Treatment options for patients with previously treated metastatic colorectal cancer (mCRC) are limited, and treatments with differing mechanisms of action are needed. PTK787/ZK 222584 (PTK/ZK) is a ...novel oral angiogenesis inhibitor with therapeutic potential for the treatment of solid tumors.
Patients (N = 855) were randomly assigned to treatment with PTK/ZK or placebo once daily in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4). Stratification factors included WHO performance status (PS; 0 v 1 to 2) and lactate dehydrogenase (LDH ≤ 1.5× the upper limit of normal ULN v > 1.5 × ULN). Treatment was given until disease progression or unacceptable toxicity. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), safety, tolerability, and pharmacokinetics of PTK/ZK.
No statistically significant differences were seen between the treatment groups for the overall comparison of OS. With PTK/ZK and placebo, respectively, median OS was 13.1 and 11.9 months (hazard ratio HR, 1.00; 95% CI, 0.87 to 1.16; P = .957). Median PFS was longer with PTK/ZK than with placebo (5.6 and 4.2 months, respectively; HR, 0.83; 95% CI, 0.71 to 0.96; P = .013). An exploratory, post hoc analysis demonstrated improved PFS in patients with high LDH, regardless of WHO PS (HR, 0.63; 95% CI, 0.48 to 0.83; P < .001).
PTK/ZK in combination with FOLFOX4 did not improve OS of patients with pretreated mCRC but did improve PFS. The effect of PTK/ZK was more pronounced in patients with high LDH at baseline.
Colorectal tumours that are wild type for KRAS are often sensitive to EGFR blockade, but almost always develop resistance within several months of initiating therapy. The mechanisms underlying this ...acquired resistance to anti-EGFR antibodies are largely unknown. This situation is in marked contrast to that of small-molecule targeted agents, such as inhibitors of ABL, EGFR, BRAF and MEK, in which mutations in the genes encoding the protein targets render the tumours resistant to the effects of the drugs. The simplest hypothesis to account for the development of resistance to EGFR blockade is that rare cells with KRAS mutations pre-exist at low levels in tumours with ostensibly wild-type KRAS genes. Although this hypothesis would seem readily testable, there is no evidence in pre-clinical models to support it, nor is there data from patients. To test this hypothesis, we determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. We found that 9 out of 24 (38%) patients whose tumours were initially KRAS wild type developed detectable mutations in KRAS in their sera, three of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between 5 and 6 months following treatment. Mathematical modelling indicated that the mutations were present in expanded subclones before the initiation of panitumumab treatment. These results suggest that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a non-invasive manner. They explain why solid tumours develop resistance to targeted therapies in a highly reproducible fashion.
Lessons Learned
The safety profile in the patient groups who received FOLFIRI and simtuzumab did not differ from that in the FOLFIRI and placebo group.
The addition of simtuzumab to chemotherapy with ...FOLFIRI does not improve clinical outcomes in patients with metastatic KRAS mutant colorectal carcinoma.
Background
Simtuzumab, a humanized IgG4 monoclonal antibody to lysyl oxidase‐like 2 (LOXL2), blocks desmoplastic reaction in colorectal carcinoma (CRC) cells in vitro.
Methods
Patients with metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant CRC were randomized to receive second‐line 5‐fluorouracil, leucovorin, and irinotecan (FOLFIRI) with either 200 or 700 mg simtuzumab or placebo every 2 weeks in cycles of 28 days. Progression‐free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were assessed.
Results
In total, 249 patients were randomized and treated with FOLFIRI/simtuzumab 700 mg (n = 84), FOLFIRI/simtuzumab 200 mg (n = 85), and FOLFIRI/placebo (n = 80). After a median follow‐up of 5.1, 3.8, and 5.5 months, respectively, median PFS for each of the respective treatment groups was 5.5 months (adjusted HR 95% CI, p value versus placebo; 1.32 0.92, 1.89; p = .10), 5.4 months (1.45 1.01, 2.06; p = .04), and 5.8 months. Median OS was 11.4 months (1.23 0.80, 1.91; p = .25), 10.5 months (1.50 0.98, 2.30; p = .06), and 16.3 months, respectively. ORR was 11.9%, 5.9%, and 10%, respectively. Simtuzumab was tolerable in metastatic KRAS mutant CRC patients.
