Treatment Arm				Total		P*
	Placebo Arm		Gefitinib Arm
	No. of Patients	%	No. of Patients	%	No. of Patients	%
Age, years							.57
Median	61.4		60.8
Range	28.0-86.5		41.6-84.4
< 65	72	62	84	69	156	65	.28
≥ 65	45	38	38	31	83	35
Sex							.75
Male	92	79	98	80	190	79
Female	25	21	24	20	49	21
Race							.59
White	101	86	102	84	203	85
Nonwhite	16	14	20	16	36	15
Performance status							.72
0	15	13	12	10	27	11
1	31	26	31	25	62	26
2	71	61	79	65	150	63
Weight loss in previous 6 months							.82
< 5% of body weight	64	55	71	58	135	57
5-10% of body weight	24	21	24	20	48	20
10 to < 20% of body weight	19	16	15	12	34	14
≥ 20% of body weight	10	9	12	10	22	9
Smoking history							.19
Never smoked	13	12	7	6	20	9
Pipe or cigar smoker only	1	1	2	2	3	1
Cigarette smoker, pack-years
< 20	17	15	10	8	27	11
20-40	35	31	46	38	81	34
> 40	47	42	56	46	103	43
Unknown	4		1		5
Average alcohol consumption							.89
< 1 drink/month	6	19	4	14	10	4
1-5 drinks/month	5	16	8	28	13	5
1-10 drinks/week	10	32	8	28	18	7
11-30 drinks/week	7	23	6	21	13	5
> 30 drinks/week	3	10	3	10	6	2
Unknown	5		5		10
Histologic grade							.90
Well differentiated	10	9	14	11	24	10
Moderately differentiated	59	50	56	46	115	48
Poorly differentiated	33	28	37	30	70	29
Undifferentiated	2	2	3	2	5	2
Grade cannot be assessed	13	11	12	10	25	11
Disease status at study entry							.53
Eradicated, no recurrence	32	28	37	31	69	29
Eradicated, recurred locally	58	51	49	42	107	45
Residual after prior therapy	21	18	27	23	48	20
Untreated	3	3	5	4	8	3
Unknown	3		4		7
Overall disease status							.82
Locally or locoregionally recurrent/persistent only	39	33	44	36	83	35
Distant metastases only	29	25	32	26	61	25
Both	49	42	46	38	95	40
Regional lymph node status							.15
Unknown	6		11		17
Never involved	17	15	19	17	36	15
Never involved but removed	1	1	5	5	6	3
Involved nodes, eradicated	49	44	32	29	81	34
Involved nodes eradicated, new involvement	22	20	26	23	48	20
Involved nodes, not treated	13	12	14	13	27	11
Other	9	8	15	14	24	10
Primary site							.40
Oral cavity	30	26	23	19	53	22
Oropharynx	36	31	42	34	78	33
Larynx	28	24	33	27	61	26
More than one	4	3	9	7	13	5
Other†	19	16	15	12	34	14
Prior chemotherapy							.38
No	33	28	28	23	61	26
Yes	84	72	94	77	178	74
Prior radiotherapy							.47
No	20	17	16	13	36	15
Yes	97	83	106	87	203	85
Prior surgery							.24
No	41	35	52	43	93	39
Yes	76	65	70	57	146	61
Prior biologic/targeted therapy							.03
No	111	96	122	100	233	98
Yes	5	4	0	0	5	2
Metastatic site involvement
Lung							.70
Unknown	2		1		3
Not involved	50	43	56	46	106	44
Involved	65	57	65	54	130	54
Liver							.78
Unknown	4		5		9
Not involved	106	95	109	93	215	90
Involved	6	5	8	7	14	6
Bone							.16
Unknown	0		1		1
Not involved	94	80	106	88	200	84
Involved	23	20	15	12	38	15

^*P value calculation excludes unknown values.

^†Lip and oral cavity, nasopharynx, hypopharynx, salivary glands, paranasal sinuses, no primary identified, other.

Overall Survival and Time-to-Progression

Seven patients (3%) were alive at the time of the analysis (arm A, four patients; arm B, three), with a median follow-up time of 35 months (range, 24 to 54 months). For all patients, median OS was 6.8 months (95% CI, 5.72 to 7.52 months). The median OS was 6.0 months (95% CI, 4.93 to 7.43) and 7.3 months (95% CI, 5.75 to 8.44) in arms A and B, respectively (HR, 0.93; 95% CI, 0.72 to 1.21; P = .60). Median TTP was 2.1 months for arm A and 3.5 months for arm B (HR, 0.81; 95% CI, 0.58 to 1.11; P = .19). Figure 2 shows the Kaplan-Meier curves for OS and TTP. The median OS and TTP for the 22 patients who registered for step 2, calculated from the time of cross-over registration, were 6.3 and 2.6 months, respectively.

