World J Gastroenterol. 2007 November 28; 13(44): 5867-5876.
Published online 2007 November 28.
©2007 Baishideng Publishing Group Co., Limited. All rights reserved.
Combining chemotherapy and targeted therapies in metastatic colorectal cancer
J Rodriguez, R Zarate, E Bandres, A Viudez, A Chopitea, J García-Foncillas, I Gil-Bazo, Unit for the Research and Treatment of Gastrointestinal Malignancies, Department of Oncology, Clinica Universitaria, Center for Applied Medical Research, University of Navarra, Spain
Received June 26, 2007; Revised August 8, 2007; Accepted October 19, 2007;
Colorectal cancer remains one of the major causes of cancer death worldwide. During the past years, the development of new effective treatment options has led to a considerable improvement in the outcome of this disease. The advent of agents such as capecitabine, irinotecan, oxaliplatin, cetuximab and bevacizumab has translated into median survival times in the range of 2 years. Intense efforts have focused on identifying novel agents targeting specific growth factor receptors, critical signal transduction pathways or mediators of angiogenesis. In addition, several clinical trials have suggested that some of these molecularly targeted drugs can be safely and effectively used in combination with conventional chemotherapy. In this article we review various treatment options combining cytotoxic and targeted therapies currently available for patients with metastatic colorectal cancer.
Keywords: Targeted therapy, Chemotherapy, Combi-nations, Clinical trials, Colorectal cancer
Chemotherapy remains the cornerstone of treatment of metastatic colorectal cancer (mCRC) and, with the exception of a minority of patients (pts) who are candidates for salvage surgery, the goal of chemotherapy is palliation. Remarkable and clinically relevant advances have been made in the last 5 years in the treatment of this disease, essentially owing to the introduction of combination chemotherapy regimens containing oxaliplatin and irinotecan (CPT-11)[1
]. The addition of either drug to 5-fluorouracil/leucovorin (5-FU/LV) proved to significantly increase overall response rates and survival times. Indeed, median overall survival is highly correlated with the percentage of patients who receive the three cytotoxic agents in the course of their disease. Results from a Phase III study by Falcone et al[2
] suggested that the up-front use of a triplet combination of irinotecan, oxaliplatin and 5-FU/LV significantly improved the outcome in terms of response rate (RR) and survival times compared to a standard doublet of irinotecan and 5-FU/LV.
Interestingly, with the more recent incorporation of bevacizumab and cetuximab into the treatment armamentarium, the median overall survival (OS) has doubled from 12 mo to approximately 2 years in Phase III trials. In fact, most recent trials that attempt to expose patients to all five drug classes (fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and anti-EGFR antibody) target an OS well over 2 years. In this review we will summarize some of the available therapeutic repertoire based on targeted therapies in combination with chemotherapy for patients with mCRC.
COMBINING CHEMOTHERAPY AND EGFR-TARGETED THERAPIES
The epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase, is one of four members of the HER receptor family. This receptor is overexpressed in a number of solid tumors of ectodermal origin, including colon adenocarcinoma[3
]. EGFR over expression has been correlated with disease progression, poor prognosis and reduced sensitivity to chemotherapy[4
]. Therefore, several strategies have been developed to target EGFR, including small molecule tyrosine kinase inhibitors and monoclonal antibodies[5
Cetuximab-based combination therapy
Cetuximab is the most advanced monoclonal antibody against EGFR in clinical development. Since preclinical and early clinical studies suggested that Cetuximab might revert irinotecan resistance in CRC both in vitro
and in vivo
, a phase II trial of cetuximab with irinotecan was performed in patients with EGFR positive colorectal cancer that was refractory to both 5-fluorouracil (5-FU) and Irinotecan. Among the 120 patients treated with this regimen, overall response rate was 22.5%[6
To confirm these clinical findings, 329 EGFR-positive, irinotecan-refractory mCRC patients were randomized in a 2:1 ratio to receive cetuximab plus irinotecan (arm A; n
= 218) or cetuximab alone (arm B; n
= 111) with the option to switch to the combination of cetuximab with irinotecan after failure of cetuximab as a single agent. Both the response rate (22.9% vs
= 0.007) and the median time to progression (4.1 vs
< 0.001) favored the combination arm. Although no survival benefit was observed for arm A, cetuxibab was demonstrated to have clinically significant activity when given alone or in combination with irinotecan and consequently received FDA approval[7
More recently, MABEL trial[8
] investigated the combination of cetuximab and CPT-11 at a dose and schedule as pre-study in an uncontrolled, multicenter study including 1123 mCRC pts with detectable EGFR. 64% of the patients had received ≥ 2 lines of chemotherapy. 76% had also been pretreated with cetuximab. The estimated median survival was 9.2 mo at as expense of an acceptable toxicity profile, including grade 3-4 diarrhea (20%) acne-like rash (19%), neutropenia (9%) and asthenia (8%). MABEL clearly confirmed in a wider setting the efficacy and safety or C225 plus CPT-11 seen in previous studies. Similarly, EPIC trial is a randomized phase III trial comparing cetuximab plus irinotecan to irinotecan as second line therapy in patients with EGFR-expressing mCRC who have failed first line oxaliplatin in combination with a fluorpyrimidine. Accrual is currently ongoing[9
Cetuximab-based combinations as salvage therapy
: Several trials have addressed the potential of cetuximab-based combinations in heavily pretreated patients. Vincenzi et al[10
] evaluated the efficacy of cetuximab plus oxaliplatin in patients previously failed on an oxaliplatin-based regimen in first line, irinotecan-based regimen in second line, and cetuximab plus irinotecan in third line. No objective clinical response was identified after the interim analysis planned according to the two-staged Simon accrual design. The same group[11
] evaluated the activity of cetuximab and weekly irinotecan (90 mg/m2
) in patients refractory to one oxaliplatin-based chemotherapy regimen (Capecitabine + Oxaliplatin or FOLFOX IV regimen, as first line) and one Irinotecan-based based-chemotherapy (FOLFIRI regimen, as second-line chemotherapy) for at least 2 mo. Overall response rate was 25.4% (95% CI: 21.7%-39.6%); 38.2% (95 CI: 18.6%-39.8%) of patients showed a disease stability as the best response. The median time to progression was 4.7 mo (95% CI: 2.5-7.1 mo) and the median survival time was 9.8 mo (95% CI: 3.9-10.1 mo). The most common G3-4 noncutaneous side toxicities were diarrhoea (16.4%), fatigue (12.7%), stomatitis (7.3%) and skin toxicity (32.6%). A statistically significant (P
= 0.006) association between the cutaneous toxicity and both tumour response and time to progression was observed. The authors also identified a borderline significant difference in terms of overall survival.
The combination of Cetuximab plus FOLFIRI has been prospectively evaluated in 41 EGFR expressing mCRC pts refractory to prior FOLFIRI for metastatic disease[12
]. Most of the patients were treated in third line. A 20% overall response rate was recorded, with a median PFS of 4.3 mo and a median overall survival of 5 mo.