Conclusion
The addition of simtuzumab to FOLFIRI did not improve clinical outcomes in patients with metastatic KRAS mutant CRC.
经验总结
• FOLFIRI+Simtuzumab组患者的安全性特征与FOLFIRI+安慰剂组没有差异。
• Simtuzumab联合FOLFIRI化疗未改善转移性KRAS突变结直肠癌患者的临床预后。
摘要
背景. Simtuzumab是赖氨酰氧化酶样蛋白‐2（LOXL2）的一种人源化IgG4单克隆抗体, 在体外可阻止结直肠癌（CRC）细胞发生促结缔组织增生性反应
方法. 携带KRAS（Kirsten大鼠肉瘤病毒癌基因同源物）突变的转移性CRC患者随机接受5‐氟尿嘧啶、甲酰四氢叶酸和伊立替康（FOLFIRI）二线治疗联合Simtuzumab 200或700 mg或者联合安慰剂治疗, 每2周给药一次, 28天为一个周期。评估无进展生存期（PFS）、总生存期（OS）、客观缓解率（ORR）和安全性
结果. 总计249例患者随机接受FOLFIRI/Simtuzumab 700 mg（n=84）、FOLFIRI/Simtuzumab 200 mg（n=85）或FOLFIRI/安慰剂（n=80）治疗。分别进行为期5.1个月、3.8个月和5.5个月的中位随访后, 相应治疗组的中位PFS分别为5.5个月校正HR（95% CI）, 与安慰剂比较的p值：1.32（0.92, 1.89）, p=0.10、5.4个月1.45（1.01, 2.06）, p=0.04和5.8个月。中位OS分别为11.4个月1.23（0.80, 1.91）, p=0.25、10.5个月1.50（0.98, 2.30）, p=0.06和16.3个月。ORR分别为11.9%、5.9%和10%。转移性KRAS突变CRC患者可以耐受Simtuzumab
结论. Simtuzumab与FOLFIRI联用未改善转移性KRAS突变CRC患者的临床预后。
Lessons Learned
The safety profile in the gemcitabine/simtuzumab group was similar to that in the gemcitabine/placebo group.
The addition of simtuzumab to gemcitabine does not improve clinical ...outcomes in patients with metastatic pancreatic adenocarcinoma
Background
The humanized IgG4 monoclonal antibody simtuzumab inhibits the extracellular matrix‐remodeling enzyme lysyl oxidase‐like 2 maintaining pathological stroma in tumors.
Methods
Adult patients with metastatic pancreatic adenocarcinoma (mPaCa) were randomly assigned to receive intravenous gemcitabine, 1,000 mg/m2, in combination with 200 or 700 mg simtuzumab or placebo. Primary endpoint was progression‐free survival (PFS), secondary endpoints included overall survival (OS), objective response rate (ORR), and safety.
Results
Of 240 patients, 80 were randomly assigned to gemcitabine/simtuzumab 700 mg, 79 to gemcitabine/simtuzumab 200 mg, and 81 to gemcitabine/placebo. After a median follow‐up of 3.0, 1.9, and 3.4 months for gemcitabine/simtuzumab 700 mg, gemcitabine/simtuzumab 200 mg, and gemcitabine/placebo, respectively, the median PFS was 3.7 months (adjusted hazard ratio HR, 95% confidence interval CI, p value vs placebo: 1.09 0.74–1.61; p = .73), 3.5 months (1.13 0.76–1.66, p = .61), and 3.7 months, respectively. Median OS was 7.6 months (0.83 0.57–1.22; p = .28), 5.9 months (1.07 0.73–1.55; p = .69), and 5.7 months, respectively. ORRs were 13.9%, 14.5%, and 23.5%, respectively. Simtuzumab was well tolerated.
Conclusion
The addition of simtuzumab to gemcitabine did not improve clinical outcomes in patients with mPaCa.
