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Published on 6 October 2008

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Panitumumab in the treatment of metastatic colorectal cancer: where are we now?

teaser

Future trials must define the possible role of panitumumab in first-line therapy in combination with conventional cancer therapies. But how can we identify patients who will benefit from treatment with the antibody?

Maria Gry Gundgaard
MD

Department of Oncology
Rigshospitalet
Copenhagen
Denmark

Colorectal cancer is the second-biggest cause of death from cancer in UK.[1] For decades, fluoropyrimidine 5-fluorouracil (5-FU) combined with folinic acid (FA) or leucovorin (LV) was the
only agent proven to benefit patients with metastatic colorectal cancer (mCRC).

With the introduction of new drugs in the last 10 years – camptothecin-derivative irinotecan and the third-generation platinum-based product oxaliplatin – new possibilities for combination chemotherapy have arisen, and the median overall survival (mOS) has increased to more than 20 months for mCRC patients.[2]

Oral formulations of 5-FU have been developed, and the oral fluoropyrimidine capecitabine has the potential to replace 5-FU in combination with oxaliplatin.[3]

The traditional chemotherapy drugs are now being supplemented by novel biological agents that act selectively on a specific target. Cancer cells depend on angiogenesis for growth; metastasis, and the production of vascular endothelial growth factor (VEGF), makes this a possible target for monoclonal antibodies (mAb).

Another target is the epidermal growth factor receptor (EGFR), which is a transmembrane protein with an intracellular tyrosine kinase domain.[4]

EGFR correlates with poor prognosis since it is associated with carcinogenic processes when overexpressed. EGFR is abnormally expressed in many malignancies, including CRC.

Two drugs, the VEGF inhibitor bevacizumab and the EGFR inhibitor cetuximab, are approved for the treatment of mCRC.

In 2006, the FDA approved the anti-EGFR antibody panitumumab for treatment of mCRC based on results from a large phase III study.[5] The trial, by Van Cutsem et al,[6] showed significant improved progression-free survival (PFS) when the patients received panitumumab plus best supportive care (BSC) versus BSC as third-line or subsequent-line therapy.

Panitumumab was granted FDA approval for patients with EGFR-expressing mCRC who progressed on, or following, regimens containing fluoropyrimidine, irinotecan and oxaliplatin.[5]

Trial results
Panitumumab is a fully human immunoglobulin G2 monoclonal antibody that acts selectively against the EGFR by blocking the extracellular domain with high affinity.

Further phase II studies demonstrated the activity of panitumumab as monotherapy in patients with irinotecan-refractory mCRC, showing RRs around 10%, similar to the results presented for cetuximab.[7,8]

Most panitumumab trials were carried out on patients with EGFR-expressing tumours. However, phase II trials that evaluated its safety and efficacy also examined patients with mCRC expressing low levels of EGFR[8,9], and similar responses were observed in patients with high- and low-expressing EGFR tumours. The EGFR level was determined by immunohistochemistry.

A study by Moroni et al[10] investigated the correlation between the gene copy number for EGFR and efficacy of anti-EGFR treatment in patients with mCRC and found an increased EGFR copy number in patients with objective responses. But the study was small, and the results need to be confirmed in larger trials.

In clinical trials, panitumumab has been shown to be well tolerated. It has not caused human antibody response, and the grade of infusion reaction has proved to be very low. It is believed that because it is a fully human antibody it causes reduced immunogenicity and thus has a high level of safety.[11]

In the phase III study by van Cutsem et al6, 463 patients were randomly assigned to receive panitumumab + BSC (n = 231) vs BSC alone (n = 232). BSC patients who progressed were then offered panitumumab. The patients had previously received at least two lines of chemotherapy for mCRC.

The mPFS was shown to be eight weeks for panitumumab and 7.3 weeks for BSC. The response rate (RR) was 10% for the panitumumab-treated group, compared with 0 for patients having BSC only.

There was no gain in mOS for the panitumumabtreated group, but since BSC patients who progressed were offered crossover to panitumumab, this could be a confounder for the results.

No treatment-related deaths were observed.

Of patients treated with panitumumab, 90% developed skin-related toxicities; however, this only occurred in 10% of the BSC group. Skin rash is a wellknown toxicity of many EGFR inhibitors and has been shown in previous trials of cetuximab to be positively related to efficacy of the drug[12,13] in terms of both mOS and RR.

