The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and ...increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken.
Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series.
The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio HR, 0.796; P = .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P = .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P < .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis.
The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.
Insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase that regulates cell growth and proliferation. Upregulation of the IGF1R pathway constitutes a common paradigm shared with ...other receptor tyrosine kinases such as EGFR, HER2, and MET in different cancer types, including colon cancer. The main IGF1R signaling pathways are PI3K-AKT and MAPK-MEK. However, different processes, such as post-translational modification (SUMOylation), epithelial-to-mesenchymal transition (EMT), and microenvironment complexity, can also contribute to intrinsic and acquired resistance. Here, we discuss new strategies for adequate drug development in metastatic colorectal cancer patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Colorectal cancer (CRC) is the second largest cause of cancer mortality in Western countries, mostly due to metastasis. Understanding the natural history and prognostic factors in patients with ...metastatic CRC (mCRC) is essential for the optimal design of clinical trials. The main prognostic factors currently used in clinical practice are related to tumor behavior (e.g., white blood counts, levels of lactate dehydrogenase, levels of alkaline phosphatase) disease extension (e.g., presence of extrahepatic spread, number of organs affected) and general functional status (e.g., performance status as defined by the Eastern Cooperative Oncology Group). However, these parameters are not always sufficient to establish appropriate therapeutic strategies. First-line therapy in mCRC combines conventional chemotherapy (CHT) (e.g., FOLFOX, FOLFIRI, CAPOX) with a number of agents targeted to specific signaling pathways (TA) (e.g., panitumumab and cetuximab for cases KRAS/NRAS WT, and bevacizumab). Although the response rate to this combination regime exceeds 50%, progression of the disease is almost universal and only less than 10% of patients are free of disease at 2 years. Current clinical trials with second and third line therapy include new TA, such as tyrosin-kinase receptors inhibitors (MET, HER2, IGF-1R), inhibitors of BRAF, MEK, PI3K, AKT, mTORC, NOTCH and JAK1/JAK2, immunotherapy modulators and check point inhibitors (anti-PD-L1 and anti- PD1). Despite the identification of multiple prognostic and predictive biomarkers and signatures, it is still unclear how expression of many of these biomarkers is modulated by CHT and/or TA, thus potentially affecting response to treatment. In this review we analyzed how certain biomarkers in tumor cells and microenvironment influence the response to new TA and immune-therapies strategies in mCRC pre-treated patients.
The current standard-of-care for metastatic colorectal cancer (mCRC) includes chemotherapy and anti-angiogenic or anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, even though the ...addition of anti-angiogenic agents to backbone chemotherapy provides little benefit for overall survival. Since the approval of anti-angiogenic monoclonal antibodies bevacizumab and aflibercept, for the management of mCRC over a decade ago, extensive efforts have been devoted to discovering predictive factors of the anti-angiogenic response, unsuccessfully. Recent evidence has suggested a potential correlation between angiogenesis and immune phenotypes associated with colorectal cancer. Here, we review evidence of interactions between tumor angiogenesis, the immune microenvironment, and metabolic reprogramming. More specifically, we will highlight such interactions as inferred from our novel immune-metabolic (IM) signature, which groups mCRC into three distinct clusters, namely inflamed-stromal-dependent (IM Cluster 1), inflamed-non stromal-dependent (IM Cluster 2), and non-inflamed or cold (IM Cluster 3), and discuss the merits of the IM classification as a guide to new immune-metabolic combinatorial therapeutic strategies in mCRC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Panitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR). We compared the activity of panitumumab plus best supportive care (BSC) to that of BSC ...alone in patients with metastatic colorectal cancer who had progressed after standard chemotherapy.
We randomly assigned 463 patients with 1% or more EGFR tumor cell membrane staining, measurable disease, and radiologic documentation of disease progression during or within 6 months of most recent chemotherapy to panitumumab 6 mg/kg every 2 weeks plus BSC (n = 231) or BSC alone (n = 232). Tumor assessments by blinded central review were scheduled from week 8 until disease progression. The primary end point was progression-free survival (PFS). Secondary end points included objective response, overall survival (OS), and safety. BSC patients who progressed could receive panitumumab in a cross-over study.
Panitumumab significantly prolonged PFS (hazard ratio HR, 0.54; 95% CI, 0.44 to 0.66, P < .0001). Median PFS time was 8 weeks (95% CI, 7.9 to 8.4) for panitumumab and 7.3 weeks (95% CI, 7.1 to 7.7) for BSC. Mean (standard error) PFS time was 13.8 (0.8) weeks for panitumumab and 8.5 (0.5) weeks for BSC. Objective response rates also favored panitumumab over BSC; after a 12-month minimum follow-up, response rates were 10% for panitumumab and 0% for BSC (P < .0001). No difference was observed in OS (HR, 1.00; 95% CI, 0.82 to 1.22), which was confounded by similar activity of panitumumab after 76% of BSC patients entered the cross-over study. Panitumumab was well tolerated. Skin toxicities, hypomagnesaemia, and diarrhea were the most common toxicities observed. No patients had grade 3/4 infusion reactions.
