Robert Lim

Bio: Robert Lim is an academic researcher from National University of Singapore. The author has contributed to research in topics: Cetuximab & FOLFIRI. The author has an hindex of 3, co-authored 6 publications receiving 3337 citations.

Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.

Abstract: Background We investigated the efficacy of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer and sought associations between the mutation status of the KRAS gene in tumors and clinical response to cetuximab. Methods We randomly assigned patients with epidermal growth factor receptor–positive colorectal cancer with unresectable metastases to receive FOLFIRI either alone or in combination with cetuximab. The primary end point was progression-free survival. Results A total of 599 patients received cetuximab plus FOLFIRI, and 599 received FOLFIRI alone. The hazard ratio for progression-free survival in the cetuximab–FOLFIRI group as compared with the FOLFIRI group was 0.85 (95% confidence interval [CI], 0.72 to 0.99; P=0.048). There was no significant difference in the overall survival between the two treatment groups (hazard ratio, 0.93; 95% CI, 0.81 to 1.07; P=0.31). There was a significant interaction between treatment group and KRAS ...

Present Status and Perspectives of Colorectal Cancer in Asia: Colorectal Cancer Working Group Report in 30th Asia-Pacific Cancer Conference

Abstract: Objective: To reveal the present status and future directions of colorectal cancer in Asia. Methods: The Working Group consisted of oncologists from six Asian countries (Japan, Korea, Hong Kong, China, Taiwan, Singapore and Philippines) discussed colorectal cancer in the 30th Asia-Pacific Cancer Conference and made a consensus report. Results: The incidence of colorectal cancer has been increasing rapidly in recent decades, and mortality has also increased except in Japan and Singapore. Colorectal screening with fecal occult blood tests is a national policy in Taiwan, Japan and Korea. Total colonoscopy is the most common examination for diagnosing colorectal cancers and neoplasms. However, there are differences in the macroscopic classification used. Laparoscopic surgery for colon cancer is extensively used, although the indication varies. Adequate lymph node harvesting of more than 12 nodes is performed in most countries. Neoadjuvant chemoradiation therapy is not routinely done for T2 or T3 rectal cancer. Total mesorectal excision is the standard surgery for rectal cancer. Survival rate data are unavailable for many countries and should be compiled in all. The differences in the health-care delivery systems affect the treatment choices for unresectable colorectal cancer. Infusional 5-FU plus leucovorin plus oxaliplatin (FOLFOX) is the most popular first-line regimen. Cetuximab is mainly used as a second- or third-line regimen with reference to k-ras mutation. Oxaliplatin-based adjuvant chemotherapy is commonly used for stage III disease, whereas the clinical practice for stage II disease varies. Conclusions: Further clinical cooperation is needed to optimize the management of colorectal cancer in Asia.

Phase II APEC trial: The impact of primary tumor side on outcomes of first-line cetuximab plus FOLFOX or FOLFIRI in patients with RAS wild-type metastatic colorectal cancer.

Abstract: Aim The open-label, nonrandomized, phase II APEC study enrolled 167 patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC) to investigate the safety and efficacy of first-line, every-2-weeks cetuximab plus investigator's choice of FOLFIRI or FOLFOX in this patient population. Methods A subgroup analysis of the APEC study population by primary tumor location was performed. Results A total of 130 patients (81.8%) had left-sided and 29 (18.2%) had right-sided mCRC. Median progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) were 14.0 months, 30.6 months and 68.5% for patients with left-sided tumors and 8.9 months, 24.6 months and 51.7% for patients with right-sided mCRC, concurring with pivotal phase III trial results. In patients with right-sided tumors, median PFS was 15.4 months vs 8.3 months with cetuximab plus FOLFIRI vs cetuximab plus FOLFOX, respectively; median OS was 32.1 months vs 21.8 months with cetuximab plus FOLFIRI vs cetuximab plus FOLFOX, respectively. Conclusion The APEC tumor-location subgroup analysis results were largely consistent with available literature regarding the equivalent efficacy of cetuximab plus FOLFIRI/FOLFOX in patients with left-sided RAS wt mCRC. A trend toward improved efficacy with cetuximab plus FOLFIRI compared with cetuximab plus FOLFOX was observed in patients with right-sided tumors; however, a direct comparison between groups cannot be made due to the nonrandomized study design. Nevertheless, the similar ORR observed with either chemotherapy backbone in patients with right-sided RAS wt mCRC suggests a potential role for both regimens in this patient population when cytoreduction is a treatment goal.

A phase II trial of weekly i.v. KW-2170 in advanced castrate-resistant prostate cancer.

Abstract: Aim: KW-2170 is a novel pyrazoloacridone derivative that intercalates nucleic acids. It has promising in vitro properties against prostate and other cancers and is active in vivo against doxorubicin-resistant cell lines. We wished to investigate its activity and toxicity profile in this Phase II trial in androgen independent prostate cancer. Methods: Overall 44 men were recruited to this multicenter, open label, non-randomized study, with 35 evaluable for prostatic specific antigen (PSA) response. Results: Five patients had a PSA fall greater than 50% (overall RR 14.3%, 95% CI 4.8–30.3%). Overall median survival was 16 months. In the evaluable group (n = 35), median survival was 18.9 months. The drug was very well tolerated, with the most common toxicities being hematological (anemia, leucopenia, thrombocytopenia), alopecia, fatigue, and nausea. However, most of these were National Cancer Institute Grade 1 or 2; Grade 3 neutropenia occurred in only 11% of patients, and there was no Grade 4 neutropenia. Quality of life as measured by the FACT–P scale was not compromised. Conclusion: KW-2170 is a very well tolerated chemotherapy agent. It has a relatively low PSA response rate, and did not meet the pre-specifed criteria for further studies.

Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer

Abstract: BACKGROUND: Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy. METHODS: In this prospective-retrospective analysis, we assessed the efficacy and safety of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) as compared with FOLFOX4 alone, according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%. RESULTS: Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval [CI], 0.58 to 0.90; P = 0.004). Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P = 0.04). A total of 108 patients (17%) with non-mutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor. No new safety signals were identified. CONCLUSIONS: Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab-FOLFOX4 therapy

Antibody therapy of cancer

Abstract: The use of monoclonal antibodies (mAbs) for cancer therapy has achieved considerable success in recent years. Antibody-drug conjugates are powerful new treatment options for lymphomas and solid tumours, and immunomodulatory antibodies have also recently achieved remarkable clinical success. The development of therapeutic antibodies requires a deep understanding of cancer serology, protein-engineering techniques, mechanisms of action and resistance, and the interplay between the immune system and cancer cells. This Review outlines the fundamental strategies that are required to develop antibody therapies for cancer patients through iterative approaches to target and antibody selection, extending from preclinical studies to human trials.

Cetuximab Plus Irinotecan, Fluorouracil, and Leucovorin As First-Line Treatment for Metastatic Colorectal Cancer: Updated Analysis of Overall Survival According to Tumor KRAS and BRAF Mutation Status

Abstract: Purpose 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 and Methods 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. Results 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. Conclusion 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.