Cetuximab-based combinations in front-line therapy:
Cetuximab established activity in the salvage setting prompted its incorporation to first-line combination therapy. Available preliminary data from Phase II trials combining cetuximab with either irinotecan or oxaliplatin-based chemotherapy have shown very encouraging activity. CALGB 80203[13
] randomized untreated mCRC patients to FOLFOX or FOLFIRI with or without C225 independent of EGFR status. ORR was similar in the FOLFIRI or FOLFOX arms, while C225 containing arms had a higher ORR (49% vs
= 0.014) when compared to non cetuximab containing arms. No significant differences in grade 3 diarrhea or any grade 4 toxicity were seen with the addition of C225. Preliminary results of the combination of C225, capecitabine (800 g/m2
bid po on d 1 to 14) and Irinotecan (200 g/m2
i.v on d 1) vs
C225 combined with capecitabine (1000 mg/m2
bid in d 1-14) and oxaliplatin (130 g/m2
on d 1) reported an overall response rate of 41% (95%; 22% to 61%) and 71% (95%; 48% to 89%) respectively, with both arms showing a manageable toxicity profile[14
Promising results have also been reported[15
] combining cetuximab with (AIO) infusional 5-FU/FA plus irinotecan regimen in EGFR-expressing mCRC.Grade 3 or 4 toxicities were acne-like rash (38%), diarrhea (29%), cardiovascular events (20%) and nausea/vomiting (5%). Objective responses were observed in 67% of the patients. The median time to progression was 9.9 mo and the median survival time was 33 mo.
The combination of cetuximab with modified FOLFOX 6 in 83 chemo-naive mCRC pts with positive or undetectable EGFR expression show a preliminary ORR of 53%[16
]. Main grade 3-4 toxicities included neutropenia (38%), diarrhea (10%), rash (10%) and neurotoxicity (7%). The combination of FOLFOX-4 plus C225[17
] has also been evaluated in 47 EGFR-expressing mCRC, with a reported ORR of 68%. Grade 3-4 adverse events included acne-like rash (18%) diarrhea (7%), nausea and vomiting (4%) and anemia (4%).
Preliminary results of the OPUS trial[18
], a randomized phase II study in the first line treatment of mCRC, confirmed the superiority of FOLFOX plus cetuximab vs
FOLFOX in terms of overall response rate (45.6% vs
These small trials supported the conduct of a multicenter Phase III clinical trial that compared FOLFIRI plus Cetuximab with FOLFIRI alone in 1217 EGFR-expressing chemotherapy-naive patients. Cetuximab plus FOLFIRI significantly increased response rate and progression-free survival, reducing the relative risk of progression by approximately 15%[19
Panitumumab-based combination therapy
Panitumumab is a fully human IgG2 monoclonal antibody directed against the epidermal growth factor receptor. Its use in combination with IFL and FOLFIRI in first line treatment of metastatic CRC has been evaluated in a multicenter, single arm, phase 2 trial[20
]. Panitumumab was given at a weekly dose of 2.5 mg/kg i.v. over 60-90 min followed by chemotherapy. The combination with IFL was considered too toxic, with grade 3-4 diarrhea in 47% of the patients. The FOLFIRI plus panitumumab combination was associated with a more manageable side effect profile with grade 3-4 diarrhea in 25% of the pts and grade 3-4 hypomagnesemia in 8%. Skin and nail toxicities occurred in at least 20% of patients but were rarely severe (grade 3 in 2 out of 24 pts). The objective response rate with FOLFIRI plus panitumumab was 66%, with a disease control rate of 79%. Median progression free survival was 10.9 mo. Further investigation of FOLFIRI with an every two weeks schedule of panitumumab is ongoing in randomized phase 3 trials.
Cetuximab-induced papulopustular skin rash is thought to be mechanism- and dose-related, and may be a surrogate indicator of an adequate degree of receptor saturation by cetuximab. The possibility of increasing Cetuximab efficacy by inducing skin rash has been recently confirmed. Cetuximab dose escalation up to 500 mg/m2
improves response rate in patients with absent or slight skin reaction on standard dose treatment[21
Large studies validating molecular predictive markers are needed in order to identify the subset of patients more likely to respond to EGFR-targeted therapies. Candidate markers include total and phosphorylated EGFR, total and phosphorylated forms of AKT, mitogen-activated protein kinase (MAPK), mitogen-activated protein/ERK (MEK), ERK, signal transducers and activators of transcription (STAT), PTEN and mTOR[22
] Although EGFR gene copy number has also been proposed[23
], EGFR amplification, measured by FISH is a rare event (4%) in colorectal cancer[24
]. Other potential predictive markers are k-ras[25
] cyclin D1 A870G polymorphisms[26
], HER-2 expression[27
] or higher gene expression levels of VEGF[28
]. More recently, a combination of various predictive biomarkers has retrospectively been able to identify subsets of patients more likely to benefit from cetuximab therapy[29
]. In addition, several polymorphisms in genes involved in the EGFR and angiogenesis pathway have been associated with clinical outcome[30
]. Prospective studies are clearly needed to confirm these preliminary findings.
EGFR tyrosine kinase inhibitor (TKI)-based combination therapy
: Gefitinib (ZD1839) selectively inhibits the EGFR tyrosine kinase and has approximately 100-fold greater potency against EGFR compared with other tyrosine or serine/threonine kinases. Unlike cetuximab, gefitinib does not induce EGFR internalization or degradation in CRC cells, nor does it reduce EGF binding sites or EGFR protein content. Both in vitro
and in vivo
studies indicated that gefitinib monotherapy had antitumor activity in some CRC cell lines[31
]. However, phaseI/II clinical studies in patients with mCRC indicated that gefitinib had negligible activity[32,33
]. Preclinical suggestions of a supra-additive, growth-inhibitory effect of gefitinib and a wide variety of cytotoxic drugs with different mechanism(s) of action[34
] prompted several trials of gefitinib in combination with chemotherapy in mCRC patients.
Gefitinib plus fluoropyrimidines
: In preclinical models a strong synergistic interaction between gefitinib and 5'-deoxy-fluorouridine (5'-DFUR) was demonstrated when ZD1839 was applied before or concurrently with 5'-DFUR[35
]. Subsequently, the combination of intermittent gefitinib (250-500 mg/d on d 1-14) plus 5-FU/LV administered as a bolus in a dose-reduced Mayo Clinic regimen (370/20 mg/m2
) on d 8-12 with 5-FU and leucovorin as first-line therapy in mCRC was tested, with no evidence of cumulative toxicity or major drug-drug pharmacokinetic interactions[36
]. In the second part of the study, gefitinib was administered continuously at 500 mg/d, and 5-FU/LV was added to the schedule on d 8-12 and 36-40. Overall response rate was 23%, with the most common toxicities being rash and diarrhea.
Preliminary results from a small phaseI/II trial combining gefitinib 250-mg daily with capecitabine 1000-1250 mg twice daily after failure of first-line therapy[37
] also suggest some evidence of activity .
Gefitinib plus irinotecan-based therapy:
A dose-finding trial of irinotecan plus gefitinib in mCRC patients pretreated with fluoropyrimidine-based chemotherapy defined irinotecan given at a dose of 225 mg/m2
every 3 wk plus gefitinib at a dose of 250 mg/d as the maximun tolerated dose (MTD) of this regimen[38
]. Dose-limiting toxicities (DLTs), such as neutropenia and diarrhea, occurred at unexpectedly low doses of irinotecan. Disease stabilization was achieved in 21% of the patients.
The combination of gefitinib plus FOLFIRI in both chemotherapy-naive mCRC patients[39
] and as salvage therapy[40
] was considered too toxic despite reduced weekly doses of 5-FU, LV, and irinotecan.
