A Phase II Trial of Gefitinib in Combination With Capecitabine and Oxaliplatin As First-Line Chemotherapy in Patients With Advanced Colorectal Cancer

By Gelibter, Alain J Gamucci, Teresa; Pollera, Camillo F; Di Costanzo, Francesco; Nuzzo, Carmen; Gabriele, Angela; Signorelli, Carlo; Gasperoni, Silvia; Ferraresi, Virginia; Giannarelli, Diana; Cognetti, Francesco; Zeuli, Massimo

Key words: Colorectal cancer – EGFR – First line – Targeted therapy ABSTRACT

Objective: This study was designed as a multicentre phase II trial to assess the efficacy and safety of gefitinib in association with capecitabine and oxaliplatin in patients with untreated metastatic colorectal cancer.

Research design and methods: Patients with metastatic colorectal cancer that had received no prior chemotherapy for advanced disease were treated with oral gefitinib (250 mg daily) plus oral capecitabine (1000 mg/m^sup 2^ twice a day on Days 1-14) and intravenous oxaliplatin (120 mg/m^sup 2^ on Day 1 of each 3-week cycle).

Results: Thirty-five patients were enrolled. In the intention-to- treat analysis, 3 (8.6%) patients experienced a complete response (CR), 14 (40%) a partial response (PR) and 11 (31.4%) had stable disease (SD). The disease control rate (CR + PR + SD) was 80%, the median time to progression was 7.3 months (95%CI: 4.76-9.2) and the estimated median overall survival was 21.9 months (95% CI: 15.1-not reached). The most common grade 3 to 4 toxicities included diarrhoea (31%) and vomiting (5.7%).

Conclusions: The combination of capecitabine, oxaliplatin and gefitinib appears to have promising activity in chemotherapy-naive metastatic colorectal cancer. A higher disease control rate and an increase in median overall survival were seen compared with previous reports with capecitabine and oxaliplatin in similar patient populations. The tolerability profile appears to be predictable and similar to capecitabine/oxaliplatin regimens.

Introduction

Oxaliplatin is a new third-generation cisplatin analogue that, in combination with infusional 5-fluorouracil and folinic acid, has shown high anti-tumour activity in advanced colorectal cancer patients in randomized phase III trials1″3.

Two large randomized studies have shown higher tumour response rates and at least equivalent time to disease progression and overall survival with oral capecitabine compared with intravenous (iv) bolus fluorouracil/leucovorin. Importantly, when considering the indirect costs associated with the treatment, hospitalization was significantly reduced with oral capecitabine compared with iv fluorouracil/ leucovorin4’5.

Combining oxaliplatin with oral capecitabine in place of infusional fluorouracil is an interesting alternative, supported by many trials6″”, in particular when considering the practicality of the treatment and the lack of major overlapping toxicities of the two drugs.

Epidermal growth factor receptor (EGFR) is expressed or over- expressed in a wide variety of solid human tumours, including colorectal cancer12. The EGFR tyrosine kinase (EGFR-TK) signalling pathway has been identified as a key driver of proliferation and survival of cancer cells and is an important target in a variety of cancers13. EGFR is over-expressed in 25-77% of colorectal cancer tumors14″16, and such overexpression is associated with a poorer prognosis.

Gefitinib (IRESSA*) is an orally active EGFR-TK inhibitor that in phase I-II studies was well tolerated with encouraging clinical efficacy17. Furthermore, preclinical models have demonstrated that inhibition of the EGFR signalling pathway can sensitize tumour cells to chemotherapy18’19.

The aim of this phase II trial was to assess the efficacy and safety of the combination of oxaliplatin, capecitabine and gefitinib in patients with untreated advanced colorectal cancer.

Patients and methods

Patients

For inclusion in the trial, patients had to fulfil all the following criteria: histologically or cytologically confirmed advanced adenocarcinoma of the colon or rectum; aged 18-75 years; progressive disease; unidimensionally measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST); life expectancy of at least 12 weeks; Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2; no previous chemotherapy for advanced disease.

