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Tumor p16 status may predict response to panitumumab plus chemotherapy in metastatic SCCHN
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The addition of panitumumab to chemotherapy did not significantly improve OS in patients with metastatic squamous cell carcinoma of the head and neck, according to results of a randomized phase 3 study.
However, panitumumab (Vectibix, Amgen) was associated with significant improvement in PFS and also demonstrated a tolerable toxicity profile.
In addition, patients with p16-negative tumors who were assigned to panitumumab plus chemotherapy experienced significantly longer median OS compared with those assigned to chemotherapy alone.
“[The findings suggest] p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy,” the researchers wrote.
The open-label SPECTRUM trial, conducted across 126 sites in 26 countries, assessed the safety and efficacy of panitumumab plus cisplatin and fluorouracil vs. cisplatin and fluorouracil alone as first-line treatment for recurrent or metastatic SCCHN.
Researchers stratified the 657 patients according to previous treatment, primary tumor site and performance status.
All patients received cisplatin 100 mg/m2 on day 1 of each 3-week cycle for up to 6 weeks and fluorouracil 1,000 mg/m2 on days 1 to 4 of each cycle.
Patients assigned to panitumumab received 9 mg/kg intravenously on day 1 of each cycle. They also were able to continue maintenance panitumumab every 3 weeks.
Median OS was 11.1 months among patients in the panitumumab arm vs. 9 months in the control arm (HR=0.873; 95% CI, 5.6-6.6). Median PFS was 5.8 months in the panitumumab arm and 4.6 months in the control arm (HR=0.780; 95% CI, 0.659–0.922).
Grade 3 and 4 adverse events were more common in the panitumumab arm. They included skin or eye toxicity (19%), hypomagnesaemia (12%), hypokaliemia (10%), diarrhea (5%) and dehydration (5%). Treatment-associated mortality occurred in 4% of patients in the panitumumab arm vs. 2% of patients in the control arm.
In a subanalysis, researchers used a validated p16 immunohistochemical assay to assess tumor HPV status as a potential predictive biomarker of outcomes.
The subanalysis included 443 patients. Of them, 99 (22%) were p16 positive.
Among patients with p16-negative tumors, median OS was longer in the panitumumab arm (11.7 months vs. 8.6 months; HR=0.73; 95% CI, 0.58–0.93). Researchers did not observe that trend among patients with p16-positive tumors.
In the control group, patients with p16-positive tumors demonstrated longer median OS than patients with p16-negative tumors (HR=0.70; 95% CI, 0.47-1.04), but the difference was not statistically significant, researchers wrote.
References:
Vermorken JB. Lancet. 2013;doi:10.1016/S1470-2045(13)70181-5.
Vokes EE. Lancet. 2013;doi:10.1016/S1470-2045(13)70215-8.
Disclosure:
The study was funded by Amgen. The researchers report research funding, honoraria and travel support from, employment relationships with, stock ownership in, and consultant, advisory or speaking roles with Amgen, Boehringer Ingelheim, Eli Lilly, Merck Serono and Roche.
Perspective
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Barbara Burtness, MD
The results reported here contrast with those reported by Psyrri and colleagues at ESMO (Psyrri A. Abstract #1018O. Presented at: European Society for Medical Oncology Congress; Sept. 28-Oct. 2, 2012; Vienna), in which a high proportion of cancers from the EXTREME trial were subjected to p16 staining, using a conventional cutpoint of 70%. In this study, p16-positive cancers had longer survival on the chemotherapy control arm, apparently mirroring in metastatic or recurrent disease patients the favorable natural history of these cancers as reported by O’Sullivan, Fakhry and others in the locally advanced setting.
Further, the benefit of cetuximab was seen in both p16-positive and p16-negative cases. Thus, further study is needed before accepting the SPECTRUM trial as evidence that panitumumab — or indeed EGFR inhibition in general — is not appropriate for p16-positive head and neck cancers.
Although the failure of this trial to demonstrate an advantage for panitumumab may have resulted from the inclusion of patients with a more favorable natural history, difference in patterns of care between Eastern Europe and other geographic regions, or undocumented differences in post-progression therapy, it is also the case that panitumumab and cetuximab are not identical drugs. Each is clearly active in squamous cell cancer of the head and neck, they have comparable single-agent response rates, and each can be safely combined with chemotherapy. However, panitumumab has higher binding affinity for the EGFR, and intuitively one would expect this to result in more potent inhibition of EGFR signaling. However, as others have shown, antibodies may encounter a binding site barrier that is enhanced by higher binding affinity. That is, if the binding affinity is quite high, antibody will bind heavily to tumor cells in close proximity to the blood vessel, with relatively poor distribution into the tumor.
Further, high affinity binding may result in a higher proportion of antibody being sequestered by EGFR expressed in normal tissues, such as skin. Additionally, panitumumab utilizes an IgG2 backbone, which is less active in induction of antibody-dependent cellular cytotoxicity. Thus, the addition of cetuximab to platinoid/5-fluorouracil chemotherapy remains the standard of care for first-line treatment of metastatic or recurrent disease off protocol, despite recognition that panitumumab is active in some patients. HPV association and p16 staining should not be used to direct utilization of EGFR inhibition with the current state of the evidence.
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