- Email: [email protected]
Phase II study of pemetrexed in combination with cisplatin and cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck
European Journal of Cancer (2013) 49, 2877– 2883
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Phase II study of pemetrexed in combination with cisplatin and cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck q J.B. Vermorken a,⇑, L. Licitra b, J. Sto¨hlmacher-Williams c, A. Dietz d, J.M. Lopez-Picazo e, O. Hamid f, A.M. Hossain f, S.-C. Chang f, T.C. Gauler g a
Antwerp University Hospital, Edegem, Belgium Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy c University Hospital Dresden, Dresden, Germany d Universita¨tsklinikum Leipzig, Leipzig, Germany e Clinica Universidad de Navarra, Pamplona, Spain f Eli Lilly and Company, Indianapolis, IN, USA g University Hospital Essen, Essen, Germany b
Available online 30 May 2013
KEYWORDS Head and neck squamous cell carcinoma Pemetrexed Cetuximab Cisplatin
q
Abstract Purpose: Platinum/5-fluorouracil plus cetuximab is a standard systemic treatment for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Pemetrexed has shown activity in SCCHN. This phase II study evaluated pemetrexed with cisplatin and cetuximab in recurrent/metastatic SCCHN. Methods: Patients received cetuximab 250 mg/m2 (loading dose: 400 mg/m2) days 1, 8 and 15; pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 on day 1, q3w up to six cycles and folic acid, vitamin B12 and prophylactic medications. After a minimum of four cycles, responding patients were eligible for maintenance with pemetrexed and cetuximab, or either as monotherapy, until progression or toxicity. Efficacy (primary end-point: progression-free survival [PFS]) and toxicity were evaluated. Results: Sixty-six patients received P1 cycle of the triplet. Most patients were male (80.3%), with a median age of 62 years and Eastern Cooperative Oncology Group (ECOG) performance status of 1 (71.2%). Diagnoses included oropharynx (45.5%) and larynx (24.2%) cancers, with locoregional disease (51.5%) alone, or combined with distant metastases (48.5%). Median (m) PFS was 4.4 months (95% confidence interval [CI]: 3.6, 5.4); median overall survival was 9.7 months (95% CI: 6.5, 13.1). Objective response rate was 29.3%; 23 patients had
Supported by: Eli Lilly and Company, Indianapolis, IN, USA.
⇑ Corresponding author: Address: Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium. Tel.:
+32 3 821 4548; fax: +32 3 821 4121. E-mail address: [email protected] (J.B. Vermorken). 0959-8049/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2013.05.002
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stable disease (39.7%). Drug-related grade 3/4 toxicities included neutropaenia (33.3%), fatigue (24.2%), anorexia (12.1%) and infection (10.6%). Five treatment-related deaths (7.6%) occurred. Conclusions: Efficacy results were consistent with current standard treatment for this patient population, but the pre-specified mPFS of 5.5 months was not achieved. Grade 3/4 toxicities were also consistent with standard treatment, although treatment-related deaths were higher than expected. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Worldwide, more than 500,000 cases of squamous cell carcinoma of the head and neck (SCCHN) were estimated in 2008.1 In Europe alone, estimates reached 130,000 cases of oral cavity, pharyngeal, and laryngeal cancers, and over 60,000 deaths.2 Recurrent and/or metastatic (R/M) SCCHN, for which no curative approaches with surgery and/or radiotherapy exist, remains a disease with poor outcomes. Patients with good Eastern Cooperative Oncology Group (ECOG) performance status (PS) have typically been treated with platinum-based combination chemotherapy, leading to more responses than single-agent treatment; however, these more aggressive regimens have not had an impact on overall survival (OS).3–7 Reported median (m) OS ranges from 6 to 9 months (1-year survival: 20–40%). Recent studies with improved patient selection and supportive care measures have shown slightly better results. Analyses of these studies have highlighted the important unfavourable predictors of survival: severe weight loss, poor PS, oral cavity or hypopharynx tumours, history of radiotherapy and well or moderately differentiated tumours.8 Recently, the European EXTREME trial,9 with support of a smaller phase III United States study,10 has changed clinical practice for R/M-SCCHN. The addition of cetuximab to standard platinum/infusional 5-fluorouracil (5-FU), significantly increased mOS (10.1 versus 7.4 months), progression-free survival (PFS): (5.6 versus 3.3 months), response rate (36% versus 20%), disease control rate (DCR): complete response [CR] + partial response [PR] + stable disease [SD], (81% versus 60%), and time to treatment failure (4.8 versus 3.0 months) with an acceptable safety profile, improved symptom control and quality of life.9,11 Despite these gains, further studies demonstrating improved efficacy with less toxicity, are urgently needed. Both single-agent pemetrexed and pemetrexed plus cisplatin have been studied in SCCHN. As a single agent, pemetrexed exhibited a response rate of 27% in the recurrent or metastatic disease setting.12 In a phase III study, pemetrexed plus cisplatin significantly increased OS and PFS in patients with adequate ECOG PS (0–1) compared with cisplatin alone (mOS 8.4 versus 6.7 months; hazard ratio [HR] = 0.83; P = 0.026; mPFS 4.0 versus 3.0 months; HR = 0.84; P = 0.044,
respectively).7 Pemetrexed plus cisplatin is a well-tolerated and efficacious combination in other tumours as well, such as non-small cell lung cancer and mesothelioma.13,14 This phase II study was designed to evaluate and determine the efficacy and toxicity of the combination of pemetrexed, cisplatin and cetuximab in first-line R/M SCCHN. 2. Materials and methods 2.1. Study design and patient population The primary objective of this multicentre, open-label, single-arm study was to estimate PFS in patients with R/ M SCCHN receiving triplet therapy with pemetrexed, cisplatin and cetuximab. Secondary objectives included estimation of OS, assessment of objective response rate (ORR) and evaluation of safety and toxicity of this triplet. Eligibility criteria included: histologically-confirmed diagnosis of SCCHN, locoregionally recurrent and/or metastatic disease not amenable to local therapy, ECOG PS of 0–1, adequate organ function and age P18 years. No more than one prior systemic regimen completed at least 6 months prior to study entry, was allowed for locoregionally, advanced disease. No prior systemic therapy was allowed for metastatic disease. Multimodality treatment such as induction chemotherapy and subsequent concurrent chemoradiation was considered one regimen. Radiation therapy or surgery was to be completed at least 4 weeks before study entry. Exclusion criteria included: patients with nasopharyngeal, paranasal sinus, lip or salivary gland cancers, symptomatic brain metastases, peripheral neuropathy of grade 1 or higher (according to National Cancer Institute Common Terminology Criteria for Adverse Events [NCICTCAE])15; clinically relevant third space fluid; concurrent antitumour therapy and systemic or psychiatric disorders. The study was conducted in accordance with the Declaration of Helsinki and approved by local ethics review boards. All patients provided written informed consent. 2.2. Baseline assessments Prior to treatment, all patients received comprehensive baseline assessments. Baseline tumour assessments