Fig 2.

Kaplan-Meier estimates of (A) overall survival by treatment arm (n = 239) and (B) time-to-progression by treatment arm (n = 239). Cens, censored.

In an unplanned subgroup analysis, we found that patients younger than 65 years derived survival benefit from combination therapy (median OS, 7.6 months with docetaxel/gefitinib v 5.2 months with docetaxel/placebo; P = .04) but patients 65 years or older did not (median OS, 5.9 months with docetaxel/gefitinib v 6.6 months with docetaxel/placebo; P = .08; Fig 3 shows forest plot of HRs of OS and Fig 4 shows survival curves). The Cox proportional hazards regression analysis showed that the interaction effect by age and treatment arm was highly significant (P = .007). There was also improvement in TTP with the addition of gefitinib in younger patients (median, 3.6 v 2.0 months; P = .01) but not in patients ≥ 65 years (median, 3.4 v 3.7 months; P = .58).

Fig 3.

Forest plot representing hazard ratios (HRs) with 95% CIs of overall survival in patient subgroups. Cav, cavity; CT, chemotherapy; LCL, lower confidence limit; Med A, median overall survival in arm A; Med B, median overall survival in arm B; PS, performance status; RT, radiotherapy; UCL, upper confidence limit.

Fig 4.

Kaplan-Meier estimates of overall survival by treatment arm for (A) patients ≥ 65 years (n = 83) and (B) patients younger than 65 years (n = 156). Cens, censored.

Response

The distribution of response in arm A was: two patients with complete responses, three patients with partial responses, 28 patients with stable disease, 48 patients with progressive disease, and 36 patients unevaluable. In arm B, there were two patients with complete responses, 10 patients with partial responses, 41 patients with stable disease, 43 patients with progressive disease, 26 patients who were unevaluable. In evaluable patients, the overall response rate (ORR) was 6.2% (95% CI, 2.01% to 13.82%) and 12.5% (95% CI, 6.61% to 20.84%), in arms A and B, respectively, a difference that was not statistically significant (P = .13). Of 16 evaluable patients registered to step 2, one had an objective response and six had stable disease as best response.

Toxicity

Toxicities were assessed in a total of 253 patients (129 in arm A; 124 in arm B) in step 1 of the study (Table 2). The incidence of grade 3/4 toxicities was comparable between the two arms, except for a higher incidence of diarrhea with gefitinib (13% v 2%; P < .001). Two treatment-related lethal toxicities occurred in patients in arm A (lung infection and pulmonary hemorrhage) and six in patients in arm B (pneumonitis, septicemia, hypotension, and three sudden deaths). No statistically significant difference in grade 3 to 5 toxicities was noted between younger (< 65 years) and older patients (≥ 65 years) in either arm, except for a higher rate of grade 3 to 5 infection on the gefitinib arm (8% in older v 0% in younger patients; P = .03).

Table 2.

