ASCO 2008: The Evolving Role of EGFR Inhibitors in Colorectal Cancer

Posted on March 8th, 2009 by

ASCO 2008: The Evolving Role of EGFR Inhibitors in Colorectal Cancer

Results from the 2008 annual meeting of the American Society of Clinical Oncology (ASCO), held May 30–June 2 in Chicago, Illinois, revealed significant steps towards the improvement of outcomes for patients with varying types of cancers. As seen during the past few years, attention has turned towards individualizing patient care through targeted therapies, optimizing patient selection for specific therapies, as well as a focus on quality of life and survivorship issues.

Of particular interest at this year’s ASCO was the undisputed understanding that the integration of genetics in everyday practice is rapidly becoming a reality for oncology patients, providing the ability for exponential progression towards individualizing therapy. Specifically, the results detailing the fact that the effectiveness of epidermal growth factor receptor (EGFR) inhibitors is completely dependent upon KRAS mutational status in colorectal cancer left no doubt that the future role of genetics in selecting patient therapy is inevitable, efficient, and will undoubtedly change the way in which oncology patients are managed.

EGFR Targeted Therapy

The recent approval and addition of EGFR inhibitors to standard therapy has demonstrated improved outcomes among patients with select EGFR-positive cancers compared with standard chemotherapy regimens; EGFR inhibitors also tend to be associated with less overall severe toxicity. However, a significant portion of patients with EGFR-overexpressing cancers never demonstrate a response to EGFR inhibitors, an issue that prompted research into the identification of potential markers or properties that predict responsiveness to these agents.

Ultimately, individualizing therapy through understanding which patients will respond to EGFR inhibitors will allow unresponsive patients to omit ineffective therapies during a crucial therapeutic window when anticancer treatment should be initiated, while obviously eliminating associated side effects, expense, and time with therapies from which no benefit is derived. Furthermore, omission of patients who are identified as non-responders to specific therapies may ultimately provide a clearer picture of the true clinical benefit of these agents.

KRAS

The v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene is involved in the intracellular signal transduction along the EGFR axis. Normally, KRAS mediates proliferation signaling intracellularly-downstream from the EGF receptor. Patients with wild-type KRAS tend to have a disruption of cellular growth signaling through the EGFR pathway with the presence of EGFR-targeted therapies. However, mutated KRAS often maintains the ability to continue its aberrant signaling of the proliferation cascade within the EGFR axis, even when an EGFR inhibitor is bound to its target, as the target(s) of currently approved EGFR inhibitors are upstream from KRAS expression and activity.1

It is estimated that between 30-40% of all patients with colorectal cancers have a KRAS mutation that would ultimately render them ineligible for EGFR targeted therapy. Obviously, understanding which patients will respond to EGFR inhibitors will allow unresponsive patients to proceed with more effective therapies while omitting therapy that will not provide benefit.

Amado R, et al. published results in the Journal of Clinical Oncology in April 2008 that demonstrated a clear association between KRAS mutation status and responsiveness to Vectibix as monotherapy in metastatic colorectal cancer; specifically, wild-type KRAS was essential for response to Vectibix.2 Amado, et al. performed a retrospective analysis in which KRAS status was ascertained in 427 patients involved in a Phase III trial comparing Vectibix as monotherapy with best supportive care among patients with metastatic colorectal cancer.

  • Patients with wild-type KRAS had a significantly improved response rate, progression- free survival, and overall survival compared with patients with a mutated KRAS.
  • Not one patient with a mutated KRAS responded to therapy with Vectibix.

At the time that these results were published, they were among the first to be published in peer-reviewed literature that provided sound evidence of the KRAS/EGFR-inhibitor link in colorectal cancer.

Results from ASCO

Several presentations at the 2008 ASCO reported confirmatory data that treatment with the EGFR inhibitors such as Erbitux® (cetuximab) and Vectibix® (panitumumab) are only effective among patients with the normal KRAS, while those with a mutated KRAS gene demonstrate virtually no response to these agents. In essence, global consent was achieved at this year’s ASCO that all patients eligible for EGFR-targeted therapies should first undergo KRAS testing prior to initiation of therapy. The understanding of issues such as KRAS mutations and associated effectiveness of EGFR inhibitors leads the way to future treatment selection based on very specific mutations and markers.

Studies this year confirmed data previously published in terms of KRAS status affecting responsiveness among EGFR-positive patients treated with EGFR inhibitors. Specifically, updated results from the CRYSTAL and OPUS trials confirmed that patients with KRAS mutations do not respond to Erbitux, while those with normal KRAS derive significant benefit from the addition of Erbitux to chemotherapy.

Updated results from the CRYSTAL study were presented at this year’s ASCO.3 The original study included nearly 2,000 patients with advanced colorectal cancer who were randomized to Erbitux (400 mg/m2 as an initial dose and then 250 mg/m2 per week) plus FOLFIRI, (irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5-fluorouracil bolus 400 mg/m2, and 5-fluorouracil infusion 2400 mg/m2 over 46 hours administered every two weeks) or FOLFIRI only as initial therapy for their disease. Overall, the results indicated an approximate 15% progression-free survival for patients treated with Erbitux.

The updated results of the CRYSTAL study included tumor samples from 587 of the patients from the original study; these patients were evaluated for KRAS mutations and associated outcomes.

  • Patients with a normal KRAS had a 59% response rate to the Erbitux plus FOLFIRI and only a 43% response rate to FOLFIRI only. (p=0.0025).
  • Patients with a normal KRAS experienced a 32% reduced risk of progression with the addition of Erbitux to FOLFIRI compared with FOLFIRI only (p=0.017).
  • Patients with KRAS mutations did not experience a benefit from the addition of Erbitux to FOLFIRI when compared with FOLFIRI only.
  • There is no need for fresh tumor sampling to acquire KRAS mutation status with reproducible results.

Tejpar S, et al. also conducted a retrospective analysis of the EVEREST trial in which Camptosar® (irinotecan)-refractory patients received subsequent therapy with Camtposar/Erbitux followed by three differing doses of Erbitux monotherapy.4 Retrospectively, DNA analysis for KRAS mutations from primary tumor samples was obtained.

  • Not one patient with mutant KRAS status (n=32) achieved a response to any dose of Erbitux.
  • Among those with wild-type KRAS, there was a trend toward a higher response rate with dose-escalation of Erbitux (41.9%) compared with standard Erbitux doses (30.4%); p=0.396.

An update from the Phase II OPUS trial, a trial that was much the same as CRYSTAL except that FOLFOX (Eloxatin®, 5-fluorouracil, leucovorin) was used as the chemotherapy regimen, was also presented.5 In the OPUS trial, 134 patients with metastatic colorectal cancer were randomized to receive either Erbitux plus FOLFOX or FOLFOX only. Upon retrospective analyses for KRAS status, the following was reported:

  • In the original OPUS trial, there was no significant benefit from the addition of Erbitux to FOLFOX compared with FOLFOX only.
  • When stratified for KRAS mutation status, it was found that patients with KRAS mutations again had virtually no response to the addition of Erbitux, while those with a normal KRAS gene derived great benefit from the addition from Erbitux. (HR: 0.448; p=0.0009).
  • Treatment with FOLFOX alone resulted in a trend toward improved PFS in patients with mutant KRAS versus those with wild-type KRAS (HR: 1.4; p=0.1655).

KRAS mutation status also affects other EGFR inhibitors such as Vectibix.6 Data from an interim efficacy analysis was also presented from the PRECEPT study, a Phase II single-arm study in which Vectibix in combination with FOLFIRI is being evaluated in patients with metastatic colorectal cancer that has progressed following prior therapy with an Eloxatin-based chemotherapy regimen plus Avastin. Prospectively defined endpoints include the efficacy of Vectibix/FOLFIRI according to KRAS status among these patients.

  • Patients with wild-type KRAS had a median progression-free survival of 26 weeks compared with only 16 weeks for those with mutant KRAS.
  • Time to treatment failure was 20 weeks for patients with wild-type KRAS versus 15 weeks for those with mutant KRAS.
  • The addition of Vectibix to FOLFIRI was tolerable in terms of safety and adverse events, with the most frequently reported serious adverse events being neutropenia (23%), skin-related toxicities (19%), and diarrhea (13%).

Combination Therapy

Researchers have been hopeful that combining biologic therapies that target different pathways may provide additive benefit for the treatment of various cancers. With Erbitux and Vectibix targeting the EGFR pathway and Avastin® (bevacizumab) targeting the vascular endothelial growth factor (VEGF) pathway, researchers had speculated that because synergistic activity between the two agents has been noted in laboratory studies, a combination of the two agents may provide additional anticancer activity over either one used alone in combination with chemotherapy., However, there have been conflicting results regarding the efficacy of the combination of these two targeted agents in colorectal cancer.

Researchers affiliated with the CAIRO2 trial reported that the addition of Erbitux to Avastin, Eloxatin, and Xeloda® (capecitabine) did not provide a clinical benefit, and actually reduced progression-free survival in metastatic colorectal cancer. These results are consistent with results from other trials indicating that combining agents targeting the EGFR and the VEGF pathways does not provide clinical benefit.

The CAIRO2 study was a Phase III trial that was conducted to further evaluate the addition of Erbitux to Avastin-containing regimens in colorectal cancer. The trial was conducted by the Dutch Colorectal Cancer Group (DCCG) in 79 Dutch hospitals that included 736 patients with metastatic colorectal cancer.7 Patients were ineligible for surgical resection and had not received prior therapy for metastatic disease. The primary endpoint was progression-free survival, with secondary endpoints being overall survival, response rates, toxicity, and translational outcomes.

Patients were randomized to either the control group, which received six cycles of Eloxatin (130 mg/m2 on day one), Xeloda (1,000 mg/m2 twice daily on days one to 14), and Avastin (7.5 mg/kg on day one), with further cycles including Xeloda (1,250 mg/m2 twice daily on days one to 14) and Avastin (7.5 mg/kg on day one) or the addition of Erbitux (weekly in a 400 mg/m2 loading dose and 250 mg/m2 thereafter) plus the control group regimen. Follow-up was nearly 19 months.

  • There was no benefit derived among any endpoint for patients treated with the addition of Erbitux; in fact, progression-free survival was significantly reduced among patients treated with Erbitux (9.6 months versus 10.7 months, HR for progression 1.21, P=0.018).
  • Overall survival was similar between the two groups at approximately 20 months (P=0.21).
  • Both groups achieved a 44% combined complete and partial response rate (P=0.88).
  • There was no significant difference between treatment groups in terms of disease stabilization.
  • Even when KRAS status and the presence of grade 3 rash were included in the statistical analysis, no benefit was noted among the group of patients who received the addition of Erbitux over the control group.

These results are consistent with the results from the analysis of the PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) trial, in which Avastin plus standard Eloxatin or Camptosar® (irinotecan)-based chemotherapy was directly compared with Avastin/chemotherapy and Vectibix as first-line therapy in metastatic colorectal cancer.8 The World Congress on Gastrointestinal Cancer meeting in 2007 was the site of the first public presentation of the PACCE data, which revealed that progression-free survival and toxicities were actually worse in the Vectibix arm, resulting in the discontinuation of treatment with Vectibix in this trial; data collection of PACCE continues despite discontinuation of Vectibix.

Overall, it appears that there is a class effect in which the combination of agents targeted against the EGFR and VEGF provide no clinical benefit and may, in fact, result in worse outcomes as initial therapy in metastatic colorectal cancer patients. Initial findings from both the CAIRO and PACCE trials were unexpected as preclinical models predicted that the combination of agents targeted against these pathways increased growth inhibition of malignant cells. Further molecular analyses may provide more answers as to potential subgroups that could derive benefit from this treatment combination or reasons as to why concurrent inhibition of both the EGFR and VEGF pathways through these biologic therapies does not provide improved outcomes for patients with colorectal cancer. It was cautioned that EGFR/VEGF treatment combinations such as Erbitux/Avastin should remain in the context of a clinical trial for colorectal cancer at this time.

Toxicities

As the EGFR inhibitors that are currently approved appear to provide fairly similar activity, the selection of agents with which to treat a patient will be determined, at least in part, by toxicity profiles. Skin rash tends to be the most known side effect among EGFR inhibitors as a class; however, other toxicities are to be included in the decision-making of treatment, particularly high-risk and/or more fragile patients.

Vectibix has been the least studied of the approved EGFR inhibitors; thus, results from safety analyses involving Vectibix are important and were released at this year’s ASCO. Two Phase III clinical trials evaluating the effectiveness of the addition of Vectibix to FOLFOX and FOLFIRI are ongoing, with pooled safety analysis based on planned interim data analysis reported at ASCO.

The first trial, 20050181 (”181″) trial is a global Phase III trial evaluating Vectibix in combination with FOLFIRI as second-line therapy for patients with metastatic colorectal cancer.9 The multicenter trial includes more than 1,000 patients with histologically/cytologically-confirmed metastatic colorectal cancer who had received one prior fluoropyrimidine-based chemotherapy regimen for metastatic disease and had an ECOG performance status (PS) of 0 to 2. Patients were randomized to Vectibix plus FOLFIRI or FOLFIRI only with co-primary endpoints being progression-free and overall survival. An independent Data Monitoring Committee (DMC) conducted planned safety interim analyses that included approximately 1,100 patients.

  • 99.6% of patients received at least one cycle of therapy.
  • Common grades III/IV pooled adverse events included neutropenia (17%), diarrhea (10%), and fatigue (5%).
  • 63% of the pooled patient population experienced skin or subcutaneous tissue events of any grade, while 15% experienced grade III or less and less than 1% experienced grade IV skin/subcutaneous tissue events.

Based upon these events, the DMC recommended the continuation of this trial per protocol. KRAS mutational status will be investigated in both treatment arms as a biomarker for Vectibix activity.

