Real world observation of fruquintinib in treatment of metastatic colorectal cancer

FOLFIRINOX for the treatment of colorectal cancer: latest evidence from clinical trials

The 2010 American Society of Clinical Oncology Gastrointestinal Cancers Symposium

Panitumumab (Vectibix) is a recombinant, fully human, IgG2 anti-epidermal growth factor receptor (EGFR) monoclonal antibody. This spotlight reviews the clinical efficacy of intravenous panitumumab in combination with chemotherapy in the first- and second-line treatment of metastatic colorectal cancer and as monotherapy in chemotherapy-refractory metastatic colorectal cancer, as well as summarizing its pharmacologic properties and tolerability. Panitumumab is indicated for use in patients with wild-type rather than mutant KRAS tumors. The efficacy of intravenous panitumumab 6 mg/kg administered every 2 weeks was examined in randomized, open-label, multicenter, phase III trials in patients with metastatic colorectal cancer. When administered as first- or second-line treatment in combination with chemotherapy, panitumumab plus chemotherapy prolonged progression-free survival to a significantly greater extent than chemotherapy alone in patients with wild-type KRAS tumors; no significant between-group difference in overall survival was seen in the second-line treatment trial. In patients with mutant KRAS tumors, progression-free survival was significantly shorter with panitumumab plus oxaliplatin-based chemotherapy (FOLFOX4) than with FOLFOX4 alone in the first-line treatment trial, with no significant difference between patients receiving panitumumab plus irinotecan-based chemotherapy (FOLFIRI) and those receiving FOLFIRI alone in the second-line treatment trial. In chemotherapy-refractory patients with metastatic colorectal cancer, panitumumab monotherapy plus best supportive care prolonged progression-free survival to a significantly greater extent than best supportive care alone in both the overall population and in patients with wild-type KRAS tumors, but not in those with mutant KRAS tumors. Intravenous panitumumab has an acceptable tolerability profile when administered as monotherapy or in combination with chemotherapy. It is associated with the skin-related toxicities characteristic of EGFR inhibitors and appears to have a low risk of immunogenicity. In conclusion, in patients with wild-type KRAS tumors, panitumumab is a useful option in combination with chemotherapy for the first- and second-line treatment of metastatic colorectal cancer or as monotherapy for the treatment of chemotherapy-refractory metastatic colorectal cancer.

Panitumumab (Vectibix(R)) is a recombinant, fully human, IgG2 anti-epidermal growth factor receptor (EGFR) monoclonal antibody. This article reviews the clinical efficacy of intravenous panitumumab in combination with chemotherapy in the first- and second-line treatment of metastatic colorectal cancer and as monotherapy in chemotherapy-refractory metastatic colorectal cancer, as well as summarizing its pharmacological properties and tolerability. Panitumumab is indicated for use in patients with wild-type rather than mutant KRAS tumours. The efficacy of intravenous panitumumab 6 mg/kg administered every 2 weeks was examined in randomized, open-label, multicentre, phase III trials in patients with metastatic colorectal cancer. When administered as first- or second-line treatment in combination with chemotherapy, panitumumab plus chemotherapy prolonged progression-free survival to a significantly greater extent than chemotherapy alone in patients with wild-type KRAS tumours; no significant between-group difference in overall survival was seen in the second-line treatment trial. In patients with mutant KRAS tumours, progression-free survival was significantly shorter with panitumumab plus oxaliplatin-based chemotherapy than with oxaliplatin-based chemotherapy alone in the first-line treatment trial, with no significant difference between patients receiving panitumumab plus irinotecan-based chemotherapy (FOLFIRI) and those receiving FOLFIRI alone in the second-line treatment trial. In chemotherapy-refractory patients with metastatic colorectal cancer, panitumumab monotherapy plus best supportive care prolonged progression-free survival to a significantly greater extent than best supportive care alone in both the overall population and in patients with wild-type KRAS tumours, but not in those with mutant KRAS tumours; there was no significant between-group difference in overall survival. Panitumumab has an acceptable tolerability profile when administered as monotherapy or in combination with chemotherapy. It is associated with the skin-related toxicities characteristic of EGFR inhibitors and appears to have a low risk of immunogenicity. In conclusion, in patients with wild-type KRAS tumours, panitumumab is a useful option in combination with chemotherapy for the first- and second-line treatment of metastatic colorectal cancer or as monotherapy for the treatment of chemotherapy-refractory metastatic colorectal cancer.