Treatment-Related Adverse Events

Adverse Event	Gefitinib Arm (n = 124)			Placebo Arm (n = 129)
	Grade 3 (%)	Grade 4 (%)	Grade 5 (%)	Grade 3 (%)	Grade 4 (%)	Grade 5 (%)
Allergic reaction	1			2
Hemoglobin				4
Leukopenia	3	2		2	2
Lymphopenia	2	1		5	2
Neutropenia	2	1		1	2
Thrombocytopenia		1
Atrial fibrillation	1			1
Ventricular flutter				1
Hypotension	2		1	2	1
Left ventricular diastolic dysfunction				1
Fatigue	11			13	3
Insomnia				1
Weight loss	1			2
International normalized ratio				1
Partial thromboplastin time				1
Nail changes	1			1
Pruritus/itching	1
Rash/desquamation				2
Hand-foot reaction				1
Death/sudden death			2
Anorexia	5			2
Dehydration	6	1		5
Diarrhea without prior colostomy	11	2		2
Dysphagia	2			1
Fistula, colon/cecum/appendix				1
Oral mucositis by examination	2
Oral mucositis by symptoms	2			2
Nausea	6			3	1
Perforation, duodenum		1
Vomiting	2	1		3
Abdomen, hemorrhage NOS	1
Esophagus, hemorrhage				1
Oral cavity, hemorrhage					1
Bronchus, hemorrhage						1
Colitis, infectious				1
Febrile neutropenia				1
Infection with neutropenia
Grade 3-4
Abdomen NOS	1
Bladder				1
Lung	1
Blood			1
Grade 0-2
Abdomen	1
Catheter				2
Colon					1
Lung	3	1		5	1	1
Neck	1				1
Skin	1			3
Urinary tract	1
Wound	1
Blood	2				1
Infection with unknown neutrophils, lung	1
Infection with unknown neutrophils, skin	1			1
Opportunistic infection with lymphopenia	1
Infection, other					1
Edema
Head and neck	2			1
Limb				1
Hypoalbuminemia				1
Alkaline phosphatase				1
ALT				1
Creatinine	1
Hyperglycemia	2			1
Hypophosphatemia				1
Hypokalemia					1
Hyponatremia	1			2	1
Non-neuropathic lower extremity muscle weakness	1			1
Non-neuropathic generalized weakness	1			5
Trismus	1
Neuropathy, motor	1
Neuropathy, sensory	3
Syncope	2
Abdomen, pain	1
Chest pain NOS	1
Head/headache				1
Adult respiratory distress syndrome		1			1
Bronchospasm, wheezing	1
Cough				1
Dyspnea	3	1		4	1
Hypoxia	1			1	1
Pleural effusion, nonmalignant	2			1
Pneumonitis/pulmonary infiltrates			1	1	2
Renal failure	1
Thrombosis/embolism	1
Vessel injury, carotid	1
Worst degree	37	6	5	36	12	2

NOTE. Grade 3, severe; grade 4, life threatening; grade 5, lethal.

Abbreviation: NOS, not otherwise specified.

Of 19 patients assessed for toxicity in step 2, two experienced grade 3 toxicities (fatigue and dysphagia, respectively). No grade 4 or 5 toxicities were reported.

Correlative Studies

SNP analysis was performed on germline DNA samples and mutation analysis was performed on somatic DNA samples from tumor tissue. Among the 239 eligible patients, 89 blood samples and 69 tumor samples were available for analysis (Table 3 and Appendix Tables 2-4). No significant difference was found in any patient characteristic between patients who had blood or tumor sample analyzed and those who did not. No association was found between SNP genotypes and toxicity or efficacy. Two EGFR mutations were detected, one EGFRvIII and one EGFR A767T (both in arm B). The patient with an EGFRvIII mutation had an objective response, whereas two of 35 patients with wild-type EGFR achieved an objective response (100% v 6%; P = .08) in arm B and had an OS of 19.6 months versus 5.7 months in patients with wild type. The patient with the EGFR A767T mutation was not evaluable for response. Regardless of treatment, the presence of c-MET mutations tended to predict decreased OS. In 10 patients with c-MET mutations, the median OS was 3.6 months (95% CI, 1.1 to 8.6) versus a median OS of 5.7 months (95% CI, 3.5 to 8.3; P = .09) in 41 patients with wild-type c-MET. TTP was also decreased, although not significantly (median TTP, 2.1 v 2.9 months; P = .07), in patients with c-MET mutations. There were no KRAS mutations identified.

Table 3.

Efficacy by the Presence of c-MET Tumor Mutation

cMET Mutation by Arm	Objective Response				P	Overall Survival		P	Time to Progression		P
	No		Yes
	No. of Patients	%	No. of Patients	%		Median	95% CI		Median	95% CI
Docetaxel (n = 23)
No	19	95	1	5	1.00	5.4	2.0 to 14.7	—	3.2	1.4 to 4.8	—
Yes	3	100	0	0		2.4	1.6 to 3.5		1.5	0.8 to 2.2
Gefitinib (n = 28)
No	20	95	1	5	1.00	5.9	3.1 to 10.3	.44	2.4	1.5 to 6.1	.19
Yes	7	100	0	0		5.7	1.1 to 9.1		2.1	1.6 to 3.8
Both (n = 51)
No	39	95	2	5	1.00	5.7	3.5 to 8.3	.09	2.9	1.8 to 3.7	.07
Yes	10	100	0	0		3.6	1.1 to 8.6		2.1	0.8 to 2.3

NOTE. If tumor mutation was observed on cMET V1110I (n = 2), H1112Y (n = 5), H112RL (n = 0), T1010I (n = 1), R988C (n = 1), V1333I (n = 1), or any cMET exon 14 del (n = 2), then cMET mutation was coded as “Yes.” If wild type was observed in all these biomarkers, then cMET mutation status was coded as “No.” Otherwise, the status was coded as missing and excluded from data analysis.

