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Panitumumab – an effective long-term treatment for patients with metastatic colorectal cancer and wild-type KRAS status
Cancer Treatment Reviews 36S1 (2010) S15–S16
Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
Case commentary
Panitumumab – an effective long-term treatment for patients with metastatic colorectal cancer and wild-type KRAS status Elena Elez, Maria Alsina, Josep Tabernero* Medical Oncology Department, Vall d’Hebron University Hospital, P. Vall d’Hebron 119–129, 08035, Barcelona, Spain
article info Keywords: Metastatic colorectal cancer Late-stage metastatic colorectal cancer Panitumumab Response Skin toxicity Diarrhoea
Since the introduction of several novel agents with different mechanisms of action in the past decade, inhibitors of the epidermal growth factor receptor (EGFR) have increased therapeutic options for patients with metastatic colorectal cancer (mCRC) requiring treatment following chemotherapy failure. Seront et al. report the noteworthy case of a patient with mCRC and wild-type KRAS status, who had progressed during two lines of standard irinotecan-based (FOLFIRI) and oxaliplatin-based (FOLFOX) chemotherapy prior to receiving the EGFR inhibitor panitumumab. 1 It is notable that this patient with relatively late-stage disease achieved a significant and sustained response to panitumumab monotherapy. The fact that this patient’s response has been maintained for over 5 years to date is remarkable, especially considering that he had disease progression 9 months and 8 months after initiation of the first- and secondline therapies (Fig. 1). The treatment history suggests that this patient initially had an aggressive tumour (poorly differentiated carcinoma histology) with rapid distant lymph node involvement, and that the long period of disease control is indeed due to the antiEGFR therapy and not to the presence of slowly progressing disease. At the time of reporting, the patient is still receiving panitumumab treatment and continues to respond, emphasising the importance of treating a patient until disease progression. In line with their clinical evaluation in randomised, controlled trials, the dosing instructions of EGFR inhibitors clearly recommend that treatment should be given until progression. 2 Furthermore, there are no data to support the shorter-term use of anti-EGFR therapy in this setting. However, it is interesting to note then, that treating until progression is often not a reality in Europe. Here, more commonly, physicians treat their mCRC patients until the best response is achieved, at which point a treatment break often occurs – the physician may then consider restarting treatment as the tumour starts to progress. There may be various reasons for this course of action – one may be that the therapeutic aim in early disease is * Corresponding author. Tel.: +34 93 274 6085; fax: +34 93 274 6059. E-mail address: [email protected] (J. Tabernero). 0305-7372/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
to improve the potential for tumour resection and so treatment is understandably viewed as short term. Early discontinuation may also be a consequence of the fact that novel agents are often given alongside chemotherapy in patients with mCRC and so antiEGFR therapy is often discontinued when chemotherapy ceases, particularly if the patient is experiencing severe chemotherapyrelated toxicity. Furthermore, in some countries, a ‘stop and go’ or intermittent treatment strategy is sometimes favoured over continuous therapy. 3–6 The need for continuing treatment after a successful response or after severe toxicity on prior therapy may also be difficult to rationalise for the patient, although a 2- or 3-weekly dose schedule may be viewed as acceptable. 7 Nonetheless, this case raises important questions about the optimal management of patients with mCRC. If a patient has progressed during prior chemotherapy and yet responds to a novel targeted agent such as panitumumab, this case suggests that further benefits may be obtained and perhaps that prognosis may be improved with continuation of maintenance therapy until progression. Although it is unlikely that a patient will be cured of any microscopic metastatic disease during long-term therapy with a novel agent, maintenance therapy does allow the potential for long-term disease control. It is also important to note that any patient who initially responds to anti-EGFR therapy is likely to have a tumour that is highly reliant on the EGFR pathway for its growth. For this reason, if inhibitory treatment is withdrawn early, one would expect to see rapid progression of the disease when the EGFR pathway is reactivated, providing further rationale for continuing to treat a responding patient. Perhaps a further reason for early discontinuation of anti-EGFR therapy is the occurrence of the dermatological toxicities that appear to be a class effect of these therapies. Such adverse events can be distressing and it is, therefore, important that any patient beginning anti-EGFR therapy is made aware of these side effects and also of the potential positive correlation between skin toxicity and improved outcome. 7,8 However, the toxicities seen with these
S16
E. Elez et al. / Cancer Treatment Reviews 36S1 (2010) S15–S16
Fig. 1. Response to panitumumab (size of inguinal lymph node metastases over time is shown in the grey boxes). 1 CEA = carcinoembryonic antigen; CT = computerised tomography; PET-CT = positron emission tomography–computerised tomography.
therapies are rarely severe, more commonly being only mild to moderate in intensity. 2,9 Moreover, the acne-like skin rash generally peaks during the first 2–8 weeks of anti-EGFR therapy, then becomes less prominent, although other types of dermatological toxicity may appear during long-term treatment. Early intervention at the first sign of rash is vital for the optimal management of dermatological toxicities, and some data even suggest a role for prophylactic intervention, 10 which is an option that should also be discussed with the patient. In the case reported by Seront et al., although skin toxicity was noted, its presentation was minimal and it was accepted by the patient and well managed by his physicians; the only other observed toxicity was diarrhoea which was easily controlled. 1 Reassuringly, and in line with current clinical data for panitumumab, no infusion reactions occurred during treatment and no neutralising human–anti-human antibodies were detected in this patient despite long-term treatment, an advantage of a fullyhuman monoclonal antibody such as panitumumab. Clinical trials would be of scientific interest to further analyse how populations of patients respond to panitumumab treatment with the aim of identifying factors associated with prolonged response. However, as it is only in rare cases that patients experience such significant and long-term disease control, this would be difficult to study in practice. It is, therefore, important that we continue the search for potential biomarkers that could better profile those patients who are likely to gain the most consistent benefit from treatment with anti-EGFR therapies such as panitumumab. To this end, it may be of interest for Seront et al. and other physicians encountering such long-term responders to analyse their patient’s tumour biomarker profile in terms of the status of other genes and proteins known to be involved in EGFR signalling. 11–14 Acknowledgements Medical writing support (funded by Amgen [Europe] GmbH) was provided by Dawn Batty PhD from Bioscript Stirling Ltd. Conflict of interests Elena Elez and Maria Alsina have no conflicts of interest to declare. Josep Tabernero declares participation in advisory boards and satellite symposia sponsored by Amgen.
References 1. Seront E, Marot L, Coche E, Gala J-L, Sempoux C, Humblet Y. Successful long-term management of a patient with late-stage metastatic colorectal cancer treated with panitumumab. Cancer Treat Rev 2010;36(Suppl 1):S11–4. 2. Merck Serono. Erbitux® (cetuximab) Summary of Product Characteristics. Available at http://emc.medicines.org.uk/medicine/19595/SPC/Erbitux+5mg+ml+solution+ for+infusion/. Accessed 11 November 2009. 3. Tournigard C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer – a GERCOR study. J Clin Oncol 2006;24:394–400. 4. Chibaudel B, Maindrault-Goebel F, Lledo G, et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol 2009;27:5727–33. 5. Labianca R, Floriani E, Cortesi L, et al. Alternating versus continuous “FOLFIRI” in advanced colorectal cancer (ACC): A randomized “GISCAD” trial. J Clin Oncol ASCO Annual Meeting Proceedings 2006;24(18S):3505. 6. Bouche´ O, Beretta GD, Garc´ıa Alfonso P, Geissler M. The role of anti-epidermal growth factor receptor monoclonal antibody monotherapy in the treatment of metastatic colorectal cancer. Cancer Treat Rev 2010;36(Suppl 1):S1–10. 7. Segaert S, Chiritescu G, Lemmens L, Dumon K, Van Cutsem E, Tejpar S. Skin toxicities of targeted therapies. Eur J Cancer 2009;45(Suppl 1):295–308. 8. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005;16:1425–33. 9. Amgen Ltd. Vectibix® (panitumumab) Summary of Product Characteristics. Available at http://www.emc.medicines.org.uk/medicine/20528/SPC/Vectibix/. Accessed 23 November 2009. 10. Mitchell EP, Lacouture M, Shearer H, et al. Final STEPP results of prophylactic versus reactive skin toxicity (ST) treatment (tx) for panitumumab (pmab)related ST in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2009;27(18S):CRA4027. 11. Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M, et al. Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS One 2009;4:e7287. 12. Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 2009;27:5924–30. 13. Jacobs B, De Roock W, Piessevaux H, et al. Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 2009;27:5068–74. 14. Tabernero J, Cervantes A, Rivera F, et al. Pharmacogenomic and pharmacoproteomic studies of cetuximab in metastatic colorectal cancer: Biomarker analysis of a phase I dose-escalation study. J Clin Oncol 2010 Jan 25 [Epub ahead of print].
Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
Case commentary
Panitumumab – an effective long-term treatment for patients with metastatic colorectal cancer and wild-type KRAS status Elena Elez, Maria Alsina, Josep Tabernero* Medical Oncology Department, Vall d’Hebron University Hospital, P. Vall d’Hebron 119–129, 08035, Barcelona, Spain
article info Keywords: Metastatic colorectal cancer Late-stage metastatic colorectal cancer Panitumumab Response Skin toxicity Diarrhoea
Since the introduction of several novel agents with different mechanisms of action in the past decade, inhibitors of the epidermal growth factor receptor (EGFR) have increased therapeutic options for patients with metastatic colorectal cancer (mCRC) requiring treatment following chemotherapy failure. Seront et al. report the noteworthy case of a patient with mCRC and wild-type KRAS status, who had progressed during two lines of standard irinotecan-based (FOLFIRI) and oxaliplatin-based (FOLFOX) chemotherapy prior to receiving the EGFR inhibitor panitumumab. 1 It is notable that this patient with relatively late-stage disease achieved a significant and sustained response to panitumumab monotherapy. The fact that this patient’s response has been maintained for over 5 years to date is remarkable, especially considering that he had disease progression 9 months and 8 months after initiation of the first- and secondline therapies (Fig. 1). The treatment history suggests that this patient initially had an aggressive tumour (poorly differentiated carcinoma histology) with rapid distant lymph node involvement, and that the long period of disease control is indeed due to the antiEGFR therapy and not to the presence of slowly progressing disease. At the time of reporting, the patient is still receiving panitumumab treatment and continues to respond, emphasising the importance of treating a patient until disease progression. In line with their clinical evaluation in randomised, controlled trials, the dosing instructions of EGFR inhibitors clearly recommend that treatment should be given until progression. 2 Furthermore, there are no data to support the shorter-term use of anti-EGFR therapy in this setting. However, it is interesting to note then, that treating until progression is often not a reality in Europe. Here, more commonly, physicians treat their mCRC patients until the best response is achieved, at which point a treatment break often occurs – the physician may then consider restarting treatment as the tumour starts to progress. There may be various reasons for this course of action – one may be that the therapeutic aim in early disease is * Corresponding author. Tel.: +34 93 274 6085; fax: +34 93 274 6059. E-mail address: [email protected] (J. Tabernero). 0305-7372/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
to improve the potential for tumour resection and so treatment is understandably viewed as short term. Early discontinuation may also be a consequence of the fact that novel agents are often given alongside chemotherapy in patients with mCRC and so antiEGFR therapy is often discontinued when chemotherapy ceases, particularly if the patient is experiencing severe chemotherapyrelated toxicity. Furthermore, in some countries, a ‘stop and go’ or intermittent treatment strategy is sometimes favoured over continuous therapy. 3–6 The need for continuing treatment after a successful response or after severe toxicity on prior therapy may also be difficult to rationalise for the patient, although a 2- or 3-weekly dose schedule may be viewed as acceptable. 7 Nonetheless, this case raises important questions about the optimal management of patients with mCRC. If a patient has progressed during prior chemotherapy and yet responds to a novel targeted agent such as panitumumab, this case suggests that further benefits may be obtained and perhaps that prognosis may be improved with continuation of maintenance therapy until progression. Although it is unlikely that a patient will be cured of any microscopic metastatic disease during long-term therapy with a novel agent, maintenance therapy does allow the potential for long-term disease control. It is also important to note that any patient who initially responds to anti-EGFR therapy is likely to have a tumour that is highly reliant on the EGFR pathway for its growth. For this reason, if inhibitory treatment is withdrawn early, one would expect to see rapid progression of the disease when the EGFR pathway is reactivated, providing further rationale for continuing to treat a responding patient. Perhaps a further reason for early discontinuation of anti-EGFR therapy is the occurrence of the dermatological toxicities that appear to be a class effect of these therapies. Such adverse events can be distressing and it is, therefore, important that any patient beginning anti-EGFR therapy is made aware of these side effects and also of the potential positive correlation between skin toxicity and improved outcome. 7,8 However, the toxicities seen with these
S16
E. Elez et al. / Cancer Treatment Reviews 36S1 (2010) S15–S16
Fig. 1. Response to panitumumab (size of inguinal lymph node metastases over time is shown in the grey boxes). 1 CEA = carcinoembryonic antigen; CT = computerised tomography; PET-CT = positron emission tomography–computerised tomography.
therapies are rarely severe, more commonly being only mild to moderate in intensity. 2,9 Moreover, the acne-like skin rash generally peaks during the first 2–8 weeks of anti-EGFR therapy, then becomes less prominent, although other types of dermatological toxicity may appear during long-term treatment. Early intervention at the first sign of rash is vital for the optimal management of dermatological toxicities, and some data even suggest a role for prophylactic intervention, 10 which is an option that should also be discussed with the patient. In the case reported by Seront et al., although skin toxicity was noted, its presentation was minimal and it was accepted by the patient and well managed by his physicians; the only other observed toxicity was diarrhoea which was easily controlled. 1 Reassuringly, and in line with current clinical data for panitumumab, no infusion reactions occurred during treatment and no neutralising human–anti-human antibodies were detected in this patient despite long-term treatment, an advantage of a fullyhuman monoclonal antibody such as panitumumab. Clinical trials would be of scientific interest to further analyse how populations of patients respond to panitumumab treatment with the aim of identifying factors associated with prolonged response. However, as it is only in rare cases that patients experience such significant and long-term disease control, this would be difficult to study in practice. It is, therefore, important that we continue the search for potential biomarkers that could better profile those patients who are likely to gain the most consistent benefit from treatment with anti-EGFR therapies such as panitumumab. To this end, it may be of interest for Seront et al. and other physicians encountering such long-term responders to analyse their patient’s tumour biomarker profile in terms of the status of other genes and proteins known to be involved in EGFR signalling. 11–14 Acknowledgements Medical writing support (funded by Amgen [Europe] GmbH) was provided by Dawn Batty PhD from Bioscript Stirling Ltd. Conflict of interests Elena Elez and Maria Alsina have no conflicts of interest to declare. Josep Tabernero declares participation in advisory boards and satellite symposia sponsored by Amgen.
References 1. Seront E, Marot L, Coche E, Gala J-L, Sempoux C, Humblet Y. Successful long-term management of a patient with late-stage metastatic colorectal cancer treated with panitumumab. Cancer Treat Rev 2010;36(Suppl 1):S11–4. 2. Merck Serono. Erbitux® (cetuximab) Summary of Product Characteristics. Available at http://emc.medicines.org.uk/medicine/19595/SPC/Erbitux+5mg+ml+solution+ for+infusion/. Accessed 11 November 2009. 3. Tournigard C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer – a GERCOR study. J Clin Oncol 2006;24:394–400. 4. Chibaudel B, Maindrault-Goebel F, Lledo G, et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol 2009;27:5727–33. 5. Labianca R, Floriani E, Cortesi L, et al. Alternating versus continuous “FOLFIRI” in advanced colorectal cancer (ACC): A randomized “GISCAD” trial. J Clin Oncol ASCO Annual Meeting Proceedings 2006;24(18S):3505. 6. Bouche´ O, Beretta GD, Garc´ıa Alfonso P, Geissler M. The role of anti-epidermal growth factor receptor monoclonal antibody monotherapy in the treatment of metastatic colorectal cancer. Cancer Treat Rev 2010;36(Suppl 1):S1–10. 7. Segaert S, Chiritescu G, Lemmens L, Dumon K, Van Cutsem E, Tejpar S. Skin toxicities of targeted therapies. Eur J Cancer 2009;45(Suppl 1):295–308. 8. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005;16:1425–33. 9. Amgen Ltd. Vectibix® (panitumumab) Summary of Product Characteristics. Available at http://www.emc.medicines.org.uk/medicine/20528/SPC/Vectibix/. Accessed 23 November 2009. 10. Mitchell EP, Lacouture M, Shearer H, et al. Final STEPP results of prophylactic versus reactive skin toxicity (ST) treatment (tx) for panitumumab (pmab)related ST in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2009;27(18S):CRA4027. 11. Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M, et al. Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS One 2009;4:e7287. 12. Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 2009;27:5924–30. 13. Jacobs B, De Roock W, Piessevaux H, et al. Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 2009;27:5068–74. 14. Tabernero J, Cervantes A, Rivera F, et al. Pharmacogenomic and pharmacoproteomic studies of cetuximab in metastatic colorectal cancer: Biomarker analysis of a phase I dose-escalation study. J Clin Oncol 2010 Jan 25 [Epub ahead of print].