Gefitinib plus oxaliplatin-based therapy:
Gefitinib plus FOLFOX has been tested in both the first line and the salvage setting. Kuo et al[41
] reported data on a phase II study of one cycle of FOLFOX-4, and then additional cycles of FOLFOX-4 with 500 mg/d of gefitinib in 27 patients with documented progressive colorectal cancer after at least one chemotherapeutic regimen (usually irinotecan based). 33% of the patients achieved objective responses, whereas 48% had stable disease for a prolonged period. Response rates did not differ depending on number of prior regimens. Median event-free survival was 5.4 mo, and overall survival was 12 mo. Another feasibility study assessed the combination of gefitinib (250 mg/d) plus capecitabine (2000 mg/m2
per day, d 1-15) plus oxaliplatin (120 mg/m2
every 3 wk for six courses) as first-line treatment in patients with mCRC[42
]. The most common grade 3 adverse events were diarrhea and neutropenia. A clinical benefit rate of 58% has been noted. Overall, toxicity rates with the addition of gefitinib to an oxaliplatin-fluoropyrimidine combination are markedly more favorable than with the irinotecan-based regimens, although higher incidences of grade III or IV diarrhea, nausea, and vomiting than with FOLFOX alone are noted. Further studies of TKI-based therapy for CRC are planned or recruiting.
Erlotinib, an orally reversible TKI reduces intratumoral EGFR autophosphorylation[43
] with no effect on EGFR expression or surface receptor density. Evidence of single agent erlotinib activity in mCRC patients derived from disease-specific phase II studies[44
] led to the design of several trials in combination with chemotherapy.
Tarceva plus fluoropyrimidines:
Additive activity of capecitabine and erlotinib in tumor models[45
] supported a phase 2 trial evaluating the combination of erlotinib 150 mg daily with capecitabine 1000 mg/m2
bid. for 14 d every 3 wk in chemotherapy-naive mCRC patients. Grade 3 diarrhea (30%) grade 3 renal insufficiency (10%) and grade 3 hiperbilirrubinemia (10%) were the most troublesome toxicities. Regarding efficacy, no complete responses were achieved whereas disease control rate was 34%[46
Tarceva plus oxaliplatin
: Meyerhardt et al[47
] reported on the results of a triplet regimen of erlotinib, 100 mg/d, capecitabine, 1650 mg/m2
per day (d 1-14), and oxaliplatin, 130 mg/m2
every 3 wk in 32 patients mostly pretreated with an irinotecan-containing regimen. By intent-to-treat analysis, 25% of the patients experienced a partial response and 44% had stable disease for at least 12 wk. 29% of the patients discontinued study therapy due to toxicity.
Other TKIs-based combinations
EKB-569, an irreversible dual inhibitor of the EGFR and HER-2 tyrosine kinases, inhibits the growth of tumor cells that overexpress EGFR or HER-2 in vitro
and in vivo
]. Dose-limiting toxicities with EKB-569 plus FOLFIRI in 47 chemotherapy-naive mCRC patients[49
] were grade 3 diarrhea and grade 3 fatigue. The MTD was selected as 25 mg EKB-569. The response rate was 38% and the clinical benefit rate was 85%. EKB-569 treatment resulted in complete inhibition of pEGFR and significant inhibition of pMAPK in both skin samples (11 patients) and tumor samples (three patients) with no change in pAkt activity.
In a dose-escalation study[50
] with FOLFOX-4 plus EKB-569, 25-75 mg/d, starting from d 3, DLTs were observed with EKB-569 at a dose of 35 mg/d (grade III diarrhea and febrile neutropenia), leaving an MTD of 25 mg/d. The most common grade III or IV adverse events were neutropenia (32%; 9 of 29 patients) and diarrhea (8%; 2 of 29 patients).
COMBINING CHEMOTHERAPY AND VEGF-TARGETED THERAPIES
Clinical development of Bevacizumab (BV) has rapidly progressed to Phase III trials after a preliminary randomized Phase II trial in which 104 previously untreated mCRC patients were randomized to two doses of BV (5 and 10 mg/kg) in addition to bolus 5-FU/LV (high dose, Rosewell-Park regimen) or to 5-FU/LV alone[51
]. The combination of 5-FU/LV with low-dose BV (5 mg/kg every 2 wk) demonstrated superiority compared with the control monotherapy arm and to the BV-containing arm at a higher dose. These results provided the rationale for the key front-line Phase III study by Hurwitz et al[52
] which demonstrated superiority of IFL plus BV over IFL plus placebo in terms of RR (45% vs
35%), PFS(10.6 mo vs
6.2 mo) and OS(20.3 mo vs
15.6 mo). A subanalysis of this trial has recently stablished the benefit of Bevacizumab in mCCR patients with poor conditions[53
The second trial (E3200) was a second-line Phase III study, designed for patients who already failed an irinotecan-containing therapy and did not receive BV in first-line treatment[54
]. Initially, the study included three randomization arms: FOLFOX4 plus BV 10 mg/kg, FOLFOX4 alone or BV 10 mg/kg alone. The BV single-agent arm was closed ahead of time since it was clearly inferior to both other arms (RR 3% and PFS 2.7 mo). The results again largely favored the BV-containing arm, especially in terms of RR (21.8% vs
< 0.0001) and PFS (7.2 mo vs
4.8 mo, P
< 0.0001). The primary end point of the study was reached, since a statistically significant increase in median survival was obtained in the experimental arm (12.5 mo vs
10.7 mo, P
Finally, updated results of N016966, a randomized phase III trial evaluating the addition of bevacizumab to oxaliplatin-based first line chemotherapy have been reported. Bevacizumab-containing arms demonstrated a significant benefit in terms of progression-free survival, although overall response rate did not significantly differ[55
More recently, several phase II trials have addressed the feasibility and activity of bevacizumab when combined with various cytotoxic regimens. The First BEATrial[56
] enrolled 1927 chemotherapy-naïve patients treated with a combination of bevacizumab and several first-line chemotherapies, including FOLFOX, FOLFIRI and XELOX. Median PFS was 10.4 mo. Combinations of XELOX or XELIRI plus bevacizumab have yielded tumor control rates in the range of 80% as front-line therapy for mCRC[57
In contrast to its efficacy when used in combination with first- and second-line chemotherapy, activity of bevacizumab in chemoresistant disease has been disappointing. Chen et al[58
] developed a treatment referral center (TRC) protocol (TRC-0301) for patients with mCRC in the third-line setting with the aim of evaluating the safety and activity of BV plus FU/LV in patients progressed after treatment with both irinotecan-based and oxaliplatin-based chemotherapy regimens. Independent review confirmed one PR (1%; 95% CI, 0% to 5.5%). Median PFS in this cohort was 3.5 mo (95% CI, 2.1 mo to 4.7 mo) and median OS was 9.0 mo (95% CI, 7.2 mo to 10.2 mo). The authors conclude that BV, alone or in combination with an ineffective chemotherapy in the third-line setting, is likely to be of minimal, if any, clinical benefit.
An important question that remains unresolved is whether to continue bevacizumab with second-line therapy following failure of a bevacizumab-containing first-line regimen. Although retrospective data from the BRiTE trial suggest that the use of bevacizumab beyond first progression correlate with an improved survival, more mature data are required to draw any firm conclusion[59
VEGF Tyrosine kinase inhibitors (TKI)-based combination therapy
Tyrosine kinase inhibitors of vascular endothelial growth factor receptors (VEGFRs) are low molecular weight, ATP-mimetic proteins that bind to the ATP-binding catalytic site of the tyrosine kinase domain of VEGFRs, resulting in a blockade of intracellular signaling. Several of these molecules have entered clinical evaluation.