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were performed with either computed tomography (CT) or magnetic resonance imaging (MRI) and the same method of measurement and technique were repeated every other cycle and approximately every 6 weeks after discontinuation. Other follow-up assessments were repeated before each cycle and 30 days after discontinuation. 2.3. Study treatment Patients received pemetrexed, cisplatin and cetuximab for a maximum of six cycles. Those who completed a minimum of four cycles of the triplet were eligible for optional maintenance therapy with pemetrexed plus cetuximab, or either as monotherapy, if one of the drugs was discontinued due to toxicity. Patients could continue on maintenance until progressive disease (PD), unacceptable toxicity or other withdrawal criteria, at the investigator’s discretion. Twenty-seven patients received maintenance therapy; 24 received pemetrexed + cetuximab, two received cetuximab alone and only one patient received pemetrexed alone. Cetuximab was administered at 400 mg/m2 (initial dose) intravenously (IV) and thereafter at 250 mg/m2 IV weekly, followed by pemetrexed 500 mg/m2 IV and cisplatin 75 mg/m2 IV, both on day 1 of each 21-day cycle. Patients received folic acid (350–1000 lg daily orally) and vitamin B12 (1000 lg intramuscular every 9 weeks) starting 1–2 weeks prior to initiation of chemotherapy, and dexamethasone (4 mg) bid for 3 days, 24 h prior to protocol treatment. An antihistamine (diphenhydramine 50 mg or equivalent) was given immediately before each cetuximab infusion to prevent allergic reactions. After two planned interim safety analyses, patients were administered prophylactic ciprofloxacin (or equivalent fluoroquinolone) 500 mg orally bid for 10 days starting on day 2 of each cycle during induction. Investigators followed current American Society of Clinical Oncology guidelines for use of haematopoietic colony-stimulating factors.16 Patients were evaluated for toxicity prior to each cycle using NCI-CTCAE v. 3.0. Drug-related toxicities were determined by the investigators. Response and progression were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST).17 All patients who received at least one cycle of pemetrexed, cisplatin and cetuximab were evaluable for response and toxicity. 2.4. Statistical analyses This study was powered as a single-arm trial. Based on the EXTREME trial by Vermorken et al. 2008, median PFS for platinum/5-FU plus cetuximab and platinum/ 5-FU alone, was approximately 5.5 and 3.5 months, respectively. For powering the sample size for this study, we assumed median PFS for the experimental combina-
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tion (pemetrexed, cisplatin and cetuximab) would be similar to the cetuximab arm in the EXTREME trial. It was hoped that this study would show at least a 2-month improvement in PFS over the 3.5 months observed in the platinum/5-FU alone arm in EXTREME (i.e. reaching 5.5 months). Fifty-two PFS events (65 patients) were required to estimate mPFS for this study with 90% power and a two-sided test significance level of 0.05. Kaplan–Meier techniques were used to estimate mPFS and mOS for all treated patients.18 All qualified patients (AQP), those who completed a baseline and at least one post-baseline tumour assessment, were evaluable for ORR. A 95% confidence interval (CI) of best ORR was estimated using an exact method.19 All efficacy tests were conducted at a 2-sided alpha level of 0.05; CIs were given at a 2-sided 95% level. Safety analyses included drug-related grade 3/4 laboratory and non-laboratory adverse events (AEs) using NCI-CTCAE v. 3.0. 3. Results Between March 2010 and March 2011, 73 patients were enrolled at 12 sites in six European countries. Six patients were screen failures; one patient was not treated; 66 patients received P1 dose of pemetrexed, cisplatin and cetuximab. Fifty-eight patients had both a baseline and at least one post-baseline tumour evaluation via CT or MRI and were qualified for response assessment. 3.1. Patient and disease characteristics Patient and disease characteristics are summarised in Table 1. Forty-seven patients (71.2%) had an ECOG PS of 1. Nineteen (28.8%) patients had recurrent/metastatic disease originating from the oral cavity and hypopharynx (unfavourable predictor); 46 (69.7%) had disease originating from the larynx and oropharynx. Thirtyfour (51.5%) patients had locoregionally recurrent disease only and 32 (48.5%) had distant metastases with locoregional disease. Approximately half of the patients received prior cytotoxic chemotherapy for treatment of their primary disease. One (1.5%) patient received prior chemotherapy as a single modality, 8 (12.1%) patients received neoadjuvant chemotherapy followed by radiotherapy or concurrent chemoradiation and 26 patients (39.4%) received concurrent chemoradiation without prior neoadjuvant chemotherapy. Cisplatin monotherapy and cisplatin combinations were the most frequently used prior chemotherapies. 3.2. Dosing and treatment The median number of cycles received was 5.0 (range: 1–26) for pemetrexed, 4.0 (range: 1–6) for cisplatin, and 4.5 for cetuximab (range: 1–27). Forty-one patients
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Table 1 Baseline patient and disease characteristics. Characteristic
Table 2 Response and survival data. Cisplatin/ pemetrexed/ cetuximab (N = 66)
Age, median (range) (years)
62 (42.0–87.0)
Sex, n (%) Female Male
13 (19.7%) 53 (80.3%)
ECOG performance status 0 1
19 (28.8%) 47 (71.2%)
Ethnicity (Caucasian)
66 (100.0%)
Pathological diagnosis Oropharynx Larynx Oral cavity Hypopharynx Othera
30 (45.5%) 16 (24.2%) 11 (16.7%) 8 (12.1%) 1 (1.5%)
Stage of disease Locoregional (recurrent) Distant metastatic plus locoregional disease (30/32 recurrent)
34 (51.5%) 32 (48.5%)
Prior therapies Radiotherapy Surgery Cytotoxic chemotherapy
64 55 45 35
(97.0%) (83.3%) (68.2%) (52.0%)
Abbreviations: ECOG, Eastern Cooperative Oncology Group; N, total population size; n, number of patients. a Carcinoma of the auditory canal.