经验总结
• 吉西他滨/Simtuzumab组的安全性特征与吉西他滨/安慰剂组相似。
• Simtuzumab与吉西他滨联用未改善转移性胰腺腺癌患者的临床预后。
摘要
背景. 人源化IgG4单克隆抗体Simtuzumab可抑制赖氨酰氧化酶样蛋白‐2这一细胞外基质重塑酶, 该酶负责维系肿瘤的病理性基质。
方法. 转移性胰腺腺癌 (mPaCa) 成年患者随机接受静脉注射用吉西他滨 1,000mg/m2 联合 Simtuzumab 200 或 700mg 或者联合安慰剂治疗。主要终点为无进展生存期 (PFS), 次要终点包括总生存期 (OS)、客观缓解率 (ORR) 和安全性。
结果. 240例患者中有80例随机分配至吉西他滨/Simtuzumab 700 mg组, 79例分配至吉西他滨/Simtuzumab 200 mg组, 81例分配至吉西他滨/安慰剂组。分别对吉西他滨/Simtuzumab 700 mg组、吉西他滨/Simtuzumab 200 mg组和吉西他滨/安慰剂组进行为期3.0个月、1.9个月和3.4个月的中位随访后, 三组的中位PFS依次为3.7个月校正风险比 (HR), 95%置信区间 (CI), 与安慰剂比较的p值：1.09 (0.74‐1.61); p = 0.73、3.5个月 1.13 (0.76‐1.66); p = 0.61 和 3.7个月。中位OS分别为7.6个月0.83 (0.57‐1.22); p = 0.28、5.9 个月 1.07 (0.73‐1.55); p = 0.69 和5.7个月。ORR分别为13.9%、14.5%和23.5%。Simtuzumab耐受性良好。
结论. Simtuzumab与吉西他滨联用未改善mPaCa患者的临床预后。
To assess potential differences in progression-free or overall survival when imatinib mesylate is administered to patients with incurable gastrointestinal stromal tumors (GIST) at a standard dose ...(400 mg daily) versus a high dose (400 mg twice daily).
Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial. At registration, patients were randomly assigned to either standard or high-dose imatinib, with close interval follow-up. If objective progression occurred by Response Evaluation Criteria in Solid Tumors, patients on the standard-dose arm could reregister to the trial and receive the high-dose imatinib regimen.
Seven hundred forty-six patients with advanced GIST from 148 centers across the United States and Canada were enrolled onto this trial in 9 months. With a median follow-up of 4.5 years, median progression-free survival was 18 months for patients on the standard-dose arm, and 20 months for those receiving high-dose imatinib. Median overall survival was 55 and 51 months, respectively. There were no statistically significant differences in objective response rates, progression-free survival, or overall survival. After progression on standard-dose imatinib, 33% of patients who crossed over to the high-dose imatinib regimen achieved either an objective response or stable disease. There were more grade 3, 4, and 5 toxicities noted on the high-dose imatinib arm.
This trial confirms the effectiveness of imatinib as primary systemic therapy for patients with incurable GIST but did not show any advantage to higher dose treatment. It appears reasonable to initiate therapy with 400 mg daily and to consider dose escalation on progression of disease.
Panitumumab, a fully human antibody targeting the epidermal growth factor receptor, is active in patients with metastatic colorectal cancer (mCRC). This trial evaluated panitumumab added to ...bevacizumab and chemotherapy (oxaliplatin- and irinotecan-based) as first-line treatment for mCRC.
Patients were randomly assigned within each chemotherapy cohort to bevacizumab and chemotherapy with or without panitumumab 6 mg/kg every 2 weeks. The primary end point was progression-free survival (PFS) within the oxaliplatin cohort. Tumor assessments were performed every 12 weeks and reviewed centrally.
A total of 823 and 230 patients were randomly assigned to the oxaliplatin and irinotecan cohorts, respectively. Panitumumab was discontinued after a planned interim analysis of 812 oxaliplatin patients showed worse efficacy in the panitumumab arm. In the final analysis, median PFS was 10.0 and 11.4 months for the panitumumab and control arms, respectively (HR, 1.27; 95% CI, 1.06 to 1.52); median survival was 19.4 months and 24.5 months for the panitumumab and control arms, respectively. Grade 3/4 adverse events in the oxaliplatin cohort (panitumumab v control) included skin toxicity (36% v 1%), diarrhea (24% v 13%), infections (19% v 10%), and pulmonary embolism (6% v 4%). Increased toxicity without evidence of improved efficacy was observed in the panitumumab arm of the irinotecan cohort. KRAS analyses showed adverse outcomes for the panitumumab arm in both wild-type and mutant groups.
The addition of panitumumab to bevacizumab and oxaliplatin- or irinotecan-based chemotherapy results in increased toxicity and decreased PFS. These combinations are not recommended for the treatment of mCRC in clinical practice.
To evaluate panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated wild-type (WT) KRAS exon 2 (codons 12 and ...13) metastatic colorectal cancer (mCRC). A prespecified secondary objective was to assess treatment effects in an extended RAS analysis that included exons 2, 3, and 4 of KRAS and NRAS.
Patients with WT KRAS exon 2 tumors were randomly assigned at a one-to-one ratio to panitumumab plus mFOLFOX6 or bevacizumab plus mFOLFOX6. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and safety.
Of 285 randomly assigned patients, 278 received treatment. In the WT KRAS exon 2 intent-to-treat group, PFS was similar between arms (hazard ratio HR, 0.87; 95% CI, 0.65 to 1.17; P = .353). Median OS was 34.2 and 24.3 months in the panitumumab and bevacizumab arms, respectively (HR, 0.62; 95% CI, 0.44 to 0.89; P = .009). In the WT RAS subgroup (WT exons 2, 3, and 4 of KRAS and NRAS), PFS favored the panitumumab arm (HR, 0.65; 95% CI, 0.44 to 0.96; P = .029). Median OS was 41.3 and 28.9 months (HR, 0.63; 95% CI, 0.39 to 1.02; P = .058) in the panitumumab and bevacizumab arms, respectively. Treatment discontinuation rates because of adverse events were similar between arms.
PFS was similar and OS was improved with panitumumab relative to bevacizumab when combined with mFOLFOX6 in patients with WT KRAS exon 2 tumors. Patients with WT RAS tumors seemed to experience more clinical benefit with anti-epidermal growth factor receptor therapy.
Summary Background Bevacizumab improves the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer. Our aim was to assess the use of bevacizumab in combination with ...oxaliplatin-based chemotherapy in the adjuvant treatment of patients with resected stage III or high-risk stage II colon carcinoma. Methods Patients from 330 centres in 34 countries were enrolled into this phase 3, open-label randomised trial. Patients with curatively resected stage III or high-risk stage II colon carcinoma were randomly assigned (1:1:1) to receive FOLFOX4 (oxaliplatin 85 mg/m2 , leucovorin 200 mg/m2 , and fluorouracil 400 mg/m2 bolus plus 600 mg/m2 22-h continuous infusion on day 1; leucovorin 200 mg/m2 plus fluorouracil 400 mg/m2 bolus plus 600 mg/m2 22-h continuous infusion on day 2) every 2 weeks for 12 cycles; bevacizumab 5 mg/kg plus FOLFOX4 (every 2 weeks for 12 cycles) followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks); or bevacizumab 7·5 mg/kg plus XELOX (oxaliplatin 130 mg/m2 on day 1 every 2 weeks plus oral capecitabine 1000 mg/m2 twice daily on days 1–15) every 3 weeks for eight cycles followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks). Block randomisation was done with a central interactive computerised system, stratified by geographic region and disease stage. Surgery with curative intent occurred 4–8 weeks before randomisation. The primary endpoint was disease-free survival, analysed for all randomised patients with stage III disease. This study is registered with ClinicalTrials.gov , number NCT00112918. Findings Of the total intention-to-treat population (n=3451), 2867 patients had stage III disease, of whom 955 were randomly assigned to receive FOLFOX4, 960 to receive bevacizumab–FOLFOX4, and 952 to receive bevacizumab–XELOX. After a median follow-up of 48 months (range 0–66 months), 237 patients (25%) in the FOLFOX4 group, 280 (29%) in the bevacizumab–FOLFOX4 group, and 253 (27%) in the bevacizumab–XELOX group had relapsed, developed a new colon cancer, or died. The disease-free survival hazard ratio for bevacizumab–FOLFOX4 versus FOLFOX4 was 1·17 (95% CI 0·98–1·39; p=0·07), and for bevacizumab–XELOX versus FOLFOX4 was 1·07 (0·90–1·28; p=0·44). After a minimum follow-up of 60 months, the overall survival hazard ratio for bevacizumab–FOLFOX4 versus FOLFOX4 was 1·27 (1·03–1·57; p=0·02), and for bevacizumab–XELOX versus FOLFOX4 was 1·15 (0·93–1·42; p=0·21). The 573 patients with high-risk stage II cancer were included in the safety analysis. The most common grade 3–5 adverse events were neutropenia (FOLFOX4: 477 42% of 1126 patients, bevacizumab-FOLFOX4: 416 36% of 1145 patients, and bevacizumab–XELOX: 74 7% of 1135 patients), diarrhoea (110 10%, 135 12%, and 181 16%, respectively), and hypertension (12 1%, 122 11%, and 116 10%, respectively). Serious adverse events were more common in the bevacizumab groups (bevacizumab–FOLFOX4: 297 26%; bevacizumab–XELOX: 284 25%) than in the FOLFOX4 group (226 20%). Treatment-related deaths were reported in one patient receiving FOLFOX4, two receiving bevacizumab–FOLFOX4, and five receiving bevacizumab–XELOX. Interpretation Bevacizumab does not prolong disease-free survival when added to adjuvant chemotherapy in resected stage III colon cancer. Overall survival data suggest a potential detrimental effect with bevacizumab plus oxaliplatin-based adjuvant therapy in these patients. On the basis of these and other data, we do not recommend the use of bevacizumab in the adjuvant treatment of patients with curatively resected stage III colon cancer. Funding Genentech, Roche, and Chugai.