Semaxanib is a small, lipophilic, synthetic molecule that inhibits VEGFR-1, and -2 tyrosine kinases[60
]. A promising response of 31.6% was observed with semaxanib at two different dose levels, 85 and 145 mg/m2
twice weekly in combination with fluorouracil plus leucovorin as first-line therapy for 28 patients with mCRC[61
]. However, a randomized, multicenter, phase III trial failed to show any improvement in clinical outcome with semaxanib in combination with fluorouracil and leucovorin (Roswell Park regimen) versus
fluorouracil and leucovorin alone as first-line therapy for 737 mCRC patients; moreover, worse toxicity in the semaxanib arm (in terms of diarrhea, cardiovascular events, vomiting, dehydration, and sepsis) was observed[62
Valatanib is a synthetic, low molecular weight, orally bio-available agent that inhibits all known VEGFR tyrosine kinases, platelet-derived growth factor receptor beta (PDGFR-β) and c-Kit tyrosine kinase[63
Vatalanib was evaluated in two phaseI/II studies as a single daily dose in combination with FOLFOX-4 or FOLFIRI. In the first study, the pharmacokinetics and toxicity profiles of both vatalanib and FOLFOX-4 were unaffected by co-administration[64
]. The reported response rate was 54%, with a median PFS of 11 mo and an estimated median OS time of 16.6 mo . In the second study[65
], co-administration of vatalanib at 1250 mg/d with FOLFIRI had minor effects on irinotecan exposure but lowered by 40% the AUC of SN-38 in patients’ serum. The response rate was 41%, with a median PFS duration of 7.1 mo and a median OS time of 24.3 mo. Two large, randomized, double-blinded, placebo-controlled, phase III trials compared the efficacy of oral vatalanib in combination with FOLFOX-4 with FOLFOX-4 alone in patients with mCRC, and none of them met the primary end points. In the CONFIRM-2 trial, the addition of PTK/ZK to FOLFOX-4 in previously treated mCRC did not meet the primary end points of the study. OS was 12.1 mo in the PTK/ZK arm and 11.8 mo in the placebo arm. The overall response rate was, respectively, 18.5 and 17.5%. PFS was significantly longer in the PSK/ZK arm (5.5 mo vs
= 0.026) As in confirm 1 trial, patients with pretreatment high LDH showed a strong improvement in PFS[66
]. Adverse events were similar to those of the CONFIRM-1 trial. Thrombotic and embolic events of all grades occurred in 6% of the patients treated with PTK/ZK vs
1% in the placebo arm. Trying to further analyze the relation between LDH levels and clinical outcome with PTK/ZK, Fixed paraffin embedded tumor samples from 36 mCRC not included in the CONFIRM trials were analyzed and tumor gene expression correlated with serum levels of LDH in the same group of patients. Intratumoral levels of LAMA, hipoxia inducible factor 1 (HIF-1), Glut-1 and VEGFA were significantly correlated. Moreover, patients with high serum LDH showed increased intratumoral gene expression of VEGFA, supporting the hypothesis of serum LDH levels as a surrogate maker for activation of the hypoxia inducible factor related genes in the tumor[66
Preliminary data of a phase I evaluation of AZD2171, a highly potent and selective inhibitor of VEGFR signaling, in combination with several chemotherapy regimens including FOLFOX-6 and CPT-11, has shown some evidence of activity[67
: Vandetalib, a once-daily oral inhibitor of VEGFR-dependent tumor angiogenesis, EGFR- and RET-dependent tumor proliferation, in combination with FOLFOX6[68
] or FOLFIRI[69
] has also shown some evidence of activity in mCRC, with diarrhea and neutropenia being the most frequent grade 3 toxicities.
So far, clinical, biochemical, and molecular markers have failed to discriminate which patients are more likely to benefit from bevacizumab-containing regimens. An analysis of predictive markers showed indeed that bevacizumab increased the activity of irinotecan plus FU/LV regardless of the level of VEGF expression, thrombospondin expression, and microvessel density[70
]. Mutations of k-ras
, and p53
could not predict for a prolonged survival on bevacizumab plus irinotecan plus bolus FU/LV[71
]. Recently, Shaye et al evaluated functionally significant polymorphisms of genes involved in the angiogenesis pathway in mCRC patients who receive bevacizumab as part of their front-line therapy. There were statistically significant associations between genomic polymorphisms of KDR, CXCR2, MMP7, leptin and both progression-free survival and response rate. Hopefully, prospectively collected samples from patients enrolled onto cooperative group studies and the development of selective micro arrays to define the angiogenesis-related genes in individual tumors, and at different stages of therapy and tumor progression may allow improved therapeutic efficacy.
COMBINATION OF TARGETED THERAPIES
The assumption that most advanced solid tumors derive their growth advantage from more than a signaling pathway and the significant level of compensatory cross talk among receptors within a signaling network as well as with heterologous receptor systems has provided the basis of a combined molecular targeting approach, in which more than one class of inhibitor is applied simultaneously.
A phase II study with the combination of FOLFOX, bevacizumab (5 mg/kg) and erlotinib (150 mg/d) every two weeks in 31 chemotherapy naive mCRC patients has been recently conducted. Grade 3-4 adverse events included diarrhea (29%) neutropenia (29%) rash (18%), fatigue (14%) and neuropathy (11%) 78% of the patients had at least one grade 3-4 toxicity. Remarkably, as much as 42% of the patients came off for toxicity. Similar results have been reported in the DREAM-OPTIMOX3 study, with a 70% incidence of grade 3-4 toxicity when adding erlotinib to a combination of bevacizumab and XELOX[73
A phase II trial of FOLFOX plus bevacizumab and cetuximab in 67 chemotherapy-naïve mCRC patients yielded a 55% response rate, with a median PFS of 9.6 mo and 71% of the patients progression-free for at least 8 mo[74
The combination of FOLFOX or FOLFIRI with panitumumab and AMG706, an oral multikinase inhibitor targeting VEGF, PDGF and Kit receptors has been tested in 45 mCRC patients, with no apparent PK/PD interactions and an overall response rate in the range of 50%[75
Based on these results, combinations of monoclonal antibodies are currently being actively tested in first-line therapy of mCRC. The Cancer and Leukemia Group B (CALGB)/South West Oncology Group (SWOG) Intergroup 80405 Phase III trial randomizes patients to either cetuximab or bevacizumab, or both antibodies in combination, with the oncologist’s choice of FOLFOX or FOLFIRI. In addition, the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) trial is currently evaluating the efficacy of FOLFOX or FOLFIRI (depending on the investigator choice) plus BV, versus the same combination plus panitumumab.
OTHER TARGETED THERAPIES-BASED COMBINATIONS
Cell cycle inhibitors
Kortmansky et al[76
] reported the results of the combi-nation of 5-FU and UCN-01, a selective inhibitor of a number of serine-threonine kinases, including calcium and phospholipid-dependent protein kinase C and cell cycle specific kinases, among 35 patients with advanced solid tumors, the majority of them with a diagnosis of mCRC. No objective responses were observed, although eight patients had stable disease. Most of the patients with stable disease had previously received and progressed on 5-fluorouracil. There was minimal toxicity attributed to the combination, although expected toxicities associated with UCN-01 were observed.
Bcl-2 plays a pivotal role in the regulation of caspase activation and apoptosis. Its overexpression is found in 30%-94% of clinocopathological colorectal carcinoma specimens and confers a multidrug resistant phenotype in several cell lines. In support of this data, antisense oligonucleotide therapy directed against bcl-2 was shown to significantly enhance the chemosensitivity in several cancer cell lines compared with controls in vitro
. A recently published phaseItrial assessed the feasibility and pharmacokinetic behaviour of the combination of oblimersen sodium, a phosphorothioate antisense oligonucleotide that hybridizes to the first six codons of the bcl-2 open reading frame mRNA, with CPT-11 in 20 pts with mCRC. Among them, 1 pt experienced a PR while 10 additional patients had stable disease lasting 2.5-10 mo. The authors recommend oblimersen at 7 g/kg/d, d 1-8 with CPT-11 280 mg/m2
on d 6 once every 3 wk was the RD for further development in phase II trials[77
The proteasome inhibitor Bortezomib (PS-341), at a dose of 1.3 mg/m2
administered twice weekly every 21 d in pretreated patients with mCRC did not prove to have clinical activity[78
The main nonhematologic toxicities were elevation of alkaline phosphatase, constipation, fatigue, nausea, and sensory neuropathy. A phamacokinetic and phamacodynamic analysis of topotecan plus PS-341 in 22 patients with advanced solid malignancies found that, with the addition of PS-341, peripheral blood mononuclear cells (PBMC) topoisomeraseIlevels got stabilised or increased. These findings suggest that PS-341 may overcome resistance to topoisomeraseIinhibitors, since in vitro exposure to campothecin results in down-regulation of the target enzyme. Preliminary data of the combination of FOLFOX4 plus bortezomib in mCRC patients[79
] show evidence of clinical activity, with bortezomib at a dose of 1 mg/m2
being the RD for phase II trials.
Numerous clinical trials are ongoing to test the efficacy of nonsteroidal anti-inflammatory COX-2 inhibitors in combination regimens for therapy of advanced solid tumors[80
]. Preliminary data on the combination of rofecoxib (50 mg/d) with weekly irinotecan and infusional fluorouracil demonstrated a good tolerability up to the irinotecan dose of 125 mg/m2
/wk. The phase II study showed a 36.7% objective response rate, a clinical benefit of 76.7% and a median TTP and overall survival of 4 and 9 mo, respectively. The combination was feasible and safe, with a reduced rate of mucositis and diarrhea[81
However, in the BICC-C trial[82
], addition of celecoxib to several Irinotecan/fluorpyrimidine combinations did not impact safety or efficacy. Results of larger studies seem warranted.
Histone deacetylase inhibitors
Histone acetylation by histone acetyltransferases is important for promoting the action of several transcription factors. Acetylation facilitates binding of transcription factors to specific target DNA sequences by destabilizing nucleosomes bound to the promoter region of the target genes[83
Vorinostat, a novel histone deacetylase inhibitor that potentiates 5-FU through a decrease in thymidylate synthase (TS) expression has been tested in combination with FOLFOX, in a phaseIstudy that enrolled mCRC patients who had failed prior FOLFOX, irinotecan and cetuximab therapy. Tolerance was acceptable, and some evidence of both, clinical activity (SD in some patients) and biological activity (down regulation of TS) are suggested[84
Rapamycin displays potent antimicrobial and immuno-suppressant effects as well as antitumor properties. Rapamycin’s antiproliferative actions are due to it’s ability to modulate key signal transduction pathways that link mitogenic stimuli to the synthesis of proteins necessary for the cell cycle to progress from the G1 to S phase[85
Rapamycin clinical development has been hampered due to the poor aqueous solubility and chemical stability of the macrolide. CCI-779, a rapamycin ester derived from 2, 2-bis (hydroxymethyl) propionic acid, is one analog that was selected for further development due to its promising pharmacological, toxicological and antitumor profiles[86
A phaseIstudy of escalating doses of CCI-779 in combination with 5-FU/leucovorin in patients with advanced solid tumors, including mCRC reported preliminary evidence of activity including 1 complete response in a patient with mCRC receiving the 15 mg/m2
dose and several patients with stable disease of a maximum duration of 12 mo. Further studies are required to determine appropriate regimens with this combination treatment[87
In conclusion, the biological agents have clearly increased the therapeutic armamentarium of patients with metastatic CRC and offer also prospects for an increased chance of a longer survival. Eventually, the availability of more predictive biological factors may allow oncologists to tailor individualized targeted combination therapy to a specific patient with a specific tumor. However, the cost of novel therapies for mCRC is particularly high. Such a heavy economical burden may be counterbalanced either by a very significant breakthrough in treatment efficacy or by selection of patients with a higher chance of responding to a specific treatment.
Kelly H, Goldberg RM. Systemic therapy for metastatic colorectal cancer: current options, current evidence. J Clin Oncol. 2005;23
:4553-4560. [PubMed] [DOI]
Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007;25
:1670-1676. [PubMed] [DOI]
Goldstein NS, Armin M. Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma: implications for a standardized scoring system. Cancer. 2001;92
:1331-1346. [PubMed] [DOI]
Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer. 2001;37 Suppl 4
:S9-15. [PubMed] [DOI]
Mendelsohn J. Blockade of receptors for growth factors: an anticancer therapy--the fourth annual Joseph H Burchenal American Association of Cancer Research Clinical Research Award Lecture. Clin Cancer Res. 2000;6
Saltz L, Rubin M, Hochster H, Tchekmeydian NS, Waksal H, Needle M, LoBuglio A. Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11 refractory colorectal cancer (CRC) that expresses epidermal growth factor rector (EGFR). Proc Am Soc Clin Oncol. 2001;20:7 (Abstract).
Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351
:337-345. [PubMed] [DOI]
Wilke H, Glynne-Jones R, Thaler J, Adenis A, Preusser P, Aranda Aguilar A, Aapro M, Van Den Berg N, Eggleton S, Siena S. MABEL. A large multinational study of cetuximab plus irinotecan in irinotecan resistant metastatic colorectal cancer. Proc Am Soc Clin Oncol. 2006;158s:3549 (Abstract).
Abubakr Y, Eng C, Wong L, Pautret V, Scheithauer W, Maurel J, Kroening H, lutz M, Zubel A, Sobrero A. Cetuximab plus irinotecan for metastatic colorectal cancer: Safety analysis of 800 patients in a randomized phase III trial. Proc Am Soc Clin Oncol. 2006;160s:3556 (Abstract).
Vincenzi B, Santini D, Tonini G. Lack of response of cetuximab plus oxaliplatin in advanced colorectal cancer patients resistant to both oxaliplatin and cetuximab plus irinotecan. Ann Oncol. 2006;17
:527-528. [PubMed] [DOI]
Vincenzi B, Santini D, Rabitti C, Coppola R, Beomonte Zobel B, Trodella L, Tonini G. Cetuximab and irinotecan as third-line therapy in advanced colorectal cancer patients: a single centre phase II trial. Br J Cancer. 2006;94
:792-797. [PubMed] [DOI]
Smith DM, Legoux J, Brunet R, Adhoute X, Blanc J, Fonck M, Vendrely V, Becouarn Y. Cetuximab in combination with FOLFIRI in second and third line treatment of metastaic colorectal cancer: Safety and efficacy analysis. Proc Am Soc Clin Oncol. 2006;160s:3558 (Abstract).
Venook A, Niedzwiecki D, Hollis D, Sutherland S, Goldberg R, Alberts S, benson A, Wade J, Schilsky R, Mayer R. Phase III study of FOLFIRI or FOLFOX with or without cetuximab for patients with untreated metastatic adenocarcinoma of the colon or rectum: CALGB 80203 preliminary results. Proc Am Soc Clin Oncol. 2006;148s:3509 (Abstract).
Heinemann V, Fischer Von Weikersthal L, Moosmann N, Vehling-Kaiser U, Stauch M, Oruzio D, Schulze M, Walther J, Weiss J, Dietzfelbinger H. Cetuximab + capecitabine + irinotecan versus cetuximab + capecitabine + oxaliplatin as first line therapy for patients with metastatic colorectal cancer: Preliminary results of a randomized phase II trial of the AIO CRC Study Group. Proc Am Soc Clin Oncol. 2006;158s:3550 (Abstract).
Folprecht G, Lutz MP, Schöffski P, Seufferlein T, Nolting A, Pollert P, Köhne CH. Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma. Ann Oncol. 2006;17
:450-456. [PubMed] [DOI]
Dakhil S, Cosgriff T, Headley D, Boccia RV, Badarinath S. Cetuximab plus FOLFOX-6 as first line therapy for metastatic colorectal cancer. (An International Oncology Network study, I-03-002). Proc Am Soc Clin Oncol. 2006;160s:3557 (Abstract).
Colucci G, Giuliani F, Mattioli R, Garufi C, Mallamaci R, Pezella G, Lopz M, Maiello E. FOLFOX-4 plus cetuximab in untreated patients with advanced colorectal cancer. A phase II study of the Gruppo Oncologico dell'Italia Meridionale (prot GOIM 2402). Proc Am Soc Clin Oncol. 2006;160s:3559 (Abstract).
Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, Zampino M, Donea S, Ludwig H, Zubel A, Koralewski P. Cetuximab plus FOLFOX versus FOLFOX4 in the first line treatment of metastatic colorectal cancer: OPUS, a randomized phase II study. Proc Am Soc Clin Oncol. 2007;172s:4035 (Abstract).
Van Cutsem E, Nowacki M, Lang I, Cascinu S, Shchepotin I, Maurel J, Rougier P, Cunningham D, Nippgen J, Kohne C. Randomized phase III study of FOLRIRI with or without Cetuximab in the first line treatment of patients with metastatic colorectal cancer: The CRYSTAL trial. Proc Am Soc Clin Oncol. 2007;164s:4000 (Abstract).
Hecht J, Posey J, Tchekmedyian S, Hu E, Chan D, Malik I, Yang L, McDonald M, Berlin J. Panitumumab in combination wiyh 5-fluorouracil, leucovorin, and irinotecan or FOLFIRI for first line treatment of metastatic colorectal cancer. Proc Am Soc GI Symp. 2006;:237 (Abstract).
Teipar S, Peeters M, Humblet Y, Gelderblom H, Vermorken J, Viret F, Glimelius F, Ciardiello F, Kisker O, Van Cutsem E. Phase I/II study of cetuximab dose escalation in patients with metastatic colorectal cancer with no or slight skin reactions on cetuximab standard dose treatment (EVEREST study)Pharmacokinetic, Pharmacodynamic and efficacy data. Proc Am Soc Clin Oncol. 2007;172s:4037 (Abstract).
Gravalos C, Sastre J, Aranda E, Massuti B, Vega-Villegas ME, Gomez A, Varella-Garcia M, Jimeno A, Diaz-Rubio E, Hidalgo M. Analysis of potential predictive factors of clinical benefit in patients with matastatic colorectal cancer treated with single agent cetuximab as first line treatment. Proc Am Soc Clin Oncol. 2007;193s:4120 (Abstract).
Moroni M, Veronese S, Benvenuti S, Marrapese G, Sartore-Bianchi A, Di Nicolantonio F, Gambacorta M, Siena S, Bardelli A. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol. 2005;6
:279-286. [PubMed] [DOI]
Garufi C, Mottolese M, Cianciulli A, Zeuli M, Buglioni S, Torsello A, Vanni B, Campanellaa C, Merola R, Terzoli E. Epidermal growth factor gene amplification is not frequent and cannot account for antitumor activity of cetuximab plus chemotherapy in advanced colorectal cancer patients. Proc Am Soc Clin Oncol. 2006;161s:3561 (Abstract).
Di Fiore F, Le Pessot F, Lamy A, Charbonnier F, Sabourin J, Paillot B, Frebourg T, Michel P. K-ras mutation is highly predictive of cetuximab resistance in metastatic colorectal cancer. Proc Am Soc Clin Oncol. 2007;565s:10502 (Abstract).
Zhang W, Yun J, Press OA, Gordon M, Yang DY, Mallik N, Sherrod A, Iqbal S, Lenz HJ. Association of cyclin D1 (CCND1) gene A870G polymorphism and clinical outcome of EGFR-positive metastatic colorectal cancer patients treated with epidermal growth factor receptor (EGFR) inhibitor cetuximab (C225). Proc Am Soc Clin Oncol. 2004;:3518 (Abstract).
Emlet DR, Schwartz R, Brown KA, Pollice AA, Smith CA, Shackney SE. HER2 expression as a potential marker for response to therapy targeted to the EGFR. Br J Cancer. 2006;94
:1144-1153. [PubMed] [DOI]
Vallböhmer D, Zhang W, Gordon M, Yang DY, Yun J, Press OA, Rhodes KE, Sherrod AE, Iqbal S, Danenberg KD. Molecular determinants of cetuximab efficacy. J Clin Oncol. 2005;23
:3536-3544. [PubMed] [DOI]
Finocchiaro G, Capuzzo F, Janne PA, Bencardino K, Carnaghi C, Franklin WA, Roncalli M, Crino L, Santoro A, Varella-Garcia M. EGFR, HER2 and Kras as predictive factors for cetuximab sensitivity in colorectal cancer. Proc Am Soc Clin Oncol. 2007;168s:4021 (Abstract).
Nagashima F, Zhang W, Gordon M, Chang HM, Lurje G, Borucka E, Yang D, Rowinsky E, Lenz HJ. EGF, Cox-2 and EGF polymorphisms associated with progression-free survival of EGFR-expressing metastatic colorectal cancer patients treated with single agent cetuximab. Proc Am Soc Clin Oncol. 2007;195s:4129 (Abstract).
Ciardiello F, Caputo R, Bianco R, Damiano V, Fontanini G, Cuccato S, De Placido S, Bianco AR, Tortora G. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res. 2001;7:1459-1465.
Rothenberg ML, Lafleur B, Washington MK, Levy DE, Morgan-Meadows DE, Ramanathan RK, Berlin JD, Benson AIB, Coffey RJ. Changes in epidermal growth factor receptor signalling in serum and tumour biopsies obtained from patients with progressive metastatic colorectal cancer (MCRC) treated with gefitinib (ZD1839): An Eastern Cooperative Oncology Group Meeting. Proc Am Soc Clin Oncol. 2004;21:3000 (Abstract).
Mackenzie MJ, Hirte HW, Glenwood G, Jean M, Goel R, Major PP, Miller WH, Panasci L, Lorimer IA, Batist G. A phase II trial of ZD1839 (Iressa) 750 mg per day, an oral epidermal growth factor receptor-tyrosine kinase inhibitor, in patients with metastatic colorectal cancer. Invest New Drugs. 2005;23
:165-170. [PubMed] [DOI]
Ciardiello F, Caputo R, Bianco R, Damiano V, Pomatico G, De Placido S, Bianco AR, Tortora G. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res. 2000;6
Magné N, Fischel JL, Dubreuil A, Formento P, Ciccolini J, Formento JL, Tiffon C, Renée N, Marchetti S, Etienne MC. ZD1839 (Iressa) modifies the activity of key enzymes linked to fluoropyrimidine activity: rational basis for a new combination therapy with capecitabine. Clin Cancer Res. 2003;9
Hammongd LA, Figueroa J, Schawrtzaberg L: Feasibility and pharmacokinetic (PK) trial of ZD1839 (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in combination with 5-Fluororaucil (5-FU) and lecovorin (LV) in patients with advanced colorectal cancer.Proc Am Soc Clin Oncol. 2001;:544 (Abstract).
Jimeno A, Sevilla I, Gravalos C. Phase I/II trial of capecitabine and gefitinib in patients with advanced colorectal cancer after failure of first-line therapy. Proc Am Soc Clin Oncol. 2005;23:3176a.
Chau I, Massey A, Higgins L, Botwood N, Cunningham D. Phase I study of gefitinib in combination with irinotecan in patients with fluoropyrimidine refractory advanced colorectal cancer (CRC). Proc Am Soc Clin Oncol. 2004;23:263 (Abstract).
Veronese ML, Sun W, Giantonio B, Berlin J, Shults J, Davis L, Haller DG, O'Dwyer PJ. A phase II trial of gefitinib with 5-fluorouracil, leucovorin, and irinotecan in patients with colorectal cancer. Br J Cancer. 2005;92
:1846-1849. [PubMed] [DOI]
Hochhaus A, Hofheinz R, Heike M. Phase I study of gefitinib in combination with FOLFIRI as 2nd-/3rd-line treatment in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol. 2005;23:3674 (Abstract).
Kuo T, Cho CD, Halsey J, Wakelee HA, Advani RH, Ford JM, Fisher GA, Sikic BI. Phase II study of gefitinib, fluorouracil, leucovorin, and oxaliplatin therapy in previously treated patients with metastatic colorectal cancer. J Clin Oncol. 2005;23
:5613-5619. [PubMed] [DOI]
Zeuli M, Gelibter A, Nardoni C. A feasibility study of gefitinib in association with capecitabine (CAP) and oxaliplatin (OXA) as first-line treatment in patients with advanced colorectal cancer (ACRC). Proc Am Soc Clin Oncol. 2004;23:306 (Abstract).
Pollack VA, Savage DM, Baker DA, Tsaparikos KE, Sloan DE, Moyer JD, Barbacci EG, Pustilnik LR, Smolarek TA, Davis JA. Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther. 1999;291
Townsley CA, Major P, Siu LL, Dancey J, Chen E, Pond GR, Nicklee T, Ho J, Hedley D, Tsao M. Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Br J Cancer. 2006;94
:1136-1143. [PubMed] [DOI]
Ouchi KF, Yanagisawa M, Sekiguchi F, Tanaka Y. Antitumor activity of erlotinib in combination with capecitabine in human tumor xenograft models. Cancer Chemother Pharmacol. 2006;57
:693-702. [PubMed] [DOI]
Nakhoul I, Grossbard M, Blum R, Malamud S, Rodriguez T, Takhir M, Kozuch P. Phase II study of erlotinib in combination with capecitabine in previously untreated metastatic colorectal cancer. Proc Am Soc Clin Oncol GI Symp. 2006;239 (Abstract).
Meyerhardt JA, Zhu AX, Enzinger PC, Ryan DP, Clark JW, Kulke MH, Earle CC, Vincitore M, Michelini A, Sheehan S. Phase II study of capecitabine, oxaliplatin, and erlotinib in previously treated patients with metastastic colorectal cancer. J Clin Oncol. 2006;24
:1892-1897. [PubMed] [DOI]
Nunes M, Shi C, Greenberger LM. Phosphorylation of extracellular signal-regulated kinase 1 and 2, protein kinase B, and signal transducer and activator of transcription 3 are differently inhibited by an epidermal growth factor receptor inhibitor, EKB-569, in tumor cells and normal human keratinocytes. Mol Cancer Ther. 2004;3
:21-27. [PubMed] [DOI]
Casado E, Folprecht L, Paz-Ares L. A Phase I/IIA pharmacokinetic and serial skin and tumor pharmacodynamic study of the EGFR irreversible tyrosine kinase inhibitor EKB-569 in combination with 5-fluorouracil leucovorin and irinotecan (FOLFIRI regimen) in patients with advanced colorectal cancer. Proc Am Soc Clin Oncol. 2004;23:256 (Abstract).
Tejpar S, Van Cutsem E, Gamelin E. Phase 1/2a study of EKB-569, an irreversible inhibitor of epidermal growth factor receptor, in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) in patients with advanced colorectal cancer (CRC). Proc Am Soc Clin Oncol. 2004;23:265 (Abstract).
Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, Griffing S, Bergsland E. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21
:60-65. [PubMed] [DOI]
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350
:2335-2342. [PubMed] [DOI]
Kabbinavar F, Sulo A, Irl C, Nurwitz N. Bevacizumab improves outcomes of patients with metastasic colorectal cancer treated with IFL with or without bevacizumab independent of baseline risk. J Clin Oncol. 2006;24:3539 (Abstract).
Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25
:1539-1544. [PubMed] [DOI]
Saltz L, Clarke S, diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, lichinister M, Yang T, Cassidy J. Bevacizumab in combination with XELOX or FOLFOX: Updated efficacy results from XELOX-1/N016966, a randomized phase III trial in first line metastatic colorectal cancer. Proc Am Soc Clin Oncol. 2007;170s:4028 (Abstract).
Kretzschmar A, Van Cutsem E, Michael M, rivera F, Berry S, DiBartolomeo M, Mazier M, Lutiger B, Cunningham D. Preliminary efficacy of bevacizumab witj first line FOLFOX, XELOX, FOLFIRI and monotherapy for m CRC: First BEATrial. Proc Am Soc Clin Oncol. 2007;181s:4072 (Abstract).
Reinacher-Schick A, Freier W, Dietrich G, Arnold D, Kanzler S, Geissier S, Graeven U, Hegewisch-Becker S, Schmoll H. Comparable safety and response rate with bevacizumab in combination with capecitabine/oxaliplatin versus capecitabine/irinotecan in advanced CRC: A randomized phase II study of the AIO GI tumor study group. Proc Am Soc Clin Oncol. 2007;172s:4034 (Abstract).
Chen HX, Mooney M, Boron M, Vena D, Mosby K, Grochow L, Jaffe C, Rubinstein L, Zwiebel J, Kaplan RS. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. J Clin Oncol. 2006;24
:3354-3360. [PubMed] [DOI]
Grothey A, Sugrue M, Hedrick E, Purdie D, Yi J, Dong W, Kozloff M. Association between exposure to bevacizumab beyond first progression and overall survival in patients with metastatic colorectal cancer: Results fom a large observational study (BRiTE). Proc Am Soc Clin Oncol. 2007;172s:4036 (Abstract).
Fong TA, Shawver LK, Sun L, Tang C, App H, Powell TJ, Kim YH, Schreck R, Wang X, Risau W. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res. 1999;59
Rosen P, Amado R, Hecht J. A phase I/II study of SU5416 in combination with 5-FU/leucovorin in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol. 2000;18:5a.
Longo R, Sarmiento R, Fanelli M, Capaccetti B, Gattuso D, Gasparini G. Anti-angiogenic therapy: rationale, challenges and clinical studies. Angiogenesis. 2002;5
:237-256. [PubMed] [DOI]
Wood JM, Bold G, Buchdunger E, Cozens R, Ferrari S, Frei J, Hofmann F, Mestan J, Mett H, O'Reilly T. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 2000;60
Steward W, Thomas A, Morgan B. Expanded phase I/II study of PTK787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in combination with FOLFOX-4 as first-line treatment for patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol. 2004;23:3556 (Abstract).
Schleucher N, Trarbach T, Junker U, Tewes M, Masson E, Lebwohl D, Seeber S, Laurent D, Vanhoefer U. Phase I/II study of PTK787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor in combination with FOLFIRI as first-line treatment for patients with metastatic colorectal cancer (CRC). Proc Am Soc Clin Oncol. 2005;23:3605 (Abstract).
Major P, Trarbach T, Lenz H, Kerr D, Pendergrass K, Douillard J, Chen B, Laurent D, Jacqes C, Van Cutsem E. A meta-analysis of two randomized, double-blind, placebo-controlled, phase III studies in patients with metastatic colorectal cncer receiving FOLFOX and PTK/ZK to determine clinical benefit on progression free survival in high LDH patients. J Clin Oncol. 2006;18s:3529 (Abstract).
Lorusso PM, heath E, Valdivieso M, Pilat M, Wozniak A, Gadgeel S, Shields A, Puchalski R. Phase I evaluation of AZD2171, a highly potent and selective inhibitor of VEGFR signaling, in combination with selected chemotherapy regimens in patients with advanced solid tumors. J Clin Oncol. 2006;24:3034 (Abstract).
Michael M, Tebbutt N, Gibbs P, Smith R, Godwood A, Oliver S. Vandetanib with FOLFOX6 in advanced colorectal adenocarcinoma: An open-label multicenter phase I study. Proc Am Soc Clin Oncol. 2007;187s:4095 (Abstract).
Saunders M, Van Cutsem E, Wilson R, Peeters M, Smith R, Godwood A, Oliver S. Vandetanib with FOLFIRI in advanced colorectal adenocarcinoma: An open-label multicenter phase I study. Proc Am Soc Clin Oncol. 2007;184s:4085 (Abstract).
Jubb AM, Hurwitz HI, Bai W, Holmgren EB, Tobin P, Guerrero AS, Kabbinavar F, Holden SN, Novotny WF, Frantz GD. Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol. 2006;24
:217-227. [PubMed] [DOI]
Ince WL, Jubb AM, Holden SN, Holmgren EB, Tobin P, Sridhar M, Hurwitz HI, Kabbinavar F, Novotny WF, Hillan KJ. Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst. 2005;97
:981-989. [PubMed] [DOI]
Shaye OS, Chang HM, Yang DY, Shriki J, Schutheis AM, Zhang W, Lurje G, Iqbal S, Lenz HJ. Polymorphisms in angiogenesis related genes predict clinical outcome in patients with metastatic colorectal cancer treated with first line 5-FU or caapecitabine in combination with oxaliplatin and bevacizumab. Proc Am Soc Clin Oncol. 2007;548s:10576 (Abstract).
Tournigand C, lledo G, Delord J, Andre T, Maindrault-Goebel F, Louvet C, Scheithauer W, de Gramont A. Modified Folfox/bevacizumab or modified Xelox/bevacizumab with or without erlotinib in first line metastatic colorectal cancer. Results of the feasibility phase of the DREAM-OPTIMOX3 study (GERCOR). Proc Am Soc Clin Oncol. 2007;187s:4097 (Abstract).
Ocean AJ, Brien K, Lee J, Matthews N, Holloway S, Christos P, Kung TS, Kaubisch A, Chen H, Wadler S. Phase II trial of FOLFOX, bevacizumab and cetuximab in patients with colorectal cancer. Proc Am Soc Clin Oncol. 2007;182s:4075 (Abstract).
Schwartzberg LS, Hurwitz H, Stephenson J, Kotasek D, Goldstein D, Tebbutt N, Greivy J, Sun Y, Yang L, Burris H. Safety and pharmacokinetics of AMG 706 with panitumumab plus FOLFIRI or FOLFOX for the treatment of patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol. 2007;183s:4081 (Abstract).
Kortmansky J, Shah MA, Kaubisch A, Weyerbacher A, Yi S, Tong W, Sowers R, Gonen M, O'reilly E, Kemeny N. Phase I trial of the cyclin-dependent kinase inhibitor and protein kinase C inhibitor 7-hydroxystaurosporine in combination with Fluorouracil in patients with advanced solid tumors. J Clin Oncol. 2005;23
:1875-1884. [PubMed] [DOI]
Mita MM, Ochoa L, Rowinsky EK, Kuhn J, Schwartz G, Hammond LA, Patnaik A, Yeh IT, Izbicka E, Berg K. A phase I, pharmacokinetic and biologic correlative study of oblimersen sodium (Genasense, G3139) and irinotecan in patients with metastatic colorectal cancer. Ann Oncol. 2006;17
:313-321. [PubMed] [DOI]
Mackay H, Hedley D, Major P, Townsley C, Mackenzie M, Vincent M, Degendorfer P, Tsao MS, Nicklee T, Birle D. A phase II trial with pharmacodynamic endpoints of the proteasome inhibitor bortezomib in patients with metastatic colorectal cancer. Clin Cancer Res. 2005;11
:5526-5533. [PubMed] [DOI]
Lacombe DA, Caponigro F, Anthoney A, bauer J, Govaerts A, Milano A, Marreaud S, Twelves C. A phase I study of bortezomib in combination with FOLFOX4 in patients with advanced colorectal cancer: EORTC 16029. Proc Am Soc Clin Oncol. 2007;186s:4090 (Abstract).
Gasparini G, Longo R, Sarmiento R, Morabito A. Inhibitors of cyclo-oxygenase 2: a new class of anticancer agents?. Lancet Oncol. 2003;4
:605-615. [PubMed] [DOI]
Morabito A, Gattuso D, Sarmiento R. Rofecoxib associated with an antiangiogenic schedule of weekly irinotecan and infusional 5-fluorouracil as second line treatment of patients with metastatic colorectal cancer: Results of a dose-finding study. Proc Am Soc Clin Oncol. 2003;22:326 (Abstract).
Fuchs C, Marshall J, Mitchell E, Wieirzbicki R, Ganju V, Jeffery M, Schultz J, Richards DA, Soufi-Mahjoubi R, barrueco J. Updated results of BICC-C study comparing first line irinotecan/fluoropyrimidine combinations with or without celecoxib in CRC: Updated efficacy data. Proc Am Soc Clin Oncol. 2007;170s:4027 (Abstract).
Struhl K. Histone acetylation and transcriptional regulatory mechanisms. Genes Dev. 1998;12
:599-606. [PubMed] [DOI]
Fakih MG, Pendyala L, Toth K, Creaven P, Soehnlein N, Litwin A, Trump D. A phase I Study of vorinostat in combination with FOLFOX in patients with advanced colorectal cancer. J Clin Oncol. 2006;24:3592 (Abstract).
Klupp J, Langrehr JM, Junge G, Neuhaus P. Inhibitors of mammalian target of rapamycin. Drugs Fut. 2001;26:1179.
Skotnicki JS, Leone CL, Smith AL, Palmer Y, Yu K, Discafani CM, Gibbons JJ, Frost P, Abou-Gharbia MA. Design, synthesis and biological evaluation of C-42 hydrox-yesters of rapamycin: The identification of CCI-779. AACR-NCI-EORTC Int Conf Mol Targets Cancer Ther. 2001;477 (Abstract).
Punt CJA, Bruntsch U, Hanauske AR, Weigang-Köhler, K. Peters M, Thielert C, Frisch J. A phase I study of escalating doses of CCI-779 in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors. Eur J Cancer. 2001;37:53 (Abstract).