(62.1%) completed P4 cycles of the triplet; 27 (40.9%) entered the maintenance phase. Twenty-two (33.3%) patients completed P7 cycles and 5 (7.6%) completed P14 cycles. Pemetrexed dose reductions occurred in 17 (25.8%) patients, cisplatin reductions in 19 (28.8%) patients and cetuximab reductions in 7 (10.6%) of the 66 treated patients. Thirty-five (53.0%) patients discontinued due to PD; 12 (18.2%) due to patient, physician or sponsor decision; 9 (13.6%) due to AEs; and 8 (12.1%) due to death. One patient was lost to followup; one patient was still on treatment at the time of analysis. 3.3. Efficacy Table 2 summarises efficacy results. The mPFS was 4.4 months (95% CI: 3.6, 5.4) and mOS was 9.7 months (95% CI: 6.5, 13.1). ORR was 29.3%, with 1 CR (1.7%) and 16 PRs (27.6%). Twenty-three (39.7%) patients had SD; the DCR was 69.0%. An exploratory subgroup analysis demonstrated that the 16 patients with recurrent/metastatic disease originating from the larynx had a more favourable outcome than the 50 patients with recurrent/metastatic disease originating from other disease sites. Response in the lar-
Efficacy measure
Cisplatin/pemetrexed/cetuximab (N = 66)
Median PFS (months) 95% CI (censoring rate)
4.4 3.6, 5.4 (13.6%)
1-Year PFS rate 95% CI
11% 3%, 19%
Median overall survival (OS) (months) 95% CI (censoring rate)
9.7 6.5, 13.1 (28.8%)
1-Year OS rate 95% CI
44% 32%, 56%
Responses (N = 58) Complete response (CR) Partial response (PR) Stable disease Progressive disease Unknown
1 (1.7%) 16 (27.6%) 23 (39.7%) 12 (20.7%) 6 (10.3%)
Overall response rate (CR + PR) 95% CI
17 (29.3%) (18.1, 42.7)
Abbreviations: CI, confidence interval, N, total population size; PFS, progression-free survival.
ynx subgroup was higher (40% versus 25.6% in the AQP, respectively), and more of these patients became eligible for maintenance therapy (56.3% versus 36%). mPFS of the larynx patients was longer than the non-larynx patients (5.2 versus 4.4 months), as was mOS (20.8 versus 8.5 months, HR 0.44, 95% CI [0.20, 0.95], censoring rate 43.8%).
3.4. Safety All patients were evaluable for toxicity. Table 3 lists grade 3–4 toxicities that occurred in P3% of patients. The most frequent (>10%) grade 3/4 toxicities (possibly drug-related) were neutropaenia (33.3%), leukopaenia (34.8%), fatigue (24.2%), skin rash (including acne; 15.2%), anorexia (12.1%), hypomagnesaemia (10.6%) and infection (10.6%). After initiation of the study, during the Safety Assessment Committee meetings, a higher-than-expected rate of infections and laboratory AEs was noted, with events disproportionately higher at one centre. Some of these patients had recently recovered from infections; some suffered from dysphagia, a complaint frequently present in patients with SCCHN. For these reasons, the Committee recommended all patients to receive prophylactic antibiotics during the first few days of each cycle of triplet treatment. There were eight deaths on treatment; five deaths were considered possibly related to study treatment. These deaths were due to: respiratory failure associated with aspiration pneumonia (2); respiratory failure and septic shock (1); sepsis, respiratory failure and tumour
J.B. Vermorken et al. / European Journal of Cancer 49 (2013) 2877–2883 Table 3 Grade 3/4 treatment-related toxicities possibly related to study drug (N = 66).
Table 4 Systemic post-discontinuation therapy.
Grade 3 Grade 4 Total grade 3/4 n (%) n (%) n (%) Laboratory Leukopaenia Neutropaenia Hypomagnesaemia Anaemia Thrombocytopenia Hypokalaemia Gamma-glutamyl transpeptidase Non-laboratory Fatigue Skin rash (includes acne) Anorexia Infection Nausea Mucositis Vomiting Diarrhoea Pneumonitis
14 (21.2) 12 (18.2) 5 (7.6) 5 (7.6) 3 (4.5) 2 (3.0) 2 (3.0)
14 (21.2) 9 (13.6) 7 (10.6) 4 (6.1) 5 (7.6) 4 (6.1) 4 (6.1) 3 (4.5) 1 (1.5)
9 (13.6) 10 (15.2) 2 (3.0) 1 (1.5) 1 (1.5) 2 (3.0) 0
2 1 1 3 0 1 0 0 2
(3.0) (1.5) (1.5) (4.5) (1.5)
(3.0)
23 (34.8) 22 (33.3) 7 (10.6) 6 (9.1) 4 (6.1) 4 (6.1) 2 (3.0)
16 (24.2) 10 (15.2) 8 (12.1) 7 (10.6) 5 (7.6) 5 (7.6) 4 (6.1) 3 (4.5) 3 (4.5)
Abbreviations: N, total population size; n, number of patients.
emboli (1); and unknown (1). Three other deaths onstudy unrelated to treatment were due to respiratory failure (1), aspiration (1) and cerebral ischaemia (1). 3.5. Post-discontinuation therapy Thirty-five of the 66 patients received systemic postdiscontinuation therapy (PDT) when they had progressed on study treatment. Many patients received P1 systemic PDT (Table 4). There was a substantial difference in the proportion of patients who received P1 PDT in the larynx subgroup compared with the non-larynx subgroup (75.0% versus 48.0%), and the use of targeted therapies was also greater in the larynx subgroup (68.8% versus 24.0%). Most PDTs were given as monotherapy, with methotrexate being the most frequently given cytotoxic chemotherapy, and cetuximab, temsirolimus or SYM004-02, as the most frequently given non-cytotoxic therapies. 4. Discussion In this, single-arm, phase II, open-label study, patients with R/M SCCHN were treated with the combination of pemetrexed, cisplatin and cetuximab. We observed a mPFS of 4.4 months and mOS of 9.7 months with 1-year PFS rate of 11%; 1-year OS rate of 44%. ORR and DCR were 29.3% and 69.0%, respectively. The mOS of 9.7 months is quite comparable to that observed in the cetuximab arm of the EXTREME trial (mOS: 10.1 months).9 Efficacy results were consistent with current standard treatment for R/M-SCCHN,8,10 but the prespecified mPFS objective of 5.5 months was not met.
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Patients with at least 1 PDT Methotrexate Cetuximab Temsirolimus (ToriselÒ) SYM004-02 (Symphogen) Docetaxel Carboplatin monotherapy 5-FU monotherapy Cyclophosphamide Paclitaxel monotherapy Gemcitabine monotherapy 5-FU + carboplatin Carboplatin + paclitaxel Bleomycin + methotrexate Tegafur + oral uracil Capecitabine 5-FU + docetaxel Afatinib Bleomycin Carboplatin + cetuximab Adriamycin Adriamycin + paclitaxel Other investigational agent
Total population N = 66 (n (%))
Larynx subgroup n = 16 (n (%))
Non-larynx subgroup n = 50 (n (%))
36 (54.5)
12 (75.0)
24 (48.0)
10 (15.2) 9 (13.6) 7 (10.6)
3 (18.8) 4 (25.0) 3 (18.8)
7 (14.0) 5 (10.0) 4 (8.0)
6 (9.1)
4 (25.0)
2 (4.0)
6 (9.1) 3 (4.5)
2 (12.5) 0
4 (8.0) 3 (6.0)
3 (4.5) 3 (4.5) 3 (4.5)
1 (6.3) 2 (12.5) 1 (6.3)
2 (4.0) 1 (2.0) 2 (4.0)
3 (4.5)
2 (12.5)
1 (2.0)
2 (3.0) 2 (3.0)
0 1 (6.3)
2 (4.0) 1 (2.0)
1 (1.5)
1 (6.3)
0
1 (1.5)
1 (6.3)
0
1 1 1 1 1
(1.5) (1.5) (1.5) (1.5) (1.5)
0 0 0 0 0
1 1 1 1 1
1 (1.5) 1 (1.5)
0 0
1 (2.0) 1 (2.0)
1 (1.5)
0
1 (2.0)
(2.0) (2.0) (2.0) (2.0) (2.0)
Abbreviations: N, total population size; n, number of patients; PDT, Post-discontinuation therapy.
