Opinion 17 October 2012

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE Opinion 17 October 2012 VECTIBIX 20 mg/ml, concentrate for solution for infusion B/1 vial of 5 ml (CIP code: ) B/1 vial of 10 ml (CIP code: ) B/1 vial of 20 ml (CIP code: ) Applicant: AMGEN S.A.S INN ATC Code (2007) Reason for the review Panitumumab L01XC08 (monoclonal antibodies) Inclusion for two extensions of the indication Lists concerned Approved for use by hospitals (PHC L ) Indications concerned "VECTIBIX is indicated for the treatment of patients with wild-type KRAS metastatic colorectal cancer (mcrc) - in first-line in combination with FOLFOX. - in second-line in combination with FOLFIRI for patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan)." HAS - Medical, Economic and Public Health Assessment Division 1/19

2 AB IAB Therapeutic use Substantial AB In the absence of a comparative study versus ERBITUX, VECTIBIX does not provide an improvement in actual benefit (non-existent IAB, V) in the treatment of wild-type KRAS metastatic colorectal cancer: - in first-line in combination with FOLFOX, - in second-line in combination with FOLFIRI for patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan). In the treatment of wild-type KRAS metastatic colorectal cancer, VECTIBIX is an alternative to ERBITUX when patients are eligible for: - first-line chemotherapy with FOLFOX or - a second-line FOLFIRI regimen and the condition of having received first-line fluoropyrimidine-based chemotherapy, excluding irinotecan or anti-egfr antibodies. HAS - Medical, Economic and Public Health Assessment Division 2/19

3 01 ADMINISTRATIVE AND REGULATORY INFORMATION Marketing Authorisation Prescription and delivery conditions Initial: 3 December 2007 (centralised procedure); Extension of the indications: 10 November 2011, amended on 27/06/2012 Conditional Marketing Authorisation List I Medicine requiring special monitoring during treatment. Prescription restricted to cancer research, haematology or medical oncology specialists and departments Medicinal product reserved for hospital use Inclusion on the extra Diagnostic Related Group List ATC Classification 2011 L L04 L04A L04AB L04AB06 Antineoplastic and immunomodulating agents Antineoplastic agents Other antineoplastic agents Monoclonal antibodies panitumumab HAS - Medical, Economic and Public Health Assessment Division 3/19

4 02 BACKGROUND Since December 2007, VECTIBIX, a totally human-derived monoclonal antibody acting against the Epidermal Growth Factor Receptor (EGFR), 1 has been authorized in the treatment of patients with wild-type KRAS metastatic colorectal cancer as a monotherapy after failure of fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy regimens. In this indication, on 30 April 2008 the Transparency Committee approved the inclusion of VECTIBIX on the list of medicines approved for hospital use and assigned a substantial actual benefit and a level V IAB (absence of improvement in actual benefit) for treatment. It this opinion, it was stipulated that: "In the light of current data, the efficacy/adverse effects ratio for VECTIBIX is insufficiently established (results from an exploratory sub-group post-hoc analysis). However, given the severity of the disease and the expected results from the two studies in progress that will be sent to the EMEA, the Transparency Committee considers that the actual benefit of VECTIBIX is substantial". Finally, the Committee requested that a descriptive study be set up of patients in France treated with VECTIBIX for colorectal cancer. Regarding the line extension as a first-line treatment in combination with FOLFOX and as a second-line treatment in combination with FOLFIRI for patients who have received fluoropyrimidine-based chemotherapy (excluding irinotecan), which is the subject of this opinion, an initially unfavourable opinion was given by CHMP on 18 March 2011, in particular due to: - a modest increase in progression-free survival without demonstrating an impact on overall survival of KRAS mutation-negative patients - a negative effect of the combination of panitumumab and FOLFOX-4 in terms of progression-free survival and overall survival in KRAS mutation-positive patients, - uncertainties concerning the efficacy (especially for patients over 75 years old or those with a ECOG score = 2), - a marked toxicity from the combination of panitumumab with chemotherapy. After re-examining and consulting with a group of experts, VECTIBIX obtained Marketing Authorisation in these line extensions on 10 November THERAPEUTIC INDICATIONS "VECTIBIX is indicated for the treatment of patients with wild-type KRAS metastatic colorectal cancer (mcrc): - in first-line in combination with FOLFOX. - in second-line in combination with FOLFIRI for patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan). - as monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens." 04 DOSAGE "Evidence of wild-type KRAS status is required before initiating treatment". "The recommended dose of VECTIBIX is 6 mg/kg of bodyweight given once every two weeks." 05 THERAPEUTIC STRATEGY In 2011, colorectal cancer was ranked third out of all types of cancer in France in terms of incidence, and second in terms of mortality. Colorectal cancer has a favourable prognosis when it is diagnosed in its early stages: relative survival at 5 years of 91% for localised grades and 70% for grades that have spread to 1 The other monoclonal anti-egfr antibody is chimeric (ERBITUX). HAS - Medical, Economic and Public Health Assessment Division 4/19