A recent pooled analysis from 920 patients across 10 clinical trials treated with panitumumab monotherapy demonstrated a high grade of skin-related toxicities (92%), but these were dose-limiting in only 2% of patients.[14] An extension study of the phase III study evaluated panitumumab monotherapy in BSC patients who had documented disease progression, and the trial confirmed activity and good tolerability for patients with refractory mCRC.[15]

Most trials conducted have focused on the benefit of panitumumab as a single agent. In a phase II study by Berlin et al,[16] frontline combination of panitumumab with bolus 5-FU, LV and irinotecan (IFL) or with infusion 5-FU, LV and oxaliplatin (FOLFIRI) was evaluated. mPFS was 5.6 months for the IFL-treated group and 10.9 months for the FOLFIRI-treated patients, with mOS 17 months and 22.5 months, respectively.

There was more grade 3-4 diarrhoea in the IFL group.

Panitumumab early in the course of treatment of mCRC and the optimal combination with other agents must be further validated in future studies.

In one large phase III study by Amgen,[17] the PACCE
trial (Panitumumab Advanced Colorectal Cancer Evaluation), panitumumab in combination with bevazicumab was investigated in combination with either oxaliplatin- or irinotecan-based chemotherapy as frontline treatment for mCRC. Recently, panitumumab treatment was discontinued in the trial because of statistically significant difference in PFS in favour of the control arm (bevacizumab plus chemotherapy).

The strategy of treatment with two biologics – that is, blocking two pathways at the same time (combination of an anti-EGFR antibody with an anti-VEGF antibody) – must be further investigated.

[[HPE40.40]]

Conclusion
The exact role of the targeted therapies that include panitumumab in the treatment of mCRC still needs to be fully addressed.

The advantage of panitumumab is that it can be administered without any premedication since it is a fully human mAb and has demonstrated good toxicity profile and promising activity when administered as a single agent and in combination with other drugs.

It remains to be established how to integrate the targeted therapy with chemotherapy. With the chemotherapy and biological agents available, we are moving towards a strategy of more individualised treatment for mCRC patients whereby they do not necessarily wait for disease progression before switching agent or combination.

The paradigm shift in treatment of mCRC also includes a stop-go strategy, with discontinuation in therapy and maintenance therapy.[18] Our goal is to expose all patients who are sufficiently well to all the treatments available while minimising toxicity and improving survival. The challenge is to define the optimal clinical use of the different agents.

Identification of patients who will benefit from panitumumab treatment is a key issue. The biological activity of the antibodies must be further analysed so that predictive markers for response to the therapy can be identified.

References
1. Cancer stats: cancer research UK 2005.
www.cancerresearchuk.org
2. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22(2):229-37.
3. Cassidy J, Tabernero J, Twelves C, et al. XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 2004;22(11):2084-91.
4. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5(5):341-54.
5. US Food and Drug Administration. www.FDA.gov
6. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007;25(13):1658-64.
7. Berlin J, Neubauer M, Swanson P, et al. Panitumumab antitumor activity in patients with metastatic colorectal cancer expressing ≥10% epidermal growth factor receptor (EGFr). Proc ASCO 2006, Annual Meeting. Abstract 3548.
8. Hecht JR, Patnaik A, Berlin J, et al. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 2007;110(5):980-8.
9. Mitchell EP, Hecht JR, Baranda J, et al. Panitumumab activity in metastatic colorectal cancer patients with low or negative tumor epidermal growth factor receptor levels: an updated analysis. Proc ASCO 2007, Annual Meeting. Abstract 4082.
10. Moroni M, Veronese S, Benvenuti S, et al. Gene copy number for epidermal growth factor receptor and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 2005;6(5):279-86.
11. Weiner LM. Fully human therapeutic monoclonal antibodies. J Immunother 2006;29(1):1-9.
12. Saltz LB, Meropol NJ, Loehrer PJ, et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004;22(7):1201-8.
13. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in  irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351(4):337-45.
14. Peeters M, Van Cutsem E, Berlin J, et al. Safety of panitumumab, a fully human monoclonal antibody against the epidermal growth factor receptor in patients with metastatic colorectal cancer (mCRC) across clinical trials. Proc ASCO 2007, Annual Meeting. Abstract 4138.
15. Van Cutsem E, Siena S, Humblet Y, et al. An open-label,
single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy. Ann Oncol 2007;4 (epub ahead of print).
16. Berlin J, Posey J, Tchekmedyian S, et al. Panitumumab with irinotecan/leucovorin/5-fluorouracil for first-line treatment of metastatic colorectal cancer. Clin Colorectal Cancer 2007;6(6):427-32.
17. Amgen. www.Amgen.com
18. Goldberg RM, Rothenberg ML, Van Cutsem E, et al. The continuum of care: a paradigm for the management of metastatic colorectal cancer. Oncologist 2007;12(1):38-50.



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