Panitumumab significantly improved PFS with manageable toxicity in patients with chemorefractory colorectal cancer.
PURPOSE The optimal therapeutic sequence of the adjuvant chemotherapy component of preoperative chemoradiotherapy (CRT) for patients with locally advanced rectal cancer is controversial. Induction ...chemotherapy before preoperative CRT may be associated with better efficacy and compliance. PATIENTS AND METHODS A total of 108 patients with locally advanced rectal cancer were randomly assigned to arm A-preoperative CRT with capecitabine, oxaliplatin, and concurrent radiation followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)-or arm B-induction CAPOX followed by CRT and surgery. The primary end point was pathologic complete response rate (pCR). Results On an intention-to-treat basis, the pCR for arms A and B were 13.5% (95% CI, 5.6% to 25.8%) and 14.3% (95% CI, 6.4% to 26.2%), respectively. There were no statistically significant differences in other end points, including downstaging, tumor regression, and R0 resection. Overall, chemotherapy treatment exposure was higher in arm B than in arm A for both oxaliplatin (P < .0001) and capecitabine (P < .0001). During CRT, grades 3 to 4 adverse events were similar in both arms but were significantly higher in arm A during postoperative adjuvant CT than with induction CT in arm B. There were three deaths in each arm during the treatment period. CONCLUSION Compared with postoperative adjuvant CAPOX, induction CAPOX before CRT had similar pCR and complete resection rates. It did achieve more favorable compliance and toxicity profiles. On the basis of these findings, a phase III study to definitively test the induction strategy is warranted.
To determine whether adding cetuximab to irinotecan prolongs survival in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine and oxaliplatin.
This multicenter, ...open-label, phase III study randomly assigned 1,298 patients with epidermal growth factor receptor-expressing mCRC who had experienced first-line fluoropyrimidine and oxaliplatin treatment failure to cetuximab (400 mg/m(2) day 1 followed by 250 mg/m(2) weekly) plus irinotecan (350 mg/m(2) every 3 weeks) or irinotecan alone. Primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR), and quality of life (QOL).
Median OS was comparable between treatments: 10.7 months (95% CI, 9.6 to 11.3) with cetuximab/irinotecan and 10.0 months (95% CI, 9.1 to 11.3) with irinotecan alone (hazard ratio HR, 0.975; 95% CI, 0.854 to 1.114; P = .71). This lack of difference may have been due to post-trial therapy: 46.9% of patients assigned to irinotecan eventually received cetuximab (87.2% of those who did, received it with irinotecan). Cetuximab added to irinotecan significantly improved PFS (median, 4.0 v 2.6 months; HR, 0.692; 95% CI, 0.617 to 0.776; P <or= .0001) and RR (16.4% v 4.2%; P < .0001), and resulted in significantly better scores in the QOL analysis of global health status (P = .047). Cetuximab did not exacerbate toxicity, except for acneform rash, diarrhea, hypomagnesemia, and associated electrolyte imbalances. Neutropenia was the most common severe toxicity across treatment arms.
Cetuximab and irinotecan improved PFS and RR, and resulted in better QOL versus irinotecan alone. OS was similar between study groups, possibly influenced by the large number of patients in the irinotecan arm who received cetuximab and irinotecan poststudy.
Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. ...Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving.
We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation.
Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R.
Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To assess the activity and toxicity of the combination of gemcitabine plus dacarbazine (DTIC) in patients with advanced soft tissue sarcoma (STS) in a randomized, multicenter, phase II study using ...DTIC alone as a control arm.
Patients with previously treated advanced STS were randomly assigned to receive either fixed-dose rate gemcitabine (10 mg/m2/min) at 1800 mg/m2 followed by DTIC at 500 mg/m2 every 2 weeks, or DTIC alone at 1200 mg/m2 every 3 weeks. The primary end point of the study was progression-free rate (PFR) at 3 months.
From November 2005 to September 2008, 113 patients were included. PFR at 3 months was 56% for gemcitabine plus DTIC versus 37% for DTIC alone (P = .001). Median progression-free survival was 4.2 months versus 2 months (hazard ratio HR, 0.58; 95% CI, 0.39 to 0.86; P = .005), and median overall survival was 16.8 months versus 8.2 months (HR, 0.56; 95% CI, 0.36 to 0.90; P = .014); both favored the arm of gemcitabine plus DTIC. Gemcitabine plus DTIC was also associated with a higher objective response or higher stable disease rate than was DTIC alone (49% v 25%; P = .009). Severe toxicities were uncommon, and treatment discontinuation for toxicity was rare. Granulocytopenia was the more common serious adverse event, but febrile neutropenia was uncommon. Asthenia, emesis, and stomatitis were the most frequent nonhematologic effects.
The combination of gemcitabine and DTIC is active and well tolerated in patients with STS, providing in this phase II randomized trial superior progression-free survival and overall survival than DTIC alone. This regimen constitutes a valuable therapeutic alternative for these patients.
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