5 neighbouring organs. In contrast, survival at 5 years is approximately 11% when it has reached the metastatic phase, which represents approximately 25% of patients at the time of diagnosis. 2 The treatment of metastatic colorectal cancer has been significantly improved over the last few years. Overall survival has been vastly increased through the use in everyday practice of irinotecan and oxaliplatin, in combination with 5-fluorouracile (5FU) and folinic acid (FA) in the form LV5FU2, combinations known as FOLFIRI and FOLFOX respectively. A study demonstrated that in first- and second-line the sequences FOLFIRI-FOLFOX and FOLFOX-FOLFIRI had equivalent efficacy. 3 Since targeted therapies have become available, the benefit of the combination of chemotherapy and a targeted therapy seems apparent in first- and second-line treatment. 4 For patients eligible for an intensive treatment, determination of the KRAS status influences the choice of treatment. 5 Given the approval of the extensions of the indication for VECTIBIX and their evaluation by the Transparency Committee: In first-line treatment, anti-vegf antibodies (bevacizumab) followed by anti-egfr antibodies (cetuximab) were evaluated. Testing of EGFR status through immunohistochemistry is no longer recommended as this method is not reliable and is not indicative of the response; investigation of the KRAS mutation from the centre of the tumour is now performed. The indication of cetuximab is limited to tumours with KRAS wild-type status, while determination of the KRAS status is not required before starting treatment with bevacizumab. In the absence of a comparative study, the role of cetuximab in comparison to bevacizumab is yet to be determined. In second-line treatment, in cases of progression with chemotherapy associated to targeted therapy, the choice is to either change chemotherapy (irinotecan or oxaliplatin based on the regimen received as a first-line treatment), or change the targeted treatment. Since January 2013, the label wording of cetuximab in the Marketing Authorisation has been changed, and the use of cetuximab in combination with FOLFOX is no longer approved in second-line treatment. In third-line treatment, in cases of progression with irinotecan and oxaliplatin (with or without bevacizumab): absence of KRAS gene mutation: o either cetuximab o or panitumumab presence of KRAS gene mutation: palliative care or treatment trial. 2 Survie des patients atteints de cancer en France : état des lieux INCa - April Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. J Clin Oncol Jan 15; 22 (2): Thésaurus de cancérologie digestive SNFGE [Thesaurus of Gastrointestinal Oncology, metastatic colon cancer. Updated on 14/10/2011]. 5 Advanced colorectal cancer: ESMO clinical practice guidelines for treatment. Annals of Oncology 2010; 21 (5): HAS - Medical, Economic and Public Health Assessment Division 5/19

6 06 RELEVANT COMPARATOR MEDICINES 06.1 Medicinal products INN Cetuximab Identical pharmacotherapeutic class Yes Name (Laboratory) ERBITUX (Merck Indication mcrc with wild-type KRAS gene expression of the epidermal growth factor receptor (EGFR) in combination with chemotherapy, 6 Serono) as monotherapy after failure of oxaliplatin- and irinotecan-based treatments and in cases of intolerance to irinotecan. Date of Opinion AB 2009 Substantial IAB 1 st and 2 nd line as a combination: V after failure, as monotherapy: IV Bevacizumab Yes AVASTIN (Roche) mcrc: metastatic colorectal cancer mcrc in combination with fluoropyrimidine-based chemotherapy 1 st line: nd line: 2009 Substantial Substantial II IV compared with FOLFOX-4 alone Conclusion In the treatment of patients with metastatic colorectal cancer with no mutation of the KRAS gene, the clinically relevant comparator medicine is ERBITUX (cetuximab), another anti-egfr antibody with a similar indication to VECTIBIX one (panitumumab) and also limited to tumours with no KRAS gene mutation. AVASTIN, an anti-vegf antibody, has a broader indication, not restricted to tumours with expression of the non-mutated KRAS gene. 6 The wording of the indication for ERBITUX was restricted to use in combination with an irinotecan-based regimen or with FOLFOX-4 on 23 June 2011, then on 13 January 2012 to first-line treatment in combination with FOLFOX. The wording now reads: "ERBITUX is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, KRAS wild-type metastatic colorectal cancer in combination with irinotecan-based chemotherapy, in first-line in combination with FOLFOX, as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan." HAS - Medical, Economic and Public Health Assessment Division 6/19

7 07 ANALYSIS OF AVAILABLE DATA To support the request for inclusion for the two line extensions, the applicant has provided a clinical dossier including two pivotal studies: - in first-line treatment: PRIME study 7 in combination with FOLFOX-4 regimen - in second-line treatment: PEETERS study 8 in combination with FOLFIRI regimen. These two studies were performed during the post-hoc analysis of the pivotal trial of panitumumab as monotherapy in third-line treatment or beyond, incorporating the presence or absence of KRAS mutation, which enabled the initial conditional marketing authorisation to be obtained in This retrospective analysis showed that the efficacy of panitumumab as monotherapy was restricted to patients with no KRAS gene mutation, and the protocol for both of these two studies was amended to enable a prospective analysis of the efficacy of panitumumab combined with chemotherapy in patients with a tumour with or without KRAS gene mutation. These amendments were made after randomisation of 974 out of 1183 patients for the study as a first-line treatment, and after the randomisation period in the second-line study. Analyses of these studies are presented in the study reports including some KRAS mutation-negative and some KRAS mutation-positive patients. There are no results available for the overall population Efficacy PRIME Study ( ): first-line treatment in combination with FOLFOX-4 An open-label, randomised, phase III study that assessed the efficacy and safety of panitumumab (VECTIBIX) in combination with FOLFOX-4 versus FOLFOX-4 alone in previously untreated patients with metastatic colorectal cancer. Inclusion criteria: - patients over 18 years with metastatic colorectal cancer confirmed through histology or cytology - presence of at least one lesion 20 mm measured according to RECIST criteria - score on ECOG scale of 0, 1 or 2 - available tumour tissue (primary tumour or metastasis). Randomisation was stratified according to geographical location (Western Europe, Canada and Australia versus the rest of the world) and ECOG score (0 or 1 versus 2). Non-inclusion criteria included: - history or presence of metastases in the central nervous system - previous treatments, especially oxaliplatin, EGFR inhibitors (e.g.: cetuximab) and radiotherapy in the 14 days prior to randomisation, etc. Treatments: - panitumumab + FOLFOX-4 group: Panitumumab was administered at a dose of 6 mg/kg intravenously over 30 to 60 minutes before administration of FOLFOX-4 regimen which combined: - oxaliplatin: 85 mg/m² IV on Day 1 - leucovorin (or equivalent): 200 mg/m² IV on Days 1 and 2-5-FU: 400 mg/m² IV bolus followed by 600 mg/m² continuous IV on Days 1 and 2. 7 Douillard JY et al. Randomized, phase III study of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010, 28 (31): Peeters M et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol (28): HAS - Medical, Economic and Public Health Assessment Division 7/19

8 - FOLFOX-4 alone group: - oxaliplatin: 85 mg/m² IV on Day 1 - leucovorin (or equivalent): 200 mg/m² IV on Days 1 and 2-5-FU: 400 mg/m² IV bolus followed by 600 mg/m² continuous IV on Days 1 and 2. Chemotherapy cycles for each group were administered every two weeks. Primary efficacy endpoint: progression-free survival, defined as the time between randomisation and the date of the occurrence of disease progression, according to modified RECIST criteria or death of the patient from any cause (centralised radiological evaluation). The primary analysis was scheduled to take place after the occurrence of at least 380 events for progression-free survival. Secondary endpoints included: - overall survival, defined as the time between randomisation and death from any cause; An interim analysis of overall survival was included in the protocol; the date that it was to be performed had to coincide with that of the primary analysis of progression-free survival. - objective response rate, defined as a complete or partial response according to modified RECIST criteria 9 evaluated by an independent review board; - delay until disease progression, defined as the time between randomisation and the date when progression occurred, based on modified RECIST criteria. Results: A total of 1183 patients with metastatic colorectal cancer were randomised: 593 patients in the panitumumab combined with FOLFOX-4 group and 590 in the FOLFOX-4 alone group. The median age was 62 years and 9% of patients were older than 75 years. The majority of patients had an ECOG performance index of 0 or 1 (94%). Approximately two-thirds of patients had colon cancer and one-third had rectal cancer. The status of the KRAS gene was known for 1096 of the 1183 patients randomised (93%): 656 (55%) had no KRAS gene mutation and 440 (37%) were KRAS muted-type status In the sub-group of KRAS wild-type status patients (corresponding to the Marketing Authorisation population): In the primary analysis, the median progression-free survival (primary endpoint) was 9.6 months in the panitumumab + FOLFOX-4 group (n = 325) and 8 months in the FOLFOX-4 alone group (n = 331), which is an absolute increase of 1.6 months in favour of the combination of panitumumab and FOLFOX-4 (HR = 0.80; [ ]; p = 0.02). In the interim analysis of overall survival scheduled and carried out at the time of the main analysis for progression-free survival, 33% (106/325) of the panitumumab + FOLFOX-4 group and 37% (124/331) of the FOLFOX-4 group died. It was not possible to estimate the median overall survival in the panitumumab + FOLFOX-4 group and it was estimated as 18.8 months in the FOLFOX-4 alone group; NS. The primary analysis (scheduled after the occurrence of at least 380 events) of overall survival did not show any difference between the median overall survival for either of the groups: 23.9 months in the panitumumab + FOLFOX-4 group versus 19.7 months in the FOLFOX- 4 group (HR = 0.83; [ ]; NS). The objective response rate was 55% (including 0% for complete response) in the panitumumab + FOLFOX-4 group and 48% (including 0% for complete response) in the FOLFOX-4 group; NS. The delay until disease progression was 10.8 months in the panitumumab + FOLFOX-4 group versus 9.2 months in the FOLFOX-4 group (HR = 0.77 [ ]; p = 0.02), see Table 1. The results are consistent with the sub-group analyses, excepted for two sub-groups in which an HR greater than 1 was observed: sub-group of patients aged over 75 years (9% of patients randomised): - median progression-free survival: HR = 1.22; [ ] - median overall survival: HR = 1.01; [ ] 9 Complete response: disappearance of all lesions, Partial response: regression by at least 30% for lesions, Progression: increase by at least 20% for lesions HAS - Medical, Economic and Public Health Assessment Division 8/19

9 sub-group of patients with an ECOG score of 2 (6% of randomised patients): - median progression-free survival: HR = 1.99; [ ] - median overall survival: HR = 1.46; [ ]. To this end, the SPC states that a positive risk-benefit relationship has not been documented in patients with an ECOG score of 2. In an analysis carried out after an additional follow-up period of approximately 24 months (with no statistical hypothesis included in the study protocol): - the median progression-free survival was 10 months in the panitumumab + FOLFOX-4 group and 8.6 months in the FOLFOX-4 group, which is an absolute increase of 1.4 months in favour of the combination of panitumumab and FOLFOX-4 (HR = 0.80; [ ]; p = 0.009); - there was no difference in overall survival between the two groups: 23.9 months versus 19.7 months; NS. In the sub-group of KRAS muted-type status patients: In the primary analysis, the median progression-free survival was 7.3 months in the panitumumab + FOLFOX-4 group (n = 221) versus 8.8 months in the FOLFOX-4 group (n = 219), which is a numerical difference of 1.5 months not in favour of panitumumab + FOLFOX-4 (HR = 1.29; [ ]; p = 0.02). In the interim analysis of overall survival, scheduled and carried out at the time of the main analysis of progression-free survival, 51% (112/221) of the panitumumab + FOLFOX-4 group and 38% (84/219) of the FOLFOX-4 group had died. The estimated median overall survival was 15.1 months in the panitumumab + FOLFOX-4 group and 18.7 months in the FOLFOX-4 alone group, which is a numerical difference of 3.6 months not in favour of panitumumab (HR = 1.53; [ ]; p = 0.003). The main analysis of overall survival did not show any difference between the median overall survival for either group: 15.5 months in the panitumumab + FOLFOX-4 group versus 19.3 months in the FOLOFOX-4 group (HR = 1.24; [ ]; NS). According to these results not showing an advantage of the addition of panitumumab to oxaliplatin-based chemotherapy (FOLFOX-4), the use of panitumumab is contraindicated in patients with a known or undetermined KRAS gene mutation. Determination of the KRAS status is vital before treatment is started. The objective response rate was approximately 40% (including 0% for complete response) in each of the groups. The delay until disease progression was 7.5 months in the panitumumab + FOLFOX-4 group versus 9 months in the FOLFOX-4 group (HR = 1.2 [ ]; NS), see Table 1. HAS - Medical, Economic and Public Health Assessment Division 9/19

10 Table 1: Efficacy results from the PRIME study in the sub-groups KRAS wild-type status patients (corresponding to the Marketing Authorisation population) and KRAS muted-type status patients (ITT) KRAS wild type status (Marketing Authorisation population) panitumumab + FOLFOX-4 (n = 325) Progression-free survival (primary endpoint) FOLFOX-4 (n = 331) panitumumab + FOLFOX-4 (n = 221) KRAS muted-type status FOLFOX-4 (n = 219) Median (months) [95 % CI] 9.6 [9.2; 11.1] 8.0 [7.5; 9.5] 7.3 [6.3; 8.0] 8.8 [7.7; 9.4] Difference in medians (months) Relative risk [95% CI]; p 0.80 [0.66; 0.97]; p = [1.04; 1.62]; p = 0.02 Overall survival Median (months), [95% CI] 23.9 [20.3; 28.3] 19.7 [17.6; 22.7] 15.5 [13.1; 17.6] 19.3 [16.5; 21.8] Difference in medians (months) Relative risk [95% CI]; p 0.83 [0.67; 1.02]; NS 1.24 [0.98; 1.57]; NS Objective response rate % [95% CI] 55.2 [49.6; 60.8] 47.7 [42.1; 53.3] 39.5 [33.0; 46.4] 40.3 [33.6; 47.2] p NS NS Delay until tumour progression Median (months) [95 % CI] 10.8 [9.4; 12.4] 9.2 [7.7; 9.9] 7.5 [7.2; 8.9] 9 [7.7; 9.5] Relative Risk [95% CI]; p 0.77 [0.62; 0.97]; p = [0.94; 1.55]; NS PEETERS Study ( ): Second-line treatment in combination with FOLFIRI An open-label, randomised, phase III study that evaluated the efficacy and safety of panitumumab (VECTIBIX) in combination with FOLFIRI versus FOLFIRI alone in the second-line treatment of patients with metastatic colorectal cancer previously treated. Inclusion criteria: - patients older than 18 years with metastatic colorectal cancer confirmed by histology or cytology - previous first-line fluoropyrimidine-based chemotherapy (excluding irinotecan) with disease progression confirmed through x-rays according to RECIST criteria in the 6 months after stopping treatment - presence of at least one lesion 20 mm measured according to RECIST criteria - score on ECOG scale of 0, 1 or 2 - tumour tissue available (primary tumour or metastasis). Randomisation was stratified according to previous treatments (oxaliplatin, bevacizumab) and ECOG score (0 or 1 versus 2). Non-inclusion criteria included: - history or presence of metastases in the central nervous system - previous treatments, especially irinotecan, EGFR inhibitors (e.g.: cetuximab) and radiotherapy in the 14 days prior to randomisation, etc. Treatments: - panitumumab + FOLFIRI group: Panitumumab was administered at a dose of 6 mg/kg IV over 30 to 60 minutes before administration of FOLFIRI regimen, which combined: - irinotecan: 180 mg/m² over 90 min on Day 1 HAS - Medical, Economic and Public Health Assessment Division 10/19

11 - leucovorin: 400 mg/m² over 120 min on Day 1-5-FU: 400 mg/m² IV bolus followed by 2400 mg/m² IV push on Days 1 and 2. - FOLFIRI group alone: - irinotecan: 180 mg/m² over 90 min on Day 1 - leucovorin: 400 mg/m² over 120 min on Day 1-5-FU: 400 mg/m² IV bolus followed by 1200 mg/m² IV push on Days 1 and 2. Chemotherapy cycles were administered every two weeks. Primary efficacy endpoints: - progression-free survival, defined as the time between randomisation and the date of occurrence of disease progression based on modified RECIST criteria or death of a patient from any cause (centralised radiological assessment). The primary analysis was scheduled after the occurrence of at least 380 progression-free survival events in the sub-group of KRAS wild-type status patients. The comparison of treatments was made with a 1% significance level. - overall survival, defined as the time from randomisation to death from any cause. An interim analysis of overall survival was scheduled after the occurrence of 285 deaths (which is 75% of deaths required for the primary analysis). Comparison of treatments was made with a 4% significance level. Secondary endpoints included: - objective response rate, defined as a complete or partial response according to modified RECIST criteria assessed by an independent review board; - delay until disease progression, defined as the time between randomisation and the date when progression occurred, based on modified RECIST criteria. Results: A total of 1186 patients with metastatic colorectal cancer were randomised: 591 in the panitumumab combined with FOLFIRI group and 595 in the FOLFIRI alone group. The median age was 61 years and 7% of patients were older than 75 years. The majority of patients had an ECOG performance index of 0 or 1 (94%). Approximately two-thirds of patients had colon cancer and one-third had rectal cancer. The status of the KRAS gene was known for 1083 of the 1186 patients randomised (91%): 597 (55%) did not have mutation of the KRAS gene and 486 (45%) were KRAS muted-type status. Previous treatments included: 5-FU (71%), capecitabine (24%), oxaliplatin (67%) and bevacizumab (18%). Note: Since 2005, the first-line treatment of metastatic colorectal cancer is generally the combination of a targeted therapy and chemotherapy. In the sub-group of KRAS wild-type status patients (corresponding to the Marketing Authorisation population): In the primary analysis, the median progression-free survival (co-primary endpoint) was 5.9 months in the panitumumab + FOLFIRI group (n = 303) and 3.9 months in the FOLFIRI alone group (n = 294), which is an absolute increase of two months in favour of the combination of panitumumab and FOLFIRI (HR = 0.73; [ ]; p = 0.004). There was no difference in median overall survival (the other co-primary endpoint) between the two groups: 14.5 months in the panitumumab + FOLFIRI group versus 12.5 months in the FOLFIRI group (HR = 0.85; [ ]; NS) in the primary analysis. Results from the interim analysis are not available in the study report. The objective response rate was 35% (including 0% for complete response) in the panitumumab + FOLFIRI group and 10% (including 0% for complete response) in the FOLFIRI alone group (p < ). The delay until disease progression was 7.3 months in the panitumumab + FOLFIRI group versus 5.3 months in the FOLFIRI group (HR = 0.68 [0.56; 0.84]; p = ), see Table 2. HAS - Medical, Economic and Public Health Assessment Division 11/19

12 Results are consistent in the scheduled sub-group analyses. An HR greater than 1 was observed in the sub-group of patients who had disease progression more than 6 months after chemotherapy (representing 11% of patients randomised, 67/597): - median progression-free survival: HR = 1.05; [ ] - median overall survival: HR = 1.17; [ ] and in the sub-group of patients aged over 75 years (representing 7% of patients randomised, 42/597) for overall survival: HR = 1.05; [ ]. In an analysis carried out with an additional follow-up period of approximately 12 months: - the median progression-free survival was 6.4 months in the panitumumab + FOLFIRI group and 4.6 months in the FOLFIRI group, which is an absolute increase of 1.8 months in favour of the combination of panitumumab and FOLFIRI (HR = 0.79; [ ]; p = 0.002); - there was no difference in median overall survival between the two groups: 14.5 months versus 12.5 months (HR = 0.92; [ ]; NS). In the sub-group of KRAS muted-type status patients: In the primary analysis, there was no difference in median progression-free survival between the two groups: 5 months in the panitumumab + FOLFIRI group (n = 238) versus 4.9 months in the FOLFIRI group (n = 248), (HR = 0.85; [ ]; NS). There was also no difference in median overall survival between the two groups: 11.8 months in the panitumumab + FOLFIRI group versus 11.1 months in the FOLFIRI group (HR = 0.94; [ ]; NS). The objective response rate was 13% (including 0% for complete response) in the panitumumab + FOLFIRI group and 14% (including 0% for complete response) in the FOLFIRI alone group (NS). The delay until disease progression was 5.5 months in both groups (HR = 0.89 [0.71; 1.11]; NS), see Table 2. Table 2: Efficacy results from the PEETERS study in the sub-groups KRAS wild-type status patients (corresponding to the Marketing Authorisation population) and KRAS muted-type status patients (ITT) KRAS mutation-negative (Marketing Authorisation population) panitumumab + FOLFIRI (n = 303) Progression-free survival (co-primary endpoint) FOLFIRI (n = 294) KRAS mutation-positive panitumumab + FOLFIRI (n = 238) FOLFIRI (n = 248) Median (months) [95 % CI] 5.9 [5.5; 6.7] 3.9 [3.7; 5.3] 5 [3.8; 5.6] 4.9 [3.6; 5.6] Difference in medians (months) Relative risk [95% CI]; p 0.73 [0.59; 0.90]; p = [0.68; 1.06]; NS Overall survival (co-primary endpoint) Median (months), [95% CI] 14.5 [13.0; 16.0] 12.5 [11.2; 14.2] 11.8 [10.4; 13.3] 11.1 [10.3; 12.4] Difference in medians (months) Relative risk [95% CI]; p 0.85 [0.70; 1.04]; NS 0.94 [0.76; 1.15]; NS Objective response rate % [95% CI] 35.4 [29.9; 41.1] 9.8 [6.6; 13.9] 13.4 [9,3; 18.4] 13.9 [9.8; 19.0] p < NS Delay until tumour progression Median (months) [95 % CI] 7.3 [5.9; 7.5] 5.3 [3.9; 5.7] 5.5 [4.5; 5.7] 5.5 [4.2; 5.7] Relative Risk [95% CI]; p 0.68 [0.56; 0.84]; p = [0.71; 1.11]; NS HAS - Medical, Economic and Public Health Assessment Division 12/19

13 07.2 Safety/Adverse effects PRIME Study ( ): First-line treatment in combination with FOLFOX-4 In the sub-group of KRAS wild-type status patients (corresponding to the Marketing Authorisation population): Treatment discontinuation due to adverse events affected 24% (78/322) of patients in the panitumumab + FOLFOX-4 group and 14% (46/327) of patients in the FOLFOX-4 alone group. The most common adverse event that led to discontinuation of panitumumab was rash (4%) and the most common event leading to the discontinuation of FOLFOX-4 was partesthesia (3% in the panitumumab + FOLFOX-4 group versus 2% in the FOLFOX-4 alone group). The percentage of patients who had serious adverse events was 40% (130/322) in the panitumumab + FOLFOX-4 group and 36% (118/327) in the FOLFOX-4 group. Grade 3 events affected 89% (286/322) of patients in the panitumumab + FOLFOX-4 group and 76% (247/327) of patients in the FOLFOX-4 group. The most common were skin related (34% versus 1%), gastrointestinal (34% versus 20%), infections (16% versus 8%) and metabolic and nutritional disorders (21% versus 11%). The grade 3 events more commonly reported (> 5%) in the panitumumab + FOLFOX-4 group than in the FOLFOX-4 alone group were: - diarrhoea (18% versus 9%) - rash (17% versus 0%) - dermatitis acneiform (10% versus 0%) - hypokalaemia (10% versus 5%) - fatigue (9% versus 3%) - hypomagnesaemia (6% versus 0%). The most common events included (panitumumab + FOLFOX-4 versus FOLFOX-4): diarrhoea (62% versus 52%), neutropenia (59% versus 61%), rash (54% versus 7%) and nausea (44% versus 50%). In the sub-group of KRAS muted-type status patients: Treatment discontinuation due to adverse events affected 19% (42/217) of patients in the panitumumab + FOLFOX-4 group and 14% (31/218) of patients in the FOLFOX-4 alone group. The most common adverse event leading to discontinuation of panitumumab was rash (5%) and the most common event leading to the discontinuation of FOLFOX-4 was paraesthesia (2% in the panitumumab + FOLFOX-4 group versus 1% in the FOLFOX-4 alone group). The percentage of patients who had a serious adverse event was 47% (102/217) in the panitumumab + FOLFOX-4 group and 29% (63/218) in the FOLFOX-4 group. Grade 3 events affected 88% (190/217) of patients in the panitumumab + FOLFOX-4 group and 76% (166/218) of patients in the FOLFOX-4 group. The most common were skin-related (29% versus < 1%), gastrointestinal (31% versus 18%), metabolic and nutritional (20% versus 6%) and infections (14% versus 7%). The grade 3 events which were more commonly reported (> 5%) in the panitumumab + FOLFOX-4 group than in the FOLFOX-4 alone group were: - rash (13% versus 0%) - neutropenia (35% versus 46%) - diarrhoea (20% versus 10%) - dermatitis acneiform (7% versus 0%) - hypomagnesaemia (6% versus 0%) - hypokalaemia (9% versus 4%). The most common events included (panitumumab + FOLFOX-4 versus FOLFOX-4): diarrhoea (59% versus 46%), neutropenia (50% versus 62%), rash (48% versus 5%) and nausea (45% versus 46%). HAS - Medical, Economic and Public Health Assessment Division 13/19

14 7.2.2 PEETERS Study ( ): Second-line treatment in combination with FOLFIRI In the sub-group of KRAS wild-type status patients (corresponding to the Marketing Authorisation population): Treatment discontinuation due to adverse events affected 21% (64/302) of patients in the panitumumab + FOLFIRI group and 13% (37/294) of patients in the FOLFIRI alone group. The most common adverse event that led to discontinuation of panitumumab was rash (3%) and the most common leading to discontinuation with FOLFIRI was neutropenia (2% in each group). The percentage of patients who had serious adverse events was 41% (124/302) in the panitumumab + FOLFIRI group and 31% (91/294) in the FOLFIRI group. Grade 3 events affected 76% (231/302) of patients in the panitumumab + FOLFIRI group and 58% (170/294) of patients in the FOLFIRI group. The grade 3 events more commonly reported (> 5%) in the panitumumab + FOLFIRI group than in the FOLFIRI alone group were: - rash (15% versus 0%) - dermatitis acneiform (9% versus 0%) - hypokalaemia (7% versus 1%). The most common adverse effects included: diarrhoea (66% versus 57%), rash (52% versus 8%), nausea (51% versus 48%) and neutropenia (37% versus 40%). In the sub-group of KRAS muted-type status patients: Treatment discontinuation for adverse events affected 19% (46/237) of patients in the panitumumab + FOLFIRI group and 10% (25/246) of patients in the FOLFIRI alone group. The most common adverse event that led to discontinuation of treatment was rash. The percentage of patients who had a serious adverse event was 37% (88/237) in the panitumumab + FOLFIRI group and 30% (74/246) in the FOLFIRI group. Grade 3 events affected 71% (168/237) of patients in the panitumumab + FOLFIRI group and 55% (136/54) of patients in the FOLFIRI group. The grade 3 events more commonly reported (> 5%) in the panitumumab + FOLFIRI group than in the FOLFIRI alone group were: - rash (16% versus 0%) - dermatitis acneiform (8% versus 0%) - mucosal inflammation (7% versus 2%). The most common adverse events were similar to those observed in the sub-group of KRAS wildtype status patients and included: diarrhoea (62% versus 56%), rash (58% versus 5%), nausea (46% versus 45%), fatigue (37% versus 35%) and neutropenia (31% versus 33%) Additional information Since the commercial launch of VECTIBIX, information has been communicated to healthcare professionals on several occasions, mainly related to pharmacovigilance data. Hypersensitivity reactions A letter in April 2010 was sent to oncology and gastroenterology specialists regarding serious hypersensitivity reactions including anaphylactic reaction and Quincke's oedema. In clinical studies, reactions linked to the infusion (occurring in the 24 hours following the infusion) were recorded for 3% of patients treated with VECTIBIX, less than 1% of which were severe. One case of Quincke's oedema, with fatal outcome, was observed in one clinical study and two cases of fatal hypersensitivity reactions that occurred during and immediately after an infusion have been reported since the commercialisation of VECTIBIX. The SmPC for VECTIBIX was updated, specifically to state that: HAS - Medical, Economic and Public Health Assessment Division 14/19

15 - VECTIBIX is contraindicated in patients with a history of severe or life-threatening hypersensitivity reactions to VECTIBIX; - hypersensitivity reactions that occurred more than 24 hours after the infusion were also reported. Keratitis and ulcerative keratitis A letter was circulated in June 2011 to healthcare professionals to inform them that rare cases of severe keratitis and ulcerative keratitis have been reported since the commercial launch of VECTIBIX. During the clinical trials, seven non-serious cases of keratitis were reported in patients treated with VECTIBIX, with an incidence of between 0.2% and 0.7%. Since the commercial launch of VECTIBIX in 2007, one serious case of keratitis and three cases of serious ulcerative keratitis have been reported in patients treated with VECTIBIX as monotherapy. In one case, ulcerative keratitis led to a total loss of sight in one eye and a severe loss of vision in the other. Determination of KRAS status In November 2011, when line extensions for VECTIBIX in combination with chemotherapy were granted, and within the scope of a risk minimisation plan, a communication to oncologists and gastroenterologists was made, which included the following information: - VECTIBIX in combination with chemotherapy including oxaliplatin is contraindicated in patients with mcrc with mutation of the KRAS gene or in those in whom the KRAS status has not been determined; - VECTIBIX has not demonstrated any benefit to patients with tumours that have the KRAS muted-type gene status; - a negative effect on the progression-free survival and overall survival has been demonstrated in patients with the KRAS muted-type status receiving VECTIBIX in combination with a FOLFOX regimen; - determination of the wild-type KRAS status is compulsory before starting treatment with VECTIBIX. Furthermore, a European investigation evaluating the understanding of the KRAS test by doctors and a retrospective study reviewing medical files assessing the use of the KRAS test will be carried out. Dermatological reactions A letter to healthcare professionals was circulated in July 2012 regarding the combination of panitumumab with infection complications from severe dermatological reactions, which were either life-threatening or fatal, including one case of necrotising fasciitis". This letter also stated that: - severe grade 3 dermatological reactions (34% 10 ) have been very commonly reported in patients treated with panitumumab. These reactions include rare cases of skin necrosis, followed in some cases by life-threatening infection complications such as cellulitis, septicaemia and necrotising fasciitis; - a review of the clinical studies and post-marketing notifications has identified five cases of necrotising fasciitis, including three with fatal outcome, in patients treated with panitumumab. Four of the five patients have been treated with panitumumab in combination with an oxaliplatincontaining polychemotherapy, and one patient received panitumumab in combination with an irinotecan-containing polychemotherapy Usage data During the initial reimbursement access of VECTIBIX in monotherapy for the treatment of patients with wild-type KRAS metastatic colorectal cancer expressing EGFR, after failure with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy regimens, the Transparency Committee requested for a descriptive study to be set up of for patients treated with VECTIBIX in 10 SmPC for VECTIBIX HAS - Medical, Economic and Public Health Assessment Division 15/19

16 France for colorectal cancer. The results from the VECTEUR study set up by the applicant are presented in the Appendix, as well as OMEDIT data from Bretagne and the Pays de la Loire. Furthermore, a monitoring study was implemented in October 2010 on management of skin toxicities (POPEC monitoring study). The results are expected at the end of Summary & discussion The combination of panitumumab (VECTIBIX) and chemotherapy was evaluated as first-line treatment versus FOLFOX-4 alone and as a second-line treatment versus FOLFIRI alone in the treatment of metastatic colorectal cancer in two open-label, randomised phase III studies. The protocols were amended during the studies, in order to enable a prospective analysis to be carried out based on the KRAS status of patients. In both studies, the median age of patients was years and 7% to 9% were at least 75 years old. The majority had an ECOG performance index of 0 or 1 (94%). Approximately two-thirds of patients had colon cancer, while one-third had rectal cancer. There was no KRAS gene mutation in 55% of patients for whom the KRAS gene status was assessable. In first-line treatment in combination with FOLFOX-4: In the sub-group of 656 previously untreated patients (55.5%) with wild-type KRAS status, the addition of panitumumab to FOLFOX-4 alone was associated with: - a modest increase of 1.6 months in median progression-free survival (primary endpoint, 9.6 months versus 8 months) with no demonstrated impact on overall survival (23.9 months versus 19.7 months, HR = 0.83; [ ]; NS), - an increase in discontinuation of treatment due to adverse effects (24% versus 14%) and grade 3 events (89% versus 76%). The most common adverse events with panitumumab + FOLFOX-4 were: diarrhoea (62% versus 52% with FOLFOX-4 alone), neutropenia (59% versus 61%), rash (54% versus 7%) and nausea (44% versus 50%). In second-line treatment in combination with FOLFIRI: The 1186 patients who had received previous treatment for metastatic colorectal cancer (except with irinotecan), received as first-line treatment: 5-FU (71%), capecitabine (24%), oxaliplatin (67%) and bevacizumab (18%). There is no data available for patients previously treated with anti-egfr antibodies. In the sub-group of 597 patients (50.3%) with wild-type KRAS status,, the addition of panitumumab to FOLFIRI alone was associated with: - an extension in median progression-free survival (co-primary endpoint) of 2 months (5.9 months versus 3.9 months, HR = 0.73; [0, ]; p = 0.004), - no change to the median overall survival (the other co-primary endpoint): 14.5 months in the panitumumab + FOLFIRI group versus 12.5 months in the FOLFIRI group (HR = 0.85; [ ]; NS), - an increase in discontinuation of treatment due to adverse effects (21% versus 13%) and grade 3 events (76% versus 58%). The most common adverse effects with panitumumab + FOLFIRI were: diarrhoea (66% versus 57% with FOLFIRI alone), rash (52% versus 8%), nausea (51% versus 48%) and neutropenia (37% versus 40%). In the absence of demonstrated superiority and due to the safety profile in the sub-group of patients with metastatic colorectal cancer with a KRAS muted-type status, the Marketing Authorisation indication was limited to tumours with no KRAS gene mutation (wild type). In addition, the inclusion of panitumumab to chemotherapy including oxaliplatin for tumours with the KRAS gene mutation (or KRAS gene status not determined) is contraindicated, due to the reduced efficacy and an increase in toxicity. HAS - Medical, Economic and Public Health Assessment Division 16/19