The second trial, the PRIME or 20050203 trial, is also a global Phase III clinical trial that is evaluating the efficacy of Vectibix in combination with FOLFOX as initial therapy for metastatic colorectal cancer among wild-type KRAS patients.10 The final enrollment to the trial was February 2008 in which a total of 1,183 patients had been enrolled and were randomized to Vectibix plus FOLFOX or FOLFOX alone as first-line therapy for metastatic disease. As with the 108 trial, the PRIME trial had a planned pooled safety data interim analysis conducted by an independent DMC for which data from 903 patients were presented at ASCO. The primary endpoint to this trial is progression-free survival, both in wild-type KRAS patients and the pooled patient populations.

  • 99% of patients received at least one cycle of therapy.
  • Common grades III/IV pooled adverse events included neutropenia (28%), diarrhea (11%), and fatigue (4%).
  • 56% of the pooled patient population experienced skin or subcutaneous tissue events of any grade, while 10% experienced grade III or less, and less than 1% experienced grade IV skin/subcutaneous tissue events.

Based upon these interim results, the DMC recommended the continuation of the PRIME trial per protocol.

Safety and toxicity issues will continue to be evaluated among EGFR inhibitors when used either as monotherapy or explored as a component in several different therapeutic combinations. Quality-of-life issues continue to gain a greater role among patients with cancer because they are living longer, and healthcare practitioners appear to increasingly take into consideration side effect profiles when deciding upon individual care.

Conclusion

The understanding that KRAS mutational status directly affects the efficacy of available anti-EGFR agents represents an important scientific breakthrough in terms of future progression with targeted therapies. As researchers continue to identify subgroups of patients that derive greater benefit from specific therapies, more attention will undoubtedly be focused on individualizing therapy for all patients diagnosed with cancer. Ultimately, the combination of the development of more refined targeted agents as well as the identification of patients who will achieve benefit from these agents will significantly reduce side effects commonly associated with cancer therapy as well as improve outcomes for all patients.

References:


1 Genetics Home Reference. KRAS. Available at: http://ghr.nlm.nih.gov/gene=kras. Accessed July 2008.

2 Amado R, Wolf M, Peeters M, et al. Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer Journal of Clinical Oncology. 2008;10: 1626-1634.

3 E. Van Cutsem, I. Lang, G. D’haens. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. Proceedings from the 2008 annual meeting of the American Society of Clinical Oncology (ASCO). Abstract #2.

4 Tejpar S, Peeters M, Humblet Y, et al. Relationship of efficacy with KRAS status (wild type versus mutant) in patients with irinotecan-refractory metastatic colorectal cancer (mCRC), treatment with irinotecan (q2w) and escalating doses of cetuximab (q1w): The EVEREST experience (preliminary data). Program and abstracts of the 44th American Society of Clinical Oncology Annual Meeting; May 30 – June 3, 2008; Chicago, Illinois. Abstract 4001.

5 Bokemeyer C, Bondarenko I, Hartmann J, et al. KRAS Status and Efficacy of First-Line Treatment of Patients with Metastatic Colorectal Cancer (mCRC) with FOLFOX with or without Cetuximab: The OPUS Experience. Proceedings from the 2008 annual meeting of the American Society of Clinical Oncology (ASCO). Abstract #4000.

6 Cohn A, Smith D, Neubauer M, et al. Panitumumab (pmab) regimen evaluation in colorectal cancer to estimate primary response to treatment (PRECEPT): Effect of KRAS mutation status on second-line treatment (tx) with pmab and FOLFIRI. Proceedings from the 2008 annual meeting of the American Society of Clinical Oncology (ASCO). Abstract #4127.

7 Punt CJ, et al “Randomized phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). Proceedings from the 2008 annual meeting of the American Society of Clinical Oncology (ASCO). Abstract LBA4011.

8 Amgen. Amgen Discontinues Vectibix(TM) Treatment In PACCE Trial Evaluating Vectibix(TM) As Part Of Triple Combination Regimen. Available at: http://www.amgen.com/media/media_pr_detail.jsp?year=2007&releaseID=977186. Accessed June 2008.

9 Peeters M, Wilson G, Ducreux M, et al. Phase III study (20050181) of panitumumab (pmab) with FOLFIRI versus FOLFIRI alone as second-line treatment (tx) in patients (pts) with metastatic colorectal cancer (mCRC): Pooled safety results. Proceedings from the 2008 annual meeting of the American Society of Clinical Oncology (ASCO). Abstract #4064.

10 Siena S, Tabernero J, Burkes R, et al. Phase III study (PRIME/20050203) of panitumumab (pmab) with FOLFOX compared with FOLFOX alone in patients (pts) with previously untreated metastatic colorectal cancer (mCRC): Pooled safety data. Proceedings from the 2008 annual meeting of the American Society of Clinical Oncology (ASCO). Abstract #4034.

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