Targeting the epidermal growth factor receptor (EGFR), an important component in carcinogenesis, is an attractive therapeutic option for selective anticancer therapy. Several EGFR inhibitors, mostly monoclonal antibodies and tyrosine kinase inhibitors are under investigation in the treatment of colorectal cancer. Although there has been some progress in the treatment of colorectal cancer with combination chemotherapy, the repertoire of active agents is still limited. More recently the anti-EGFR drugs cetuximab and panitumumab have made an impact in the treatment of metastatic disease but with variable response rates. Although the appearance of a skin rash confers a higher response rate, immunohistochemical staining of EGFR at baseline does not. Several studies have now focused on identifying predictive biological markers at a molecular level. Exciting data has demonstrated KRAS mutation status to be the first predictive marker of response to anti-EGFR monoclonal antibodies (mAbs) and has led a new era in the development of targeted therapies in colorectal malignant disease. The aim of this review is to evaluate the impact of anti-EGFR therapies in the treatment of metastatic colorectal cancer; and to present the current data on predictive markers including KRAS status, PTEN expression and germinal gene polymorphisms. The relevant patents are discussed.

TNK2 as a key drug target for the treatment of metastatic colorectal cancer

Objective: To investigate and evaluate the mastery and recognition degree of Chinese clinicians on the 2015 edition of the Chinese Criteria for Diagnosis and Treatment of Colorectal Cancer in order to provide useful suggestions for updating and formulating diagnosis and treatment standards. Methods: Simple random sampling was used to conduct a questionnaire survey in 1500 colorectal cancer-related doctors in general hospitals and cancer hospitals from 115 cities in China. The study included the following guidelines: (1) Chinese Criteria for Diagnosis and Treatment of Colorectal Cancer (2015 edition); (2) Chinese Society of Clinical Oncology Colorectal Cancer Guidelines 2017 (CSCO 2017); (3) National Comprehensive Cancer Network (NCCN) Colon Cancer Guidelines 2017.v1; (4) European Society for Medical Oncology (ESMO) Rectal Cancer Guidelines. The survey was carried out in 2017 and 2019 respectively. In the first phase, the questionnaire included 4 dimensions (guideline cognition, detection and diagnosis, pathology and staging, treatment), and 1500 questionnaires were distributed. In the second phase, the questionnaire contained 3 dimensions (basic information, current treatment status of metastatic colorectal cancer, academic expectations), and 350 questionnaires were distributed. Case (%) was used to indicate the categorical variable data, and chi-square test was used for comparison between groups. P<0.05 indicated that the difference was statistically significant. Results: In the first phase, 1472 valid questionnaires were collected, and the questionnaire efficiency was 98.1% (1472/1500). In the second phase, 337 valid questionnaires were collected, and the questionnaire efficiency was 96.3% (337/350). In the survey of the first phase, doctors had some knowledge and compliance with various guidelines, but the most familiar one was the NCCN guidelines, accounting for 90.7% (1335/1472). In the dimension of detection and diagnosis, the overall correct rate was 64.1% (944/1472). The correct rate of doctors in the first-tier cities was 55.6% (148/266), which was lower than 59.1% (182/308) and 72.9% (369/506) in the second- and the third-tier cities, and the difference was statistically significant (χ(2)=42.140, P<0.001). More than 60.0% (883/1472) of doctors was clear about the specification requirements of the staging evaluation and pathological examination. However, in terms of rectal cancer local staging evaluation, the ratio of doctors who would choose rectal MRI in the first-tier cities was lower than that of those in other tier cities [51.5% (137/266) vs. 65.6% (202/308), 63.2% (320/506) and 61.2% (240/392)], and the difference was statistically significant (χ(2)=41.886, P<0.001). In the dimensions of staging evaluation and pathological examination, there were no statistically significant differences in cognition between general and specialist hospitals (P>0.05). In the treatment dimension, 79.8% (1175/1472) of doctors considered the preoperative treatment as a necessary option for patients with middle and low locally advanced (over cT3) rectal cancer. 46.3% (681/1472) of doctors, including 60.3% (433/718) of surgeons, and 31.4% (225/716) of physicians, had a vague idea that irinotecan could not be used for postoperative adjuvant treatment of colorectal cancer. In the survey of the second phase, 93.8% (316/337) of doctors approved potentially curative systemic (conversion) therapy, and 95.3% (321/337) of doctors followed the clinical guidelines in the treatment of metastatic colorectal cancer. Regarding academic expectations, the clinician's concern for surgery was more practical, and 79.2% (267/337) of doctors wanted to know the best options of conversion therapy for potentially curable metastatic colorectal cancer. In contrast, the clinician's concern for internal medicine was more exploratory, and 80.1% (270/337) of doctors focused on selecting targeted drugs and the sequence of treatment. Conclusions: This investigation has a preliminary understanding of the diagnosis and treatment of colorectal cancer in China. (1) There are many guidelines for doctors' reference, but doctors' understanding of domestic guidelines is not as good as NCCN guidelines. (2) The degree of understanding of the guidelines varies significantly among doctors in different cities. (3) The promotion of guidelines should focus on basic concepts and theories. (4) The detection, diagnosis, and treatment of colorectal cancer should be better trained and promoted. (5) The concept of conversion therapy for metastatic colorectal cancer is highly recognized.