DISCUSSION

This trial was one of the first phase III, placebo-controlled trials in poor PS and/or heavily pretreated patients with R/M SCCHN. For this patient population, we did not demonstrate a survival benefit by adding gefitinib to docetaxel. The median overall survival with or without gefitinib was 7.3 months versus 6.0 months, respectively, a difference that did not reach statistical significance. Moreover, there was no significant difference in TTP between the two arms (median TTP was 2.1 months for arm A and 3.5 months for arm B). The addition of gefitinib to docetaxel resulted in a higher rate of grade 3 or 4 diarrhea but other toxicities were comparable between the two arms.

Unplanned subgroup analysis showed that patients younger than 65 years derived survival benefit with the addition of gefitinib to docetaxel (median, 7.6 v 5.2 months), but not patients ≥ 65 years. There were no significant differences in grade 3 to 5 toxicities between younger and elderly patients except a higher incidence of infections with docetaxel and gefitinib in the elderly. However, the elderly required more dose interruptions of gefitinib dosing, which may explain the differential survival outcome by age. It has been previously reported that elderly patients with R/M SCCHN treated with chemotherapy have increased toxicities when compared with younger patients, even though survival outcomes appear comparable.^35,36 With advancing age, there are biologic changes and a higher incidence of comorbidities that may predispose the elderly to increased risks from chemotherapy.³⁷ Our observation of a potential survival benefit with the addition of gefitinib to docetaxel in younger but not older patients may warrant further validation in clinical studies.

A prior ECOG trial showed poor survival results in previously treated patients with R/M SCCHN dosed with irinotecan and docetaxel resulting in an ORR of 3% and median OS of 5 months.³⁸ The results seen with single-agent docetaxel in the control arm of the current trial were as expected. Although cross-over to single-agent gefitinib was initially allowed in this trial, only 18 eligible patients received it. This is unlikely to have had any impact on the survival results of our study.

Two phase II trials explored the addition of an EGFR-TKI to cisplatin and docetaxel in patients with R/M SCCHN.^15,39 Kim et al³⁹ reported an ORR of 66% in the first 37 patients treated with cisplatin/docetaxel plus erlotinib, whereas Belon et al¹⁵ reported an ORR of 50% in 24 patients treated with cisplatin/docetaxel plus gefitinib. The combination of an EGFR-TKI (erlotinib) and chemotherapy resulted in survival benefit, albeit marginal, in advanced pancreatic cancer⁴⁰ but not in advanced non–small-cell lung cancer.^41–44 Whether the lack of efficacy in combined EGFR-TKI and chemotherapy in lung cancer can be attributed to a sequence-dependent effect is the subject of ongoing research.⁴⁵

Our analysis of correlative biomarkers in a rather small fraction of available patient samples indicate that c-MET mutations are possible prognostic markers for survival and disease progression but do not predict outcomes after EGFR inhibitor therapy, which is consistent with other reports that suggest the c-MET amplification does not predict response to EGFR inhibitors and that c-MET is a negative prognostic marker.^46–48 The single patient found to have a tumor with an EGFRvIII mutation responded to docetaxel/gefitinib in our study. Although mutations in EGFR are rare in SCCHN,⁴⁹ the potential benefit with EFGR-TKI treatment for these patients may warrant further study.

In conclusion, the addition of gefitinib to docetaxel was well tolerated but it did not enhance therapeutic efficacy across all patients in this clinical setting. The outcome of patients with SCCHN with previously treated disease or performance status of 2 remains poor and the study of other novel agents in this setting should continue.

Appendix

Table A1.

Reasons Eligible Patients Withdrew From Treatment (Step 1)

Reason	Placebo (n = 110)		Gefitinib (n = 117)
	No. of Patients	%	No. of Patients	%
Treatment completed per protocol criteria	1	1	0	0
Disease progression during active treatment	55	50	62	53
Adverse events/adverse effects/complications	14	13	19	16
Death on study	11	10	12	10
Withdrawal or refusal after beginning protocol therapy	10	9	15	13
Alternative therapy	0	0	0	0
Other complicating disease	3	3	1	1
Other	16	15	8	7

Table A2.

