A phase III, multicenter, randomized controlled trial of panitumumab plus best supportive care (BSC) versus BSC alone in patients with metastatic colorectal cancer
Reviewer: John P. Plastaras, MD, PhD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 27 de abril del 2006
Presenter: Marc Peeters
Presenter's Affiliation: Ghent University Hospital, Ghent, Belgium
Type of Session: Clinical Plenary
- Epidermal growth factor receptor (EGFR) signaling contributes to tumor growth, and overexpression of EGFR is associated with worse prognosis in metastatic colorectal cancer.
- Cetuximab (Erbitux) is a partially humanized mouse monoclonal antibody directed against EGFR that is in clinical use for patients with metastatic colorectal cancer.
- Panitumumab is a fully human monoclonal antibody against EGFR, whereas cetuximab is about 35% mouse. Cetuximab is associated with rare but potentially severe infusion reactions.
- Phase I and II trials of panitumumab in solid tumors did not reach a maximally tolerated dose, and the most common reactions were skin reactions that did not require discontinuation.
- A randomized, multicenter Phase III trial comparing panitumumab to best supportive care (BSC) was conducted in order to test the efficacy and safety of this fully human anti-EGFR antibody in the setting of chemotherapy-refractory metastatic colorectal cancer.
Material and Methods
- Eligibility: Patients with metastatic colorectal cancer with ECOG performance status of 0-2 who had failed at least two lines of chemotherapy (fluoropyrimidine, irinotecan, and oxaliplatin). Patients had to have measurable disease that showed radiologic evidence of progression during or within 6 months after the most recent chemotherapy. They had to have at least 1% of tumor cells positive for EGFR by immunohistochemistry (IHC), which was centrally reviewed.
- Randomization: 1:1 to either BSC or BSC plus panitumumab (6 mg/kg every 2 weeks). After progression, patients on BSC were permitted to cross over to panitumumab treatment.
- Responses were assessed at weeks 8, 12, 16,24, 32, 40, 48, and every 12 weeks thereafter. Modified RECIST criteria were used to evaluate responses, which were performed by blinded, central reviewers.
- Primary Endpoint: Progression-free survival (PFS) tested by stratified log-rank test, adjusted for ECOG performance status and geographic region.
- Secondary Endpoints: Best objective response rate and safety.
- 231 patients were treated with panitumumab and 232 with BSC alone.
- 174 (75%) of the patients on the BSC only arm crossed over to panitumumab treatment after progression
- 63% were men; 40% were ECOG 0; 67% colon cancer, 33% rectal cancer
- 70% had 2+ or 3+ EGFR staining on IHC
- All but one patient had received at least 2 prior chemotherapy regimens, and 37% had received at least 3. Of note, no patients had been previously treated with any other antibody therapy (cetuximab or bevacizumab)
- Median Follow-up: 19 weeks
- Panitumumab significantly improved PFS (HR=0.54, 95% CI: 0.44-0.66)
- this highly significant difference was seen at the first evaluation period (8 weeks) and persisted through 32 weeks
- the PFS difference was not changed by any sensitivity analyses
- Objective response rate: 8% (panitumumab) vs. 0% (BSC)
- Panitumumab was associated with more skin reactions (90% vs. 9%), more fatigue (24% vs. 15%), more hypomagnesemia (38% vs. 2%), more abdominal pain (23% vs. 17%), and more diarrhea (21% vs. 11%)
- No patients had grade 3/4 infusion-related reactions, and only 1 patient discontinued the drug due to a grade 2 hypersensitivity reaction. Of the 83% patients with pre- and post-treatment serum samples, no patients developed anti-panitumumab antibodies.
- Exploratory Analyses:
- There was no survival difference between the groups, which may have been due to allowed crossover from the BSC group. An analysis that subtracted out the crossover period showed an intriguing overall survival difference (HR 0.78, CI 0.61-1.01)
- Grade 2-4 skin rash was associated with an overall survival difference compared with Grade 1 rash (HR 0.61, CI 0.4-0.95)
- Panitumumab (6 mg/kg every 2 weeks) improved PFS and was well tolerated in patients with metastatic colorectal cancer who failed standard chemotherapy.
The highly significant PFS benefit seen in this Phase III trial of panitumumab, an anti-EGFR antibody, is expected based on the results observed with cetuximab (e.g. BOND study had a ~10% response rate, 6.9 month median survival). No patients who had been previously treated with cetuximab were included, and it is unknown if there will be cross-resistance with panitumumab. The lack of serious transfusion reactions is presumably due to the fact that panitumumab is a fully human antibody. In contrast, cetuximab is a partial mouse antibody and causes a ~3% rate of Grade 3 infusion reactions, a difference that may make panitumumab clinically easier to use. A direct comparison of panitumumab and cetuximab will be required to truly determine if there is any difference in efficacy.
Randomized Controlled HCC Screening Trial Not Feasible
Dec 8, 2011 - A randomized controlled trial of hepatocellular carcinoma (HCC) screening is not feasible for informed patients with cirrhosis; and small HCC detection is not improved by ultrasonographic screening every three versus six months, according to two studies published in the December issue of Hepatology.
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