Colorectal cancer is among the most common malignancies in developed countries. Screening can reduce mortality significantly, although the most appropriate method is still under debate. Observational studies have revealed that lifestyle measures may also be beneficial for prevention of colorectal cancer. Surgery is still the most effective treatment modality for colorectal cancer. The survival benefits of chemotherapy are only modest. For nearly 5 decades, 5-fluorouracil (5-FU) has been the main cytotoxic agent for treatment of colorectal cancer. In the last decade, the new cytotoxic agents raltitrexed, irinotecan and oxaliplatin have been introduced, next to the oral 5-FU analogues capecitabine and tegafur in combination with uracil (UFT). Moreover, the immunotherapeutics bevacizumab and cetuximab have become approved for treatment of metastatic colorectal cancer. The economic implications of colorectal cancer treatment are substantial. The costs of treatment are mainly attributable to the early and terminal stage of the disease (i.e. surgery, hospitalisation, chemo- and immunotherapy and supportive care). The introduction of new chemo- and immunotherapeutics has caused a continuing increase of treatment expenditures. Therefore, comparative costs and cost effectiveness are important for assessing the value of new treatment regimens. The available study results suggest that addition of irinotecan or oxaliplatin to 5-FU/folinic acid dosage regimens is cost effective. Also, capecitabine is calculated to be cost effective when compared with 5-FU/folinic acid. For UFT, no comparative studies of cost effectiveness were found. Since raltitrexed and 5-FU/folinic acid have shown equal efficacy in terms of survival, cost-effectiveness analysis is considered not to be applicable and cost-minimisation analysis may be sufficient. At present, pharmacoeconomic analyses of combination treatment with the immunotherapeutics bevacizumab or cetuximab are not available, except for recent cost-effectiveness considerations by the UK National Institute for Health and Clinical Excellence with negative recommendations for both agents in the treatment of metastatic colorectal cancer. Given the high treatment costs, substantial toxicity and relatively limited efficacy of the fast changing chemo- and immunotherapeutic combinations for colorectal cancer, examination of cost-effectiveness studies should be conducted on a routine basis along with determination of clinical benefits.