Frequency and Percentage by Polymorphism and Genotype (SNP analysis)

Genotype	No. of Patients	%
ABCB1_3435	19	21
CC
CT	52	58
TT*	18	20
ABCB1_2677	3	—
Unknown
GG	25	2
GT	44	51
TT*	16	19
AT*	1	1
ABCB1_1236	4	—
Unknown
CC	22	2
CT	46	54
TT*	17	20
CYP3A4	73	82
AA
AG	15	17
GG*	1	1
CYP3A5	2	2
AA
AG	19	21
GG*	68	76
ABCG2_C421A	13	15
AC
CC*	76	85
ABCG2_C1143T	1	—
Unknown
CC	53	60
CT	29	33
TT*	6	7
EGFR_Q787Q	2	—
Unknown
AA	23	27
AG	42	48
GG*	22	25

Abbreviation: SNP, single nucleotide polymorphisms.

^*Refers to variant.

Table A3.

Frequency and Percentage by EGFR Biomarker and Genotype/Mutation

Genotype	No. of Patients	%
EGFR_CA_SSR1_CA repeats	4	—
Unknown
Mutant (n < 16)	14	22
WT	51	78
EGFR_vIII	3	—
Unknown
Mutant	1	2
WT	65	98
EGFR_L858R	4	—
Unknown
TT*	65	100
EGFR_del_746_759	4	—
Unknown
WT	65	100
EGFR_E749K	4	—
Unknown
GG*	65	100
EGFR_T790M	69	100
CC
EGFR_L861Q	3	—
Unknown
TT*	66	100
EGFR_E762G	1	—
Unknown
AA*	68	100
EGFR_A767T	4	—
Unknown
GA	1	2
GG*	64	98

Abbreviations: EGFR, epidermal growth factor receptor; WT, wild type.

^*Refers to WT.

Table A4.

Frequency and Percentage by c-MET Mutation and Genotype

Genotype	No. of Patients	%
cMET_Y1230C
Unknown	6	—
GG*	63	100
cMET_Y1230D
Unknown	6	—
GG*	63	100
cMET_Y1235D
Unknown	6	—
TT*	63	100
cMET_V1110I
Unknown	14	—
GA	2	4
GG*	53	96
cMET_H1112Y
Unknown	7	—
CC*	57	92
CT	3	5
TT	2	3
cMET_H1112RL
Unknown	6	—
AA*	63	100
cMET_M1149T
Unknown	3	—
TT*	66	100
cMET_V1206L
Unknown	3	—
TT*	66	100
cMET_V1238I
Unknown	3	—
GG*	66	100
cMET_D1246NH
Unknown	4	—
AA*	65	100
cMET_Y1248HD
Unknown	2	—
TT*	67	100
cMET_Y1248C
Unknown	3	—
AA*	66	100
cMET_M1268T
Unknown	3	—
TT*	66	100
cMET_T1010I
Unknown	12	—
CC*	56	98
TT	1	2
cMET_R988C
Unknown	12	—
CC*	56	98
TT	1	2
cMET_E168D
Unknown	3	—
GG*	66	100
cMET_T230M
Unknown	3	—
CC	66	100
cMET_T1275I
Unknown	6	—
CC	63	100
cMET_V1333I
Unknown	3	—
GA	1	2
GG	65	98
cMET_Exon14_del*
cMET_ex14_1GAT
WT	69	100
cMET_lnt13ex14_del_n16_3078
Mutant	2	3
WT	67	97
cMET_ln13_del_n26_n48
WT	69	100
cMET_ln13_del_n8_n18
Mutant	1	1
WT	68	99
cMET_ln13_del_n27_n6
WT	69	100
cMET_ex14_del_3195_p7
WT	69	100

Abbreviation: WT, wild type.

^*Refers to WT.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. 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 or Leadership Position: None Consultant or Advisory Role: Barbara Burtness, AstraZeneca (C), Boehringer Ingelheim (C), Genentech (C), sanofi-aventis (C) Stock Ownership: None Honoraria: Athanassios Argiris, AstraZeneca Research Funding: Athanassios Argiris, AstraZeneca; Jill M. Kolesar, AstraZeneca; Barbara Burtness, Genentech, sanofi-aventis Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Athanassios Argiris, Musie Ghebremichael, Jill Gilbert, Barbara Burtness, Arlene A. Forastiere

Administrative support: Athanassios Argiris, Arlene A. Forastiere

Provision of study materials or patients: Athanassios Argiris

Collection and assembly of data: Athanassios Argiris, Musie Ghebremichael, Kamakshi Sachidanandam, Jill M. Kolesar

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors