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Links to prescribing information and adverse event reporting information can be found at the bottom of the page. For UK Healthcare professionals only.
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Clinical Evidence

Vectibix® is recommended by NICE for previously untreated RAS wild-type mCRC in combination with FOLFOX or FOLFIRI1

PRIME STUDY: Vectibix® + FOLFOX4 for first-line treatment of mCRC2

  • The first phase 3 study to evaluate outcomes by RAS status in first-line2
  • A pre-defined retrospective analysis assessed the effect of Vectibix® + FOLFOX4 versus FOLFOX4 on outcomes among patients with wild-type RAS mCRC3
  • Primary endpoint: progession-free survival3
  • Secondary endpoints: overall survival and safety3
  • RAS ascertainment rate was 90% (1060 patients)3
  • RAS analysis was exploratory3

Study design

PRIME was a multicentre, randomised study evaluating the efficacy and safety of Vectibix® + FOLFOX4 versus FOLFOX4 alone in patients with previously untreated mCRC.2
study-design-map

Results of the clinical trial

Among 512 patients without RAS mutations, patients treated with panitumumab + FOLFOX4 had a greater median progression-free survival time than patients treated with FOLFOX4 alone3:
On average, patients in the panitumumab + FOLFOX4 group had longer overall survival time than patients treated with FOLFOX4 alone3:
All p-values are descriptive.

PRIME study: WT KRAS mCRC safety analysis set4

AEs (grade 3/4)

WT KRAS (n = 649)
AE, % Panitumumab + FOLFOX4
(n = 322) 		FOLFOX4
(n = 327)
Neutropenia 43 42
Skin toxicity 37 2
Diarrhoea 18 9
Neurologic toxicities 16 16
Hypokalaemia 10 5
Fatigue 10 3
Mucositis*† 9 < 1
Hypomagnesaemia 7 < 1
Paronychia† 3 0
Pulmonary embolism 3 2
Febrile neutopenia 2 2
Infusion-related reaction
(panitumumab)†︎ 		< 1 -
*Includes preferred terms: stomatitis, mucosal inflammation, aphthous stomatitis, mouth ulceration, mucosal dryness, and mucosal ulceration; †No grade 4

STUDIES OF CETUXIMAB AND PANITUMUMAB IN COMBINATION WITH FOLFIRI FOR mCRC

Study 314: Vectibix® + FOLFIRI for first-line treatment of mCRC5,6

  • Phase II single-arm study to evaluate first-line panitumumab plus FOLFIRI* in patients with mCRC5
  • n=68 RAS WT received first-line panitumumab + FOLFIRI every 14 days5
  • Primary endpoint: objective response rate (ORR)5,6
  • Secondary endpoints: duration of response, progression-free survival (PFS), time to progression, disease control rate, safety5
  • RAS analysis was exploratory6
*FOLFIRI regimen (irinotecan 180 mg/m2; leucovorin 400 mg/m2; fluorouracil bolus 400 mg/m2, then 46-hour infusion 2400–3000 mg/m2)

CRYSTAL: FOLFIRI + cetuximab for first-line treatment of mCRC7,8

  • Phase III open-label, randomised controlled trial to evaluate outcomes for FOLFIRI† + cetuximab vs FOLFIRI† alone in mCRC7
  • 599 patients received FOLFIRI† + cetuximab and 599 received FOLFIRI† alone7
  • 178 RAS WT patients in the FOLFIRI† + cetuximab weekly arm8
  • Primary endpoint: progression-free survival7,8
  • Secondary endpoint: overall survival (OS)7
  • Post hoc retrospective analysis of RAS WT patients8
†FOLFIRI regimen (irinotecan 180 mg/m2 and leucovorin 400 mg/m2; fluorouracil bolus 400 mg/m2, then 46-hour infusion 2400 mg/m2)

FIRE-3: FOLFIRI + cetuximab for first-line treatment of mCRC9,10

  • Phase III open-label, randomised controlled trial to evaluate outcomes for FOLFIRI* + cetuximab vs FOLFIRI† + bevacizumab in mCRC9
  • 297 patients received FOLFIRI* + cetuximab and 295 received FOLFIRI† + bevacizumab9
  • n = 199 RAS WT in the FOLFIRI* + cetuximab weekly arm10
  • Primary endpoint: objective response9,10
  • Secondary endpoints: progression-free survival (PFS), overall survival (OS), depth of remission, secondary resection of liver metastases with curative intent, safety and tolerability9,10
*FOLFIRI regimen (irinotecan 180 mg/m2 and leucovorin 400 mg/m2; fluorouracil bolus 400 mg/m2, then 46-hour infusion 2400 mg/m2)
†FOLFIRI regimen (irinotecan 180 mg/m2 and leucovorin 400 mg/m2; fluorouracil bolus 400 mg/m2, then 46-hour infusion 2400–3000 mg/m2)

Key inclusion/exclusion criteria

Inclusion criteria Exclusion criteria
Study 3145,6 ≥ 18 years of age
  • Histologically or cytologically confirmed, radiologically measurable mCRC
  • ECOG status 0 – 2
  • Disease sites evaluated ≤ 28 days prior to enrolment and tissue from the primary or metastatic site had to be available
  • Prior systemic therapy (including EGFRI) for mCRC (except adjuvant fluoropyrimidine-based chemotherapy given ≥ 6 months previously)