Most gastrointestinal stromal tumors (GIST) are driven by KIT/PDGFRa mutations. Tyrosine kinase inhibitor benefit is progressively less after imatinib failure. This phase II trial analyzed the ...efficacy of nivolumab (N) or nivolumab + ipilimumab (N + I) in patients with refractory GIST.
Patients with advanced/metastatic GIST refractory to at least imatinib were randomized 1:1 in a noncomparative, parallel group, unblinded phase II trial of N (240 mg every 2 weeks) or N + I (240 mg every 2 weeks + 1 mg/kg every 6 weeks). The primary endpoint was the objective response rate of N alone or N+I by RECIST 1.1 in the intent-to-treat population.
A total of 36 patients with a median of 3 (1-6) prior lines of therapies were enrolled. Ten of 19 (52.6%) patients had stable disease (SD) for a clinical benefit rate (CBR) of 52.6% in the N arm and the median progression-free survival (PFS) was 11.7 weeks 95% confidence interval (CI), 7.0-17.4. In the N+I arm, 1 of 16 (6.7%) patients had a complete response (CR) and 4/16 (25.0%) had SD for a CBR of 31.3% and a median PFS of 8.3 weeks (95% CI, 5.6-22.2). The 4- and 6-month PFS were 42.1% and 26.3%, respectively for N, and 31.3% and 18.8%, respectively for N+I. The most common adverse events (AE) attributed to N and N+I were fatigue: 13.9% and 22.2%, respectively. There were nine total attributable grade 3-4 AEs.
The primary endpoint of response rate > 15% was not observed for N or N + I. In a heavily pretreated GIST population, responses and long-term disease control with both N and N+I were observed. No new safety signals have been observed.
In recent retrospective analyses of early-stage colorectal cancer (CRC), low and high body mass index (BMI) scores were associated with worsened outcomes. Whether BMI is a prognostic or predictive ...factor in metastatic CRC (mCRC) is unclear.
Individual data from 21,149 patients enrolled onto 25 first-line mCRC trials during 1997 to 2012 were pooled. We assessed both prognostic and predictive effects of BMI on overall survival and progression-free survival, and we accounted for patient and tumor characteristics and therapy type (targeted v nontargeted).
BMI was prognostic for overall survival (P < .001) and progression-free survival (P < .001), with an L-shaped pattern. That is, risk of progression and/or death was greatest for low BMI; risk decreased as BMI increased to approximately 28 kg/m(2), and then it plateaued. Relative to obese patients, patients with a BMI of 18.5 kg/m(2) had a 27% increased risk of having a PFS event (95% CI, 20% to 34%) and a 50% increased risk of death (95% CI, 43% to 56%). Low BMI was associated with poorer survival for men than women (interaction P < .001). BMI was not predictive of treatment effect.
Low BMI is associated with an increased risk of progression and death among the patients enrolled on the mCRC trials, with no increased risk for elevated BMI, in contrast to the adjuvant setting. Possible explanations include negative effects related to cancer cachexia in patients with low BMI, increased drug delivery or selection bias in patients with high BMI, and potential for an interaction between BMI and molecular signaling pathways.
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