Adjuvant or neo-adjuvant chemotherapy, administered more than 6 months before the study entry, was allowed. The following exclusion criteria were applied: potentially resectable liver metastases as the only site of disease; symptomatic peripheral neuropathy; central nervous system metastases; known, severe hypersensitivity to gefitinib, capecitabine, oxaliplatin or any of the excipients of these products. Patients were considered not eligible if they had other co-existing malignancies or malignancies diagnosed within the last 10 years, with the exception of basal cell carcinoma or cervical cancer in situ; any unresolved chronic toxicity greater than Common Toxicity Criteria (CTC) grade 2 from previous adjuvant anticancer therapy (except alopecia); absolute neutrophil count less than 2.0 x 10^sup 9^/L or platelets less than 100 x 10^sup 9^/ L; serum bilirubin greater than 1.25 times the upper limit of reference range (ULRR) if no demonstrable liver metastases, or greater than 1.5 times the ULRR in the presence of liver metastases; serum creatinine greater than 140 [mu]mol/l (1.6mg/dL); alanine aminotransferase or aspartate aminotransferase greater than 3 times the ULRR if no demonstrable liver metastases, or greater than 5 times the ULRR in the presence of liver metastases; evidence of peripheral sensory neuropathy.

Patients were accrued in the following Italian cancer centres: Regina Elena National Cancer Institute of Rome; SS. Trinita Hospital, Sora; Belcolle Hospital, Viterbo; Careggi Hospital, Florence. The study was approved by the independent ethics committees in each institution and was carried out in accordance with the Declaration of Helsinki (1996), all patients provided written informed consent.

Treatment

Eligible patients received: oxaliplatin (Eloxatin, SanofiAventis, Paris, France) 120mg/m2 administered as a 2-h iv infusion on Day 1 of each 3-week cycle plus capecitabine (Xeloda, F. Hoffman-La Roche Ltd, Basel, Switzerland) 2000 mg/m^sup 2^/day administered orally (1000mg/m^sup 2^ twice daily) on Days 1-14 of each 3-week cycle.

Patients received chemotherapy for up to 6 cycles or until disease progression, unacceptable toxicity or withdrawal of consent. Patients with a response (complete response [CR] or partial response [PR]) or stable disease (SD) after 6 cycles, continued therapies for a further 2 consolidation cycles.

Patients received oral gefitinib as a 250 mg tablet, starting on Day 1, until progression of disease, unacceptable toxicity or withdrawal of consent.

Chemotherapy drug dose adjustment rules were the following: if any grade 1 toxicity occurred, treatment continued at the original dose without interruption. If grade 2, 3 or 4 toxicity occurred, treatment interruption was followed by a selective dose reduction depending on the types of toxicity as described below and treatment was re-administered when the absolute neutrophil count was 1.5 x 10^sup 9^/L. Patients experiencing febrile neutropenia or absolute neutrophil count < 0.5 x 10^sup 9^/L (grade 4) for > 1 week, the dose of capecitabine and oxaliplatin was reduced by 25%. If the AE recurred at 75% of the original dose, the dose of capecitabine and oxaliplatin was decreased to 50% of the original dose. No dose reduction was allowed for patients receiving gefitinib. In the event of CTC grade 3 or 4 diarrhoea, immediate appropriate supportive care was initiated and gefitinib discontinued up to a maximum of 14 days until resolution or until the diarrhoea decreased in severity to CTC grade 1. Patients with poorly tolerated skin toxicity were managed by providing a brief (up to 14 days) therapy interruption; after the interruption, patients restarted with the same dose.

Evaluation

Pre-treatment evaluation included a complete clinical history, physical examination, neurological status, electrocardiogram and computed tomography scan of assessable target lesions. Complete blood cell counts and differential blood chemistry were obtained at baseline and were repeated every chemotherapy cycle.

Objective response rate was the primary endpoint and was recorded according to the RECIST response criteria. Assessment of response was performed every 3 chemotherapy cycles and the scans were reviewed blind in our institution. According to RECIST, assessments of CR or PR had to be confirmed a minimum of 4 weeks after the criteria for response was initially met. Toxicities were evaluated every 3 weeks and were graded using the National Cancer Institute CTC (NCI CTC) grading system.