Differences in Efficacy and Safety Between Capecitabine and Infusional 5-Fluorouracil When Combined With Irinotecan for the Treatment of Metastatic Colorectal Cancer

Objectives: Bevacizumab is a monoclonal antibody that directly inhibits vascular endothelial growth factor, a key regulator of angiogenesis. Bevacizumab significantly improves progression-free and/or overall survival in metastatic colorectal cancer in combination with standard chemotherapy. This review describes the evolution of irinotecan-based regimens for metastatic colorectal cancer and evaluates the addition of bevacizumab to these regimens. Methods: Literature searches from large publication databases (PubMed, ASCO, ASCO GI, ESMO) were performed to capture key data relevant to bevacizumab, irinotecan, and the treatment of colorectal cancer. Results: Data from numerous large, multinational studies support the addition of bevacizumab to irinotecan-containing chemotherapy regimens for further improvement in patient outcomes. In a randomized, placebo-controlled trial, addition of bevacizumab to irinotecan significantly improved progression-free survival, overall survival and response rate in patients with metastatic colorectal cancer, and these results are supported by a number of other clinical trials and observational studies. Furthermore, the addition of bevacizumab to irinotecan improves outcomes regardless of K-ras mutational status. Bevacizumab has a well-established safety profile and the toxicities associated with its use are usually mild in severity and easily manageable. Conclusions: Addition of bevacizumab to irinotecan-containing regimens is an effective therapy option for the treatment of metastatic colorectal cancer.

Cetuximab and panitumumab, monoclonal antibodies (mAbs) against the epidermal growth factor receptor (EGFR), have demonstrated efficacy in the treatment of advanced colorectal cancer as single agents and in combination with conventional chemotherapy. Since the US Food and Drug Administration approval of cetuximab in 2004 and panitumumab in 2006, EGFR mAbs have become standard components of treatment algorithms for this disease. The discovery of KRAS mutations as a negative predictive marker for this class of agents in colorectal cancer has rapidly been integrated into clinical practice and has opened the door for a new era in translational and clinical research. In KRAS wild-type colorectal cancer, EGFR mAbs have documented activity in various therapeutic settings and have been successfully combined with different chemotherapy backbones in randomized trials, including irinotecanand oxaliplatin-based regimens. Until recently, the body of evidence from randomized trials suggested that (1) EGFR mAbs as single agents or in combination with chemotherapy showed activity only in KRAS wild-type colorectal cancer; (2) the observed improvement of progression-free survival (PFS) was independent of the line of therapy in which the EGFR mAb was used; (3) the increased response rate with EGFR mAbs in patients with KRAS wild-type tumors was observed even in trials that did not meet their time-related end points of PFS or overall survival (OS); and (4) cetuximab and panitumumab had interchangeable activity. Several questions remained, however, despite extensive clinical experience with EGFR antibodies. The negative data of the large COIN (Continuous Chemotherapy Plus Cetuximab, or Intermittent