17 In summary, in the sub-group of patients with metastatic colorectal cancer with no KRAS gene mutation, the level of effect for panitumumab as a first-line treatment, in combination with FOLFOX-4, and as a second line treatment in combination with FOLFIRI, compared with chemotherapy alone is modest: increase in median progression-free survival of months with no impact on overall survival demonstrated and at the cost of increased toxicity, especially concerning grade 3 adverse effects affecting the skin Study programmes Three comparative studies versus other targeted therapies are in progress: - one phase III study, ASPECCT (panitumumab versus cetuximab), on patients with metastatic colorectal cancer with no KRAS gene mutation (wild type) and who have failed previous treatments (initial results expected in 2013); - two phase II studies: PEAK study as first-line treatment (panitumumab + FOLFOX-6 versus bevacizumab + FOLFOX-6) and SPIRITT study as second-line treatment (panitumumab + FOLFIRI versus bevacizumab + FOLFIRI). 08 THERAPEUTIC USE Up to the approval of the extensions of the indication for VECTIBIX in first-line and second-line treatment of metastatic colorectal cancer, two monoclonal antibodies were available: ERBITUX (cetuximab) for KRAS wild-type status patients and AVASTIN (bevacizumab) for tumours regardless of the KRAS gene mutation status. As there are no comparative clinical studies to date, the place of ERBITUX in comparison to AVASTIN is yet to be determined According to the National Thesaurus of Gastrointestinal Oncology (Thésaurus National de Cancérologie Digestive) of October 2011, in the absence of contraindications to AVASTIN and/or if there is no KRAS gene mutation, the addition of a monoclonal antibody, ERBITUX, VECTIBIX or AVASTIN to chemotherapy is one of the treatment options. Determination of the KRAS gene mutation status of the tumour (and optionally the BRAF gene) is useful in selecting the therapeutic strategy (for the initial tumour, or for the metastases). 11 A better understanding of biomarkers, especially the BRAF gene status of the tumor, the benefit of which is suggested by preliminary data from a retrospective study, 12 will enable patients to be identified who will not see substantial benefit in the addition of an anti-egfr antibody to chemotherapy. The optimal therapeutical strategy as a first-line treatment or beyond is not established. 13 According to available data, VECTIBIX should not be used in combination with: - a regimen other than FOLFOX in first-line treatment and other than FOLFIRI in second-line treatment in patients with metastatic colorectal cancer with KRAS wild-type status; - chemotherapy in patients treated in the first-line with anti-egfr antibodies (absence of data in the PEETERS study); - polychemotherapy including oxaliplatin in patients with metastatic colorectal cancer with a KRAS muted type status or those who have not had the KRAS gene status determined; - chemotherapy including AVASTIN, as the risk/benefit ratio is unfavourable, regardless of the KRAS mutation status. 14 In light of the current data, the exact therapeutic use of VECTIBIX is difficult to establish, particularly in the absence of studies: - comparing VECTIBIX to another monoclonal antibody, in particular ERBITUX, in combination with chemotherapy, 11 Thésaurus National de Cancérologie Digestive [National Thesaurus of Gastrointestinal Oncology], metastatic colon cancer, 14/10/ Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008; 26 (35): ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Annals of Oncology 23: , Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009; 360: HAS - Medical, Economic and Public Health Assessment Division 17/19

18 - assessing VECTIBIX in second-line treatment after failure with therapy including an anti-egfr (VECTIBIX or ERBITUX) or in patients intolerant to ERBITUX. In the treatment of metastatic colorectal cancer with no mutation of the KRAS gene, VECTIBIX provides an alternative to ERBITUX when patients are eligible for: - first-line FOLFOX-type chemotherapy or - a second-line FOLFIRI regimen and on the condition of having received chemotherapy as a first-line treatment that included fluoropyrimidine, but neither irinotecan nor an anti-egfr antibody. 09 TRANSPARENCY COMMITTEE CONCLUSIONS Considering all of the information and after a discussion and a vote, the Committee has concluded: 09.1 Actual benefit Metastatic colorectal cancer is a severe, life-threatening disease. VECTIBIX is intended as a specific curative treatment for metastatic colorectal cancer. The efficacy / adverse effects ratio is moderate. Public health benefit: Colorectal cancer is a serious and common clinical condition, which represents a major public health burden. The burden represented by metastatic colorectal cancer is considerable. The burden represented by the population of patients likely to benefit from this proprietary medicinal product (presenting with no KRAS gene mutation) can also considered as substantial. Improved treatment of this disease is a public health need which is an established priority (French Public Health Law 2004, Cancer Plan). In view of the available data (two studies in combination with chemotherapy showing a modest improvement in progression-free survival versus chemotherapy alone), VECTIBIX when used concomitantly is not expected to have an impact on morbidity or mortality and quality of life. VECTIBIX is therefore not expected to provide any additional response to an identified public health need. Consequently, in light of current knowledge, VECTIBIX is not expected to be of public health benefit. Alternative medicinal products exist. It is either a first- or second-line treatment. Consequently, the Committee considers that: the actual benefit of VECTIBIX is substantial in the treatment of patients with wild-type metastatic colorectal cancer (no KRAS gene mutation): - in the first-line in combination with a FOLFOX regimen, - in the second-line in combination with FOLFIRI for patients who have received firstline fluoropyrimidine-based chemotherapy (excluding irinotecan). The Transparency Committee recommends inclusion on the list of medicines approved for hospital use in the extension of the indications and at the dosages in the Marketing Authorisation Improvement in actual benefit (IAB) In the absence of a comparative study versus ERBITUX, VECTIBIX does not provide an improvement in actual benefit (IAB V, non-existent) in the treatment of wild-type KRAS metastatic colorectal cancer: - in the first-line in combination with FOLFOX, HAS - Medical, Economic and Public Health Assessment Division 18/19