Statistical analysis

Fleming’s method was used to calculate the number of patients required. A sample size of 35 patients was sufficient to give an 80% probability of rejecting a baseline response rate of 20% with an exact 5% one-sided significance test when the true response is at the clinically relevant rate of 40%. The hypothesis that the response rate is equal to or less than the baseline is rejected if 12 or more responses are observed out of the 35 patients.

An assessment of safety and tolerability was conducted after the first 6 patients completed 1 cycle of treatment. Toxicities were assessed to determine whether a change in dose was required.

A comprehensive statistical analysis plan was prepared before database lock. All patients that were enrolled and received trial treatment were included within the intention-to-treat (ITT) population. The analysis population for all efficacy endpoints was the ITT population. All patients who received at least 1 dose of trial medication were included in the safety analysis.

The standard summary statistics for continuous variables are: mean, standard deviation, median, quartiles, maximum and minimum. The standard summary statistics for discrete variables are: count and proportion. The objective response rate was summarized by proportions together with a 95% confidence interval. Durations of response, progression free survival (PFS) and overall survival were summarized by Kaplan-Meier methods. Tolerability was summarized by the appropriate standard summary statistics.

Results

Patient characteristics

Between October 2002 and October 2004, 35 patients (male/female: 23/12) were enrolled. The baseline characteristics of the enrolled patients are shown in Table 1.

The majority of patients had a PS 0-1 (97%). Twenty-one patients (60%) had one site of disease, 14 (40%) had 2 or more sites. Eleven patients received previous adjuvant or neo-adjuvant chemotherapy, while 4 patients received previous radiotherapy alone.

Table 1. Patient characteristics

A total of 194 cycles of chemotherapy were delivered with a median of 6 cycles per patient (range 1-11). Two patients received 11 cycles of chemotherapy, according to investigator judgement, due to an optimal increasing clinical response after 6 and 8 cycles.

Primary analyses were based on intent-to-treat; thus, all 35 patients enrolled were included in efficacy and safety analyses.

Efficacy

The primary endpoint of the study was the objective response rate (ORR). The results of the response evaluation are summarized in Table 2 for the ITT and per protocol (PP) analyses. Non-assessable patients in the PP analysis received only 1 treatment cycle (n = 5) due to adverse event withdrawal before radiological evaluation (3 patients), lost to follow-up (1 patient) and clinical progression of disease (1 patient).

The objective response rate (CR + PR), and disease control rate (CR + PR + SD) achieved with this schedule were 48.6% (95% CI 31.3- 66.0), and 80% (95% CI 63.1-91.6), respectively.

Three CRs were obtained during the experimental treatment. A 63 year-old rectal cancer patient, previously treated with adjuvant CT/ RT, achieved a CR that was seen in multiple liver and lung metastases and had a PFS of 11 months, while the two other patients, both with only liver disease, had a CR lasting 11 and 15 months.

The median follow-up time for all patients was 14 months. The median time to progression was 7.3 months (95% CI: 4.76-9.2). The median duration of response was 5.75 months (95% CI: 3.23-8.05). The estimated median overall survival was 21.9 months (95% CI: 15.1-not reached).

Table 2. Clinical activity in the intention-to-treat (ITT) and per-protocol (PP) populations

At the time of this analysis, 27 out of 35 patients had received further lines of chemotherapy and 20 out of 35 patients were still alive.

Safety

An assessment of safety and tolerability has been conducted after the first six patients completed 1 cycle of treatment. Toxicity observed did not require any dose changing because no patients experienced grade 3-4 severe adverse events.

All 35 patients were assessed for safety. The major grade 3-4 toxicities experienced by the patients treated with this regimen are shown in Table 3.

The most frequent toxicity, as expected, was diarrhoea: 11 patients (31%) suffered from grade 3-4 diarrhoea, while 2 patients experienced grade 3-4 vomiting during all the cycles.

Although it never reached grade 3-4, peripheral neuropathy did affect 6 patients (17%); this was due to the oxaliplatin infusion, as previously reported.

During treatment, the incidence of haematological toxicities was quite low, grade 3 or 4 thrombocytopenia was recorded in only 2 patients, while grade 3 or 4 neutropenia was recorded in only 1 patient.

Skin toxicity was observed in 31 % of patients, but only 1 patient experienced a grade 3 toxicity. Grade 3 respiratory failure was noted in 2 patients.

Sixty-nine per cent (134/194) of cycles were delivered at full dose and without delay, 24% (46/194) of cycles were administered at full dose but were delayed due to toxicity in the previous cycle, 5% (9/194) of cycles required a treatment reduction and a delay and 3% (5/194) of cycles required a treatment reduction but were not delayed (see Table 4). Most delay/reductions were due to diarrhoea.

Table 3. Grade 3-4 adverse events

Table 4. Cycle delays and dose reductions

Discussion

There is a strong theoretical rationale for the use of EGFR- targeting agents in patients with large bowel malignancies. EGFR is expressed in most colorectal tumours and its presence is associated with a poor prognosis20. Recent data suggest that adding a targeted agent does improve the efficacy of standard oxaliplatinbased regimens in advanced colorectal cancer patients21’22. In particular, the EGFR-targeting agents, cetuximab and panitumumab (monoclonal antibodies against EGFR), have activity as monotherapy23″26 and enhance the efficacy of chemotherapy.

In contrast, oral EGFR TK inhibitors, such as erlotinib and gefitinib, do not appear to have activity in this setting as single agents27″29, but potentially they may augment the activity of combination chemotherapy against metastatic colorectal cancer.

Kuo et al.21 conducted a phase II study of gefitinib plus fluorouracil, leucovorin and oxaliplatin (IFOX) in 27 patients with documented progressive colorectal cancer after at least one chemotherapeutic irinotecan containing regimen. EGFR positivity was not required for trial entry, a decision which in itself is reasonable, given that expression as measured by immunohistochemistry is not required for predicting activity of gefitinib in non-small cell lung cancer, or for activity in colorectal cancer with other EGFR inhibitors, such as cetuximab. The authors stated that IFOX had a higher response rate than FOLFOX4 alone, comparing their 33% response rate to the 10% seen by Rothenberg et al.30 in patients receiving FOLFOX-4 after experiencing treatment failure with irinotecan, bolus fluorouracil and leucovorin. They concluded that EGFR inhibition with gefitinib may enhance the cytotoxicity of FOLFOX-4 and that it provides ‘substantial benefits’ to patients.

Zampino et al.31 recently reported promising activity (74% response rate) for the combination of gefitinib, infusional fluorouracil, leucovorin and oxaliplatin as first-line treatment in patients with advanced colorectal cancer. EGFR status did not correlate with clinical response. Similarly, Fisher et al.12, reported a 78% response rate in their phase II study in chemotherapyuntreated colorectal cancer patients.

We performed a multi-institution phase II study of the combination of capecitabine, oxaliplatin and gefitinib as first- line treatment for patients with advanced colorectal cancer to assess the efficacy and tolerability of this combination. An important argument for the choice of the oral fluoropyrimidine was that this treatment offers an advantage over infusional fluorouracil in terms of convenience, practicality and health care costs. In our study no unexpected adverse events occurred and the most common toxicities observed were those of each drug: the main toxicities were diarrhoea (grade 3-4 in 31.4% of patients), skin toxicity (grade 3, 2.9% and grade 1-2, 28%) and sensory neuropathy (grade 1- 2, 17%).