Chemotherapy With Standard Continuous Palliative Combination Chemotherapy With Oxaliplatin and a Fluoropyrimidine in First-Line Treatment of Metastatic Colorectal Cancer) trial, which investigated cetuximab added to an oxaliplatin-based chemotherapy backbone, seemed to contrast with the positive data of the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial, which used an irinotecan-based regimen. These findings suggested that there may be a preferred chemotherapy partner for EGFR antibodies. In addition, the randomized phase II trial, OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer), demonstrated that the use of cetuximab in combination with oxaliplatin-based treatment for KRAS-mutated colorectal cancer appeared to have a detrimental effect. Eventually, the well-conducted first-line phase III PRIME (Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) trial, which investigated the addition of panitumumab to infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX), appeared to clarify the situation by demonstrating that in KRAS wild-type cancers, an EGFR mAb can indeed add efficacy to a FOLFOX backbone. In addition, PRIME also confirmed that, in KRAS-mutated colorectal cancers, the use of an EGFR mAb added to chemotherapy can decrease efficacy. Although this detrimental effect in KRAS-mutated cancers was initially thought to be linked only to an oxaliplatin-based chemotherapy backbone, recently presented data from the second-line phase III trial PICCOLO (Panitumumab, Irinotecan & Ciclosporin in Colorectal Cancer Therapy; irinotecan with or without panitumumab) demonstrated a similar negative effect on PFS and response rate in this group of patients. In the adjuvant setting, the addition of cetuximab to FOLFOX did not improve outcomes in stage III colon cancer, not even in patients with KRASwild-typetumors. InKRAS-mutatedstageIIIcancers, cetuximab was associated with inferior outcome, mirroring the detrimental effect observed in some trials in the metastatic setting. The most recent National Comprehensive Cancer Network guidelines suggest that cetuximab should be not combined with oxaliplatin. The guidelines, however, somewhat inconsistently do allow the use of panitumumab in combination with FOLFOX, on the basis of results from the PRIME trial. The NORDIC (5-Fluorouracil/Folinate/Oxaliplatin [Eloxatin] [FLOX Regimen] Given Continuously or Intermittently, in Combination With Cetuximab [Erbitux] in First-Line Treatment of Metastatic Colorectal Cancer) trial published in this issue of Journal of Clinical Oncology now adds another layer of confusion to the already complex and somewhat inconsistent results on the use of EGFR mAbs in colorectal cancer. In this first-line phase III study, cetuximab was added to bolus fluorouracil (FU)/leucovorin plus oxaliplatin (FLOX), a combination regimen commonly used in Scandinavia, but not in other parts of the world. The primary end point of the trial was PFS, with secondary end points of OS, response rate, R0-resection rate of metastases, and safety. During the conduct of the trial, KRAS mutation emerged as a negative predictive marker for EGFR mAbs, and a prospective KRAS status–based outcomes analysis was integrated into the trial, but no adjustment of the sample size was performed. In the end, the number of patients in the two main comparison arms, FLOX with JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 15 MAY 2