Despite the limitations of cross-trial comparisons, our efficacy results compare favourably with those from the study evaluating pemetrexed and cisplatin without cetuximab, which demonstrated a mPFS of 3.6 months and a mOS of 7.3 months.7 Our results also compare favourably with efficacy results in other randomised studies using cisplatin-based chemotherapy without cetuximab,6,10 underscoring the potential benefit of cetuximab in this population. The most frequent grade 3/4 toxicities possibly related to this triplet were similar to those reported for other head-and-neck cancer combination chemotherapies.9,20 The most common included neutropaenia, hypomagnesaemia, fatigue, skin rash, anorexia and infection. The incidence of serious infections was higher in this study than reported in other studies (10.6% versus 4–6%); in fact, grade 4 neutropaenia was approximately 10% higher than that observed in the cetuximab arm of
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the EXTREME trial, and may have been a contributing factor to the higher-than-expected percent of deaths possibly related to the study drug (7.6% versus 2.3– 5.5%, respectively). Examination of this patient population compared with that in the EXTREME trial, indicates that more patients in this study received prior chemotherapy (54.5% versus 41%) and prior concurrent chemoradiation (39.4% versus 31.1%). However, more patients in our study had a better PS than in the EXTREME trial (0/1: 100% versus 88%). Other negative predictors for survival were quite comparable in the two studies suggesting that the patient population in our study was not strikingly worse than that in the EXTREME study. Therefore, the pemetrexed, cisplatin and cetuximab regimen, although easier to administer, does not seem to be more efficacious than the present standard platinum/5FU/cetuximab (EXTREME) regimen. Also, the toxicity profile of pemetrexed, cisplatin and cetuximab does not seem to be more favourable than the platinum/5-FU/ cetuximab regimen. On the contrary, compared with the EXTREME regimen, more grade 3/4 leukopaenia (34.8% versus 11%), neutropaenia (33.3% versus 26%), skin rash (15.2% versus 9%), and treatment-related deaths (7.6% versus 1.4%) were observed in our study. The results observed in the larynx subgroup are intriguing, with a 40% response rate, 5.2-month mPFS and 20.8-month mOS. Survival analyses are limited by sample size (16 patients) and a censoring rate of 43.8% should be interpreted with caution. More patients received maintenance therapy in the larynx group (9/ 16; 56.3%) than those in the non-larynx group (18/50; 36.0%). Additionally, strikingly more patients in the larynx group received PDT, mainly targeted therapies (11/ 16; 69% versus 12/50; 24%) including cetuximab, temsirolimus and SYM004-02. Limited data exist on re-introducing cetuximab after previous use. Temsirolimus, an mTOR inhibitor, has shown activity in refractory SCCHN after failure of platinum-based chemotherapy and cetuximab.21 SYM004-02, a mixture of two antiEGFR monoclonal antibodies directed against distinct non-overlapping epitopes in EGFR extracellular domain III, has interesting preclinical anti-tumour activity and the potential to overcome acquired resistance to other EGFR-targeted agents, such as cetuximab.22 It may be tempting to attribute the better survival in the larynx subgroup with these observations.
5. Conclusion The efficacy results demonstrate that this triplet aligns with current standard treatment in R/M SCCHN; however, the pre-specified mPFS of 5.5 months was not achieved. Toxicity results are also consistent with current standard treatment; however, a higherthan-expected number of treatment-related deaths was
reported. As such, there is no compelling rationale to further develop this combination for treatment of R/ M SCCHN. Conflict of interest statement Dr. Jan B. Vermorken is a consultant/advisor for Merck-Serono, Amgen, Boehringer-Ingelheim, Genentech, Vaccinogen, Oncolytics and PCI Biotech. Dr. Vermorken received travel compensation and/or honoraria for lecturing from Merck-Serono, Amgen, Eli Lilly and Company, and Bristol-Myers Squibb. Dr. Jan Sto¨hlmacher-Williams received funding for translational research projects exceeding $25,000 (US dollars) from Eli Lilly and Company (unrelated to this study), and has received travel grants and honoraria from Eli Lilly and Company and Merck-Serono. Dr. Lisa Licitra is a consultant/advisor for Bristol-Myers Squibb, Glaxo SmithKline, Eli Lilly and Company, Merck-Serono, Amgen and Boehringer Ingelheim. Her institution receives research funding from EISAI Co., Ltd., Exelixis, Eli Lilly and Company, Merck-Serono, Amgen and Boehringer Ingelheim. Dr. Licitra also received travel compensation for medical meetings. Dr. Andreas Dietz reports no disclosures. Dr. Jose M. Lopez-Picazo is a consultant for, and has received paid expert testimony on behalf of Eli Lilly and Company. Drs. Oday Hamid and Shao-Chun Chang and Mr. Anwar Hossain, are employees of Eli Lilly and Company, and as such employees, have stock ownership in said company. Dr. Thomas C. Gauler is a consultant for and has received honoraria from Eli Lilly and Company and Merck Serono. Acknowledgments The authors would like to thank Donna L. Miller of Eli Lilly and Company for help with manuscript preparation, and Anastasia Perkowski of ImClone Systems LLC, a wholly-owned subsidiary of Eli Lilly and Company, for editorial support. This study was funded by Eli Lilly and Company, Indianapolis, IN. This study is registered on ClinicalTrials.gov, identifier: NCT01057589. References 1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893–917. 2. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010;46:765–81. 3. 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 1992;10:1245–51. 4. Jacobs C, Lyman G, Velez-Garcı´a E, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in
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combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992;10:257–63. Clavel M, Vermorken JB, Cognetti F, et al. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol 1994;5:521–6. 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 2005;23:3562–7. Urba S, van Herpen CM, Sahoo TP, et al. Pemetrexed in combination with cisplatin versus cisplatin monotherapy in patients with recurrent or metastatic head and neck cancer: final results of a randomized, double-blind, placebo-controlled, phase 3 study. Cancer 2012;118:4694–705. Argiris A, Li Y, Forastiere A. Prognostic factors and long-term survivorship in patients with recurrent or metastatic carcinoma of the head and neck. Cancer 2004;101:2222–9. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116–27. 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 2005;23:8646–54 [Erratum in J Clin Oncol 2006;24:724]. Mesı´a R, Rivera F, Kawecki A, et al. Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 2010;21:1967–73. Pivot X, Raymond E, Laguerre B, et al. Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck. Br J Cancer 2001;85:649–55.
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13. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naı¨ve patients with advanced-stage nonsmall-cell lung cancer. J Clin Oncol 2008;26:3543–51. 14. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636–44. 15. National Cancer Institute. Cancer therapy evaluation program common terminology criteria for adverse events, version 3.0.; 2006. 16. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24(19):3187–205. 17. 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 2000;92:205–16. 18. Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Am Stat Assoc 1958;53:457–81. 19. Leemis LM, Trivedi KS. A comparison of approximate interval estimators for the Bernoulli parameter. Am Stat 1996;50:63–8. 20. Price KA, Cohen EE. Current treatment options for metastatic head and neck cancer. Curr Treat Options Oncol 2012;13:35–46. 21. Gru¨nwald V, Keilholz U, Boehm A, et al. Temsirolimus is active in refractory squamous cell carcinoma of the head and neck (SCCHN) failing platinum-based chemotherapy and cetuximab: efficacy and toxicity data from the phase II TEMHEAD study. ESMO 2012 [abstract 1023]. 22. Pedersen MW, Jacobsen HJ, Koefoed K, et al. Sym004: a novel synergistic anti-epidermal growth factor receptor antibody mixture with superior anticancer efficacy. Cancer Res 2010;70:588–97.
Available at www.sciencedirect.com
journal homepage: www.ejcancer.com
Phase II study of pemetrexed in combination with cisplatin and cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck q J.B. Vermorken a,⇑, L. Licitra b, J. Sto¨hlmacher-Williams c, A. Dietz d, J.M. Lopez-Picazo e, O. Hamid f, A.M. Hossain f, S.-C. Chang f, T.C. Gauler g a
Antwerp University Hospital, Edegem, Belgium Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy c University Hospital Dresden, Dresden, Germany d Universita¨tsklinikum Leipzig, Leipzig, Germany e Clinica Universidad de Navarra, Pamplona, Spain f Eli Lilly and Company, Indianapolis, IN, USA g University Hospital Essen, Essen, Germany b
Available online 30 May 2013
KEYWORDS Head and neck squamous cell carcinoma Pemetrexed Cetuximab Cisplatin
q
Abstract Purpose: Platinum/5-fluorouracil plus cetuximab is a standard systemic treatment for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Pemetrexed has shown activity in SCCHN. This phase II study evaluated pemetrexed with cisplatin and cetuximab in recurrent/metastatic SCCHN. Methods: Patients received cetuximab 250 mg/m2 (loading dose: 400 mg/m2) days 1, 8 and 15; pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 on day 1, q3w up to six cycles and folic acid, vitamin B12 and prophylactic medications. After a minimum of four cycles, responding patients were eligible for maintenance with pemetrexed and cetuximab, or either as monotherapy, until progression or toxicity. Efficacy (primary end-point: progression-free survival [PFS]) and toxicity were evaluated. Results: Sixty-six patients received P1 cycle of the triplet. Most patients were male (80.3%), with a median age of 62 years and Eastern Cooperative Oncology Group (ECOG) performance status of 1 (71.2%). Diagnoses included oropharynx (45.5%) and larynx (24.2%) cancers, with locoregional disease (51.5%) alone, or combined with distant metastases (48.5%). Median (m) PFS was 4.4 months (95% confidence interval [CI]: 3.6, 5.4); median overall survival was 9.7 months (95% CI: 6.5, 13.1). Objective response rate was 29.3%; 23 patients had
Supported by: Eli Lilly and Company, Indianapolis, IN, USA.
⇑ Corresponding author: Address: Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium. Tel.:
+32 3 821 4548; fax: +32 3 821 4121. E-mail address: [email protected] (J.B. Vermorken). 0959-8049/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2013.05.002
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stable disease (39.7%). Drug-related grade 3/4 toxicities included neutropaenia (33.3%), fatigue (24.2%), anorexia (12.1%) and infection (10.6%). Five treatment-related deaths (7.6%) occurred. Conclusions: Efficacy results were consistent with current standard treatment for this patient population, but the pre-specified mPFS of 5.5 months was not achieved. Grade 3/4 toxicities were also consistent with standard treatment, although treatment-related deaths were higher than expected. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Worldwide, more than 500,000 cases of squamous cell carcinoma of the head and neck (SCCHN) were estimated in 2008.1 In Europe alone, estimates reached 130,000 cases of oral cavity, pharyngeal, and laryngeal cancers, and over 60,000 deaths.2 Recurrent and/or metastatic (R/M) SCCHN, for which no curative approaches with surgery and/or radiotherapy exist, remains a disease with poor outcomes. Patients with good Eastern Cooperative Oncology Group (ECOG) performance status (PS) have typically been treated with platinum-based combination chemotherapy, leading to more responses than single-agent treatment; however, these more aggressive regimens have not had an impact on overall survival (OS).3–7 Reported median (m) OS ranges from 6 to 9 months (1-year survival: 20–40%). Recent studies with improved patient selection and supportive care measures have shown slightly better results. Analyses of these studies have highlighted the important unfavourable predictors of survival: severe weight loss, poor PS, oral cavity or hypopharynx tumours, history of radiotherapy and well or moderately differentiated tumours.8 Recently, the European EXTREME trial,9 with support of a smaller phase III United States study,10 has changed clinical practice for R/M-SCCHN. The addition of cetuximab to standard platinum/infusional 5-fluorouracil (5-FU), significantly increased mOS (10.1 versus 7.4 months), progression-free survival (PFS): (5.6 versus 3.3 months), response rate (36% versus 20%), disease control rate (DCR): complete response [CR] + partial response [PR] + stable disease [SD], (81% versus 60%), and time to treatment failure (4.8 versus 3.0 months) with an acceptable safety profile, improved symptom control and quality of life.9,11 Despite these gains, further studies demonstrating improved efficacy with less toxicity, are urgently needed. Both single-agent pemetrexed and pemetrexed plus cisplatin have been studied in SCCHN. As a single agent, pemetrexed exhibited a response rate of 27% in the recurrent or metastatic disease setting.12 In a phase III study, pemetrexed plus cisplatin significantly increased OS and PFS in patients with adequate ECOG PS (0–1) compared with cisplatin alone (mOS 8.4 versus 6.7 months; hazard ratio [HR] = 0.83; P = 0.026; mPFS 4.0 versus 3.0 months; HR = 0.84; P = 0.044,