The tolerability of the combination was fairly good and comparable to other studies of capecitabine and oxaliplatin33,34. In our previous experience in chemotherapy-naive colorectal cancer patients using capecitabine (1000mg/m^sup 2^ twice a day for 14 days) plus oxaliplatin (120mg/m^sup 2^ every 3 weeks) we observed the following grade 3-4 toxicities: diarrhoea (28%), emesis (5%) and neurotoxicity (7%)7. Although a comparison of two different trials must always be interpreted with caution, the current study with capecitabine and oxaliplatin plus gefitinib resulted in a small decrease in overall tolerability (60% any grade 3-4 toxicity compared with 53.4%) with a slight exacerbation of grade 3-4 diarrhoea (31.4% vs. 28%). The increased diarrhoea seems to suggest an additive toxicity of capecitabine and gefitinib. Nonetheless, regimens of capecitabine and oxaliplatin seem to be more toxic than FOLFOX, particularly at the 1000mg/m^sup 2^ twice daily of capecitabine dose34, which most likely contributed to the high rate of dose reductions in this study. This study, therefore, demonstrates that daily oral gefitinib in combination with capecitabine and oxaliplatin has a predictable tolerability profile and gefitinib appears to slightly increase the overall toxicity of chemotherapy.

The gefitinib dose of 250 mg seems to be more appropriate for combination chemotherapy as opposed to 500mg as used by Fisher et al.32 where all 56 patients experienced SAEs. Besides toxicity, efficacy is a critical endpoint in order to assess the utility of a new treatment combination. We reported a response rate of 48.6% and the median overall survival for this population was about 22 months. These findings seem to suggest a slight improvement in overall survival compared to those observed with first-line regimens with fluoropyrimidine and oxaliplatin-containing combinations (see Table 5). In particular, compared to our previous phase II study with capecitabine and oxaliplatin in advanced colorectal cancer patients7, we observed a small increase in ORR (48.6% vs. 44%) and a marked increase in disease control rate (CR + PR + SD) (80% vs. 67.5%) leading to an improvement of about 2 months in median overall survival.

The results seen in this study seem to support the hypothesis that the use of gefitinib in colorectal cancer is associated with a high rate of disease stabilization. This is as expected based on the mechanism of action of the drug – gefitinib is an inhibitor of cell growth and proliferation – and preclinical observations that have shown higher rates of disease stabilization or slowing of disease progression rather than tumour regression35’36. In conclusion, further studies are necessary to assess the optimal use of gefitinib in association with chemotherapy, particularly with regard to toxicity profile management and sequencing versus concomitant regimens.

Conclusions

The combination of capecitabine, oxaliplatin and gefitinib appears to have promising activity in chemotherapy-naive metastatic colorectal cancer. Compared to a previous phase II study with capecitabine and oxaliplatin in advanced colorectal cancer patients7, a small increase in ORR (48.6% vs. 44%) was observed and a marked increase in disease control rate (CR + PR + SD) (80% vs. 67.5%) leading to an improvement of about 2 months in median overall survival. The tolerability profile of capecitabine, oxaliplatin and gefitinib appears to be predictable and similar to capecitabine/ oxaliplatin regimens. Further studies are necessary to determine the optimal use of gefitinib in association with chemotherapy in the treatment of colorectal cancer.

Table 5. Efficacy of selected phase II studies with oxaliplatin/ capecitabine regimens in first-line therapy for advanced colorectal cancer

Acknowledgements

This trial was coordinated and supervised by the principal investigators with funding and organisational support from the trial sponsor AstraZeneca. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

* IRESSA is a trademark of the AstraZeneca group of companies. AstraZeneca, Macclesfield, UK

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3966_2, Accepted for publication: 28 June 2007

Published Online: 24 July 2007

doi: 10.1185/030079907X226113

Alain J. Gelibter(a), Teresa Gamucci(b), Camillo F. Pollera(c), Francesco Di Costanzo(d), Carmen Nuzzo(a), Angela Gabriele(b), Carlo Signorelli(c), Silvia Gasperoni(d), Virginia Ferraresi(a), Diana Giannarelli(e), Francesco Cognetti(a) and Massimo Zeuli(a) a Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy

b Division of Medical Oncology, SS Trinita Hospital, Sora, Italy

c Division of Medical Oncology, Belcolle Hospital, Viterbo, Italy

d Division of Medical Oncology, Azienda Ospedale Careggi, Florence, Italy

e Statistic Unit, Regina Elena National Cancer Institute, Rome, Italy

Address for correspondence: Alain J. Gelibter, MD, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy. Tel: +39 06 52666919; Fax: +39 06 52665637; e-mail: agelibter@yahoo.it

Copyright Librapharm Sep 2007

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