Despite being one of the most frequently diagnosed cancers worldwide, prognosis of metastatic colorectal cancer (CRC) was poor. Development and introduction of biologic agents in treatment of patients with metastatic CRC have brought improved outcomes. Monoclonal antibodies directing epidermal growth factor receptors and vascular endothelial growth factor are main biologic agents currently used in treatment of metastatic CRC. Encouraged by results from many clinical trials demonstrating efficacy of those monoclonal antibodies, the combination therapy with those targeted agents and conventional chemotherapeutic agents has been established as the standard therapy for patients with metastatic CRC. However, emergency of resistance to those target agents has limited the efficacy of treatment, and strategies to overcome the resistance are now being investigated by newly developed biological techniques clarifying how to acquire resistance. Here, we introduce mechanisms of action of the biologic agents currently used for treatment of metastatic CRC and several landmark historical clinical studies which have changed the main stream of treatment. The mechanism of resistance to those agents, one of serious problems in treatment metastatic CRC, and ongoing clinical trials to overcome the limitations and improve treatment outcomes will also be presented in this review.

Treatment of metastatic colorectal disease has evolved over the last decade. Two epidermal growth factor receptor (EGFR) monoclonal antibodies--cetuximab and panitumumab--have been developed in an effort to provide yet another therapeutic option. The EGFR is a transmembrane glycoprotein, expressed constitutively throughout the body and found on many epithelial tissues. The monoclonal antibodies bind to and inhibit the activation of the receptor in the body. This inhibition prevents tumor cell growth, angiogenesis, invasion, and metastasis, and induces apoptosis. Cetuximab and panitumumab exhibit nonlinear pharmacokinetics. Both monoclonal antibodies are approved for the treatment of refractory metastatic colorectal cancer. Cetuximab in combination with irinotecan has significantly better response rates and progression-free survival compared with those of cetuximab or irinotecan alone. Cetuximab and panitumumab as monotherapy have shown significantly better response rates and progression-free survival compared with best supportive care in patients refractory to irinotecan and oxaliplatin. In the Cetuximab Combined with Irinotecan in First Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial, treatment-naïve patients received cetuximab in combination with the chemotherapy regimen infusional leucovorin, fluorouracil, and irinotecan (FOLFIRI) or FOLFIRI alone; the difference in progression-free survival was statistically significant but suggested only a modest benefit over FOLFIRI alone (8.9 vs 8 mo, p=0.036). Results of a preplanned analysis of the first 231 events in the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) trial favored the control group (chemotherapy regimen with folinic acid [leucovorin], fluorouracil, and oxaliplatin [FOLFOX] plus bevacizumab) instead of the control group plus panitumumab. For clinical consideration, many trials have shown that the intensity or absence of EGFR expression is not a clinically significant predictor of outcomes. Development and intensity of a rash are suggested to be a positive predictor of outcomes in patients. The most common adverse events of EGFR monoclonal antibody therapy are rash, diarrhea, and hypomagnesemia. Other serious but not common adverse events include hypersensitivity reactions and pulmonary toxicity. The availability of EGFR monoclonal antibodies has provided another weapon in the arsenal to treat refractory metastatic colorectal cancer. They have shown safety and efficacy in combination with other chemotherapy regimens and as monotherapy; however, their use as metastatic colorectal cancer therapy needs to be further explored.

For more than three decades, the therapeutic options for patients with advanced colorectal cancer have almost exclusively been based on fluoropyrimidines. With the recognition that topoisomerase-I (TOP-I) is an important therapeutic target in cancer therapy, irinotecan, a semisynthetic TOP-I-interactive camptothecin derivative, has been clinically established in the treatment of colorectal cancer. Irinotecan was investigated as second-line chemotherapy after prior treatment with fluorouracil (FU)-based regimens in two large randomized phase III trials comparing irinotecan with either best supportive care or an infusional FU/leucovorin (LV) regimen. The outcomes of these trials established irinotecan as the standard therapy in the second-line treatment of colorectal cancer. The therapeutic value of irinotecan in the first-line treatment of metastatic colorectal cancer was investigated in two large randomized phase III trials comparing the combination of irinotecan and FU/LV with FU/LV alone. Both trials demonstrated significant superior efficacy for the combination of irinotecan and FU/LV in terms of response rate, median time to disease progression, and median survival time. Consequently, the combination of irinotecan and FU/LV has been approved as first-line chemotherapy for patients with metastatic colorectal cancer and constitutes the reference therapy against which other treatment options must be tested in the future. In this review, the clinical rationale and update of the present clinical status of irinotecan in the treatment of colorectal cancer and future prospects of irinotecan-based combinations are discussed.

Modern chemotherapy regimens, combining bolus or infused schedules of 5‐fluorouracil (5‐FU) with irinotecan or oxaliplatin, have significantly improved the treatment outcomes of patients with metastatic colorectal cancer (CRC). The addition of novel targeted agents to chemotherapy has the potential to increase the median survival of patients with metastatic CRC beyond 2 years. Bevacizumab, a monoclonal antibody (mAb) to vascular endothelial growth factor, has an established role in first‐line treatment in combination with either 5‐FU/leucovorin or irinotecan/5‐FU/leucovorin regimens, while cetuximab, a mAb to epidermal growth factor receptor, in combination with irinotecan is more suitable for the treatment of refractory metastatic CRC. The use of bevacizumab in later stages of the disease and cetuximab in chemotherapy‐naive patients as well as concurrent treatment with both agents is still under investigation. The landmark studies leading to the approval of these agents in the treatment of metastatic CRC as well as associated toxicity profiles and detailed treatment recommendations are discussed in this review.