respectively).7 Pemetrexed plus cisplatin is a well-tolerated and efficacious combination in other tumours as well, such as non-small cell lung cancer and mesothelioma.13,14 This phase II study was designed to evaluate and determine the efficacy and toxicity of the combination of pemetrexed, cisplatin and cetuximab in first-line R/M SCCHN. 2. Materials and methods 2.1. Study design and patient population The primary objective of this multicentre, open-label, single-arm study was to estimate PFS in patients with R/ M SCCHN receiving triplet therapy with pemetrexed, cisplatin and cetuximab. Secondary objectives included estimation of OS, assessment of objective response rate (ORR) and evaluation of safety and toxicity of this triplet. Eligibility criteria included: histologically-confirmed diagnosis of SCCHN, locoregionally recurrent and/or metastatic disease not amenable to local therapy, ECOG PS of 0–1, adequate organ function and age P18 years. No more than one prior systemic regimen completed at least 6 months prior to study entry, was allowed for locoregionally, advanced disease. No prior systemic therapy was allowed for metastatic disease. Multimodality treatment such as induction chemotherapy and subsequent concurrent chemoradiation was considered one regimen. Radiation therapy or surgery was to be completed at least 4 weeks before study entry. Exclusion criteria included: patients with nasopharyngeal, paranasal sinus, lip or salivary gland cancers, symptomatic brain metastases, peripheral neuropathy of grade 1 or higher (according to National Cancer Institute Common Terminology Criteria for Adverse Events [NCICTCAE])15; clinically relevant third space fluid; concurrent antitumour therapy and systemic or psychiatric disorders. The study was conducted in accordance with the Declaration of Helsinki and approved by local ethics review boards. All patients provided written informed consent. 2.2. Baseline assessments Prior to treatment, all patients received comprehensive baseline assessments. Baseline tumour assessments
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were performed with either computed tomography (CT) or magnetic resonance imaging (MRI) and the same method of measurement and technique were repeated every other cycle and approximately every 6 weeks after discontinuation. Other follow-up assessments were repeated before each cycle and 30 days after discontinuation. 2.3. Study treatment Patients received pemetrexed, cisplatin and cetuximab for a maximum of six cycles. Those who completed a minimum of four cycles of the triplet were eligible for optional maintenance therapy with pemetrexed plus cetuximab, or either as monotherapy, if one of the drugs was discontinued due to toxicity. Patients could continue on maintenance until progressive disease (PD), unacceptable toxicity or other withdrawal criteria, at the investigator’s discretion. Twenty-seven patients received maintenance therapy; 24 received pemetrexed + cetuximab, two received cetuximab alone and only one patient received pemetrexed alone. Cetuximab was administered at 400 mg/m2 (initial dose) intravenously (IV) and thereafter at 250 mg/m2 IV weekly, followed by pemetrexed 500 mg/m2 IV and cisplatin 75 mg/m2 IV, both on day 1 of each 21-day cycle. Patients received folic acid (350–1000 lg daily orally) and vitamin B12 (1000 lg intramuscular every 9 weeks) starting 1–2 weeks prior to initiation of chemotherapy, and dexamethasone (4 mg) bid for 3 days, 24 h prior to protocol treatment. An antihistamine (diphenhydramine 50 mg or equivalent) was given immediately before each cetuximab infusion to prevent allergic reactions. After two planned interim safety analyses, patients were administered prophylactic ciprofloxacin (or equivalent fluoroquinolone) 500 mg orally bid for 10 days starting on day 2 of each cycle during induction. Investigators followed current American Society of Clinical Oncology guidelines for use of haematopoietic colony-stimulating factors.16 Patients were evaluated for toxicity prior to each cycle using NCI-CTCAE v. 3.0. Drug-related toxicities were determined by the investigators. Response and progression were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST).17 All patients who received at least one cycle of pemetrexed, cisplatin and cetuximab were evaluable for response and toxicity. 2.4. Statistical analyses This study was powered as a single-arm trial. Based on the EXTREME trial by Vermorken et al. 2008, median PFS for platinum/5-FU plus cetuximab and platinum/ 5-FU alone, was approximately 5.5 and 3.5 months, respectively. For powering the sample size for this study, we assumed median PFS for the experimental combina-
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tion (pemetrexed, cisplatin and cetuximab) would be similar to the cetuximab arm in the EXTREME trial. It was hoped that this study would show at least a 2-month improvement in PFS over the 3.5 months observed in the platinum/5-FU alone arm in EXTREME (i.e. reaching 5.5 months). Fifty-two PFS events (65 patients) were required to estimate mPFS for this study with 90% power and a two-sided test significance level of 0.05. Kaplan–Meier techniques were used to estimate mPFS and mOS for all treated patients.18 All qualified patients (AQP), those who completed a baseline and at least one post-baseline tumour assessment, were evaluable for ORR. A 95% confidence interval (CI) of best ORR was estimated using an exact method.19 All efficacy tests were conducted at a 2-sided alpha level of 0.05; CIs were given at a 2-sided 95% level. Safety analyses included drug-related grade 3/4 laboratory and non-laboratory adverse events (AEs) using NCI-CTCAE v. 3.0. 3. Results Between March 2010 and March 2011, 73 patients were enrolled at 12 sites in six European countries. Six patients were screen failures; one patient was not treated; 66 patients received P1 dose of pemetrexed, cisplatin and cetuximab. Fifty-eight patients had both a baseline and at least one post-baseline tumour evaluation via CT or MRI and were qualified for response assessment. 3.1. Patient and disease characteristics Patient and disease characteristics are summarised in Table 1. Forty-seven patients (71.2%) had an ECOG PS of 1. Nineteen (28.8%) patients had recurrent/metastatic disease originating from the oral cavity and hypopharynx (unfavourable predictor); 46 (69.7%) had disease originating from the larynx and oropharynx. Thirtyfour (51.5%) patients had locoregionally recurrent disease only and 32 (48.5%) had distant metastases with locoregional disease. Approximately half of the patients received prior cytotoxic chemotherapy for treatment of their primary disease. One (1.5%) patient received prior chemotherapy as a single modality, 8 (12.1%) patients received neoadjuvant chemotherapy followed by radiotherapy or concurrent chemoradiation and 26 patients (39.4%) received concurrent chemoradiation without prior neoadjuvant chemotherapy. Cisplatin monotherapy and cisplatin combinations were the most frequently used prior chemotherapies. 3.2. Dosing and treatment The median number of cycles received was 5.0 (range: 1–26) for pemetrexed, 4.0 (range: 1–6) for cisplatin, and 4.5 for cetuximab (range: 1–27). Forty-one patients
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Table 1 Baseline patient and disease characteristics. Characteristic
Table 2 Response and survival data. Cisplatin/ pemetrexed/ cetuximab (N = 66)
Age, median (range) (years)
62 (42.0–87.0)
Sex, n (%) Female Male
13 (19.7%) 53 (80.3%)
ECOG performance status 0 1
19 (28.8%) 47 (71.2%)
Ethnicity (Caucasian)
66 (100.0%)
Pathological diagnosis Oropharynx Larynx Oral cavity Hypopharynx Othera
30 (45.5%) 16 (24.2%) 11 (16.7%) 8 (12.1%) 1 (1.5%)
Stage of disease Locoregional (recurrent) Distant metastatic plus locoregional disease (30/32 recurrent)
34 (51.5%) 32 (48.5%)
Prior therapies Radiotherapy Surgery Cytotoxic chemotherapy
64 55 45 35
(97.0%) (83.3%) (68.2%) (52.0%)
Abbreviations: ECOG, Eastern Cooperative Oncology Group; N, total population size; n, number of patients. a Carcinoma of the auditory canal.
(62.1%) completed P4 cycles of the triplet; 27 (40.9%) entered the maintenance phase. Twenty-two (33.3%) patients completed P7 cycles and 5 (7.6%) completed P14 cycles. Pemetrexed dose reductions occurred in 17 (25.8%) patients, cisplatin reductions in 19 (28.8%) patients and cetuximab reductions in 7 (10.6%) of the 66 treated patients. Thirty-five (53.0%) patients discontinued due to PD; 12 (18.2%) due to patient, physician or sponsor decision; 9 (13.6%) due to AEs; and 8 (12.1%) due to death. One patient was lost to followup; one patient was still on treatment at the time of analysis. 3.3. Efficacy Table 2 summarises efficacy results. The mPFS was 4.4 months (95% CI: 3.6, 5.4) and mOS was 9.7 months (95% CI: 6.5, 13.1). ORR was 29.3%, with 1 CR (1.7%) and 16 PRs (27.6%). Twenty-three (39.7%) patients had SD; the DCR was 69.0%. An exploratory subgroup analysis demonstrated that the 16 patients with recurrent/metastatic disease originating from the larynx had a more favourable outcome than the 50 patients with recurrent/metastatic disease originating from other disease sites. Response in the lar-
Efficacy measure
Cisplatin/pemetrexed/cetuximab (N = 66)
Median PFS (months) 95% CI (censoring rate)
4.4 3.6, 5.4 (13.6%)
1-Year PFS rate 95% CI
11% 3%, 19%
Median overall survival (OS) (months) 95% CI (censoring rate)
9.7 6.5, 13.1 (28.8%)
1-Year OS rate 95% CI
44% 32%, 56%
Responses (N = 58) Complete response (CR) Partial response (PR) Stable disease Progressive disease Unknown
1 (1.7%) 16 (27.6%) 23 (39.7%) 12 (20.7%) 6 (10.3%)
Overall response rate (CR + PR) 95% CI
17 (29.3%) (18.1, 42.7)
Abbreviations: CI, confidence interval, N, total population size; PFS, progression-free survival.
ynx subgroup was higher (40% versus 25.6% in the AQP, respectively), and more of these patients became eligible for maintenance therapy (56.3% versus 36%). mPFS of the larynx patients was longer than the non-larynx patients (5.2 versus 4.4 months), as was mOS (20.8 versus 8.5 months, HR 0.44, 95% CI [0.20, 0.95], censoring rate 43.8%).
3.4. Safety All patients were evaluable for toxicity. Table 3 lists grade 3–4 toxicities that occurred in P3% of patients. The most frequent (>10%) grade 3/4 toxicities (possibly drug-related) were neutropaenia (33.3%), leukopaenia (34.8%), fatigue (24.2%), skin rash (including acne; 15.2%), anorexia (12.1%), hypomagnesaemia (10.6%) and infection (10.6%). After initiation of the study, during the Safety Assessment Committee meetings, a higher-than-expected rate of infections and laboratory AEs was noted, with events disproportionately higher at one centre. Some of these patients had recently recovered from infections; some suffered from dysphagia, a complaint frequently present in patients with SCCHN. For these reasons, the Committee recommended all patients to receive prophylactic antibiotics during the first few days of each cycle of triplet treatment. There were eight deaths on treatment; five deaths were considered possibly related to study treatment. These deaths were due to: respiratory failure associated with aspiration pneumonia (2); respiratory failure and septic shock (1); sepsis, respiratory failure and tumour
J.B. Vermorken et al. / European Journal of Cancer 49 (2013) 2877–2883 Table 3 Grade 3/4 treatment-related toxicities possibly related to study drug (N = 66).
Table 4 Systemic post-discontinuation therapy.
Grade 3 Grade 4 Total grade 3/4 n (%) n (%) n (%) Laboratory Leukopaenia Neutropaenia Hypomagnesaemia Anaemia Thrombocytopenia Hypokalaemia Gamma-glutamyl transpeptidase Non-laboratory Fatigue Skin rash (includes acne) Anorexia Infection Nausea Mucositis Vomiting Diarrhoea Pneumonitis
14 (21.2) 12 (18.2) 5 (7.6) 5 (7.6) 3 (4.5) 2 (3.0) 2 (3.0)
14 (21.2) 9 (13.6) 7 (10.6) 4 (6.1) 5 (7.6) 4 (6.1) 4 (6.1) 3 (4.5) 1 (1.5)
9 (13.6) 10 (15.2) 2 (3.0) 1 (1.5) 1 (1.5) 2 (3.0) 0
2 1 1 3 0 1 0 0 2
(3.0) (1.5) (1.5) (4.5) (1.5)
(3.0)
23 (34.8) 22 (33.3) 7 (10.6) 6 (9.1) 4 (6.1) 4 (6.1) 2 (3.0)
16 (24.2) 10 (15.2) 8 (12.1) 7 (10.6) 5 (7.6) 5 (7.6) 4 (6.1) 3 (4.5) 3 (4.5)
Abbreviations: N, total population size; n, number of patients.
emboli (1); and unknown (1). Three other deaths onstudy unrelated to treatment were due to respiratory failure (1), aspiration (1) and cerebral ischaemia (1). 3.5. Post-discontinuation therapy Thirty-five of the 66 patients received systemic postdiscontinuation therapy (PDT) when they had progressed on study treatment. Many patients received P1 systemic PDT (Table 4). There was a substantial difference in the proportion of patients who received P1 PDT in the larynx subgroup compared with the non-larynx subgroup (75.0% versus 48.0%), and the use of targeted therapies was also greater in the larynx subgroup (68.8% versus 24.0%). Most PDTs were given as monotherapy, with methotrexate being the most frequently given cytotoxic chemotherapy, and cetuximab, temsirolimus or SYM004-02, as the most frequently given non-cytotoxic therapies. 4. Discussion In this, single-arm, phase II, open-label study, patients with R/M SCCHN were treated with the combination of pemetrexed, cisplatin and cetuximab. We observed a mPFS of 4.4 months and mOS of 9.7 months with 1-year PFS rate of 11%; 1-year OS rate of 44%. ORR and DCR were 29.3% and 69.0%, respectively. The mOS of 9.7 months is quite comparable to that observed in the cetuximab arm of the EXTREME trial (mOS: 10.1 months).9 Efficacy results were consistent with current standard treatment for R/M-SCCHN,8,10 but the prespecified mPFS objective of 5.5 months was not met.
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Patients with at least 1 PDT Methotrexate Cetuximab Temsirolimus (ToriselÒ) SYM004-02 (Symphogen) Docetaxel Carboplatin monotherapy 5-FU monotherapy Cyclophosphamide Paclitaxel monotherapy Gemcitabine monotherapy 5-FU + carboplatin Carboplatin + paclitaxel Bleomycin + methotrexate Tegafur + oral uracil Capecitabine 5-FU + docetaxel Afatinib Bleomycin Carboplatin + cetuximab Adriamycin Adriamycin + paclitaxel Other investigational agent
Total population N = 66 (n (%))
Larynx subgroup n = 16 (n (%))
Non-larynx subgroup n = 50 (n (%))
36 (54.5)
12 (75.0)
24 (48.0)
10 (15.2) 9 (13.6) 7 (10.6)
3 (18.8) 4 (25.0) 3 (18.8)
7 (14.0) 5 (10.0) 4 (8.0)
6 (9.1)
4 (25.0)
2 (4.0)
6 (9.1) 3 (4.5)
2 (12.5) 0
4 (8.0) 3 (6.0)
3 (4.5) 3 (4.5) 3 (4.5)
1 (6.3) 2 (12.5) 1 (6.3)
2 (4.0) 1 (2.0) 2 (4.0)
3 (4.5)
2 (12.5)
1 (2.0)
2 (3.0) 2 (3.0)
0 1 (6.3)
2 (4.0) 1 (2.0)
1 (1.5)
1 (6.3)
0
1 (1.5)
1 (6.3)
0
1 1 1 1 1
(1.5) (1.5) (1.5) (1.5) (1.5)
0 0 0 0 0
1 1 1 1 1
1 (1.5) 1 (1.5)
0 0
1 (2.0) 1 (2.0)
1 (1.5)
0
1 (2.0)
(2.0) (2.0) (2.0) (2.0) (2.0)
Abbreviations: N, total population size; n, number of patients; PDT, Post-discontinuation therapy.
Despite the limitations of cross-trial comparisons, our efficacy results compare favourably with those from the study evaluating pemetrexed and cisplatin without cetuximab, which demonstrated a mPFS of 3.6 months and a mOS of 7.3 months.7 Our results also compare favourably with efficacy results in other randomised studies using cisplatin-based chemotherapy without cetuximab,6,10 underscoring the potential benefit of cetuximab in this population. The most frequent grade 3/4 toxicities possibly related to this triplet were similar to those reported for other head-and-neck cancer combination chemotherapies.9,20 The most common included neutropaenia, hypomagnesaemia, fatigue, skin rash, anorexia and infection. The incidence of serious infections was higher in this study than reported in other studies (10.6% versus 4–6%); in fact, grade 4 neutropaenia was approximately 10% higher than that observed in the cetuximab arm of
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the EXTREME trial, and may have been a contributing factor to the higher-than-expected percent of deaths possibly related to the study drug (7.6% versus 2.3– 5.5%, respectively). Examination of this patient population compared with that in the EXTREME trial, indicates that more patients in this study received prior chemotherapy (54.5% versus 41%) and prior concurrent chemoradiation (39.4% versus 31.1%). However, more patients in our study had a better PS than in the EXTREME trial (0/1: 100% versus 88%). Other negative predictors for survival were quite comparable in the two studies suggesting that the patient population in our study was not strikingly worse than that in the EXTREME study. Therefore, the pemetrexed, cisplatin and cetuximab regimen, although easier to administer, does not seem to be more efficacious than the present standard platinum/5FU/cetuximab (EXTREME) regimen. Also, the toxicity profile of pemetrexed, cisplatin and cetuximab does not seem to be more favourable than the platinum/5-FU/ cetuximab regimen. On the contrary, compared with the EXTREME regimen, more grade 3/4 leukopaenia (34.8% versus 11%), neutropaenia (33.3% versus 26%), skin rash (15.2% versus 9%), and treatment-related deaths (7.6% versus 1.4%) were observed in our study. The results observed in the larynx subgroup are intriguing, with a 40% response rate, 5.2-month mPFS and 20.8-month mOS. Survival analyses are limited by sample size (16 patients) and a censoring rate of 43.8% should be interpreted with caution. More patients received maintenance therapy in the larynx group (9/ 16; 56.3%) than those in the non-larynx group (18/50; 36.0%). Additionally, strikingly more patients in the larynx group received PDT, mainly targeted therapies (11/ 16; 69% versus 12/50; 24%) including cetuximab, temsirolimus and SYM004-02. Limited data exist on re-introducing cetuximab after previous use. Temsirolimus, an mTOR inhibitor, has shown activity in refractory SCCHN after failure of platinum-based chemotherapy and cetuximab.21 SYM004-02, a mixture of two antiEGFR monoclonal antibodies directed against distinct non-overlapping epitopes in EGFR extracellular domain III, has interesting preclinical anti-tumour activity and the potential to overcome acquired resistance to other EGFR-targeted agents, such as cetuximab.22 It may be tempting to attribute the better survival in the larynx subgroup with these observations.
5. Conclusion The efficacy results demonstrate that this triplet aligns with current standard treatment in R/M SCCHN; however, the pre-specified mPFS of 5.5 months was not achieved. Toxicity results are also consistent with current standard treatment; however, a higherthan-expected number of treatment-related deaths was
reported. As such, there is no compelling rationale to further develop this combination for treatment of R/ M SCCHN. Conflict of interest statement Dr. Jan B. Vermorken is a consultant/advisor for Merck-Serono, Amgen, Boehringer-Ingelheim, Genentech, Vaccinogen, Oncolytics and PCI Biotech. Dr. Vermorken received travel compensation and/or honoraria for lecturing from Merck-Serono, Amgen, Eli Lilly and Company, and Bristol-Myers Squibb. Dr. Jan Sto¨hlmacher-Williams received funding for translational research projects exceeding $25,000 (US dollars) from Eli Lilly and Company (unrelated to this study), and has received travel grants and honoraria from Eli Lilly and Company and Merck-Serono. Dr. Lisa Licitra is a consultant/advisor for Bristol-Myers Squibb, Glaxo SmithKline, Eli Lilly and Company, Merck-Serono, Amgen and Boehringer Ingelheim. Her institution receives research funding from EISAI Co., Ltd., Exelixis, Eli Lilly and Company, Merck-Serono, Amgen and Boehringer Ingelheim. Dr. Licitra also received travel compensation for medical meetings. Dr. Andreas Dietz reports no disclosures. Dr. Jose M. Lopez-Picazo is a consultant for, and has received paid expert testimony on behalf of Eli Lilly and Company. Drs. Oday Hamid and Shao-Chun Chang and Mr. Anwar Hossain, are employees of Eli Lilly and Company, and as such employees, have stock ownership in said company. Dr. Thomas C. Gauler is a consultant for and has received honoraria from Eli Lilly and Company and Merck Serono. Acknowledgments The authors would like to thank Donna L. Miller of Eli Lilly and Company for help with manuscript preparation, and Anastasia Perkowski of ImClone Systems LLC, a wholly-owned subsidiary of Eli Lilly and Company, for editorial support. This study was funded by Eli Lilly and Company, Indianapolis, IN. This study is registered on ClinicalTrials.gov, identifier: NCT01057589. References 1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893–917. 2. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010;46:765–81. 3. 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 1992;10:1245–51. 4. Jacobs C, Lyman G, Velez-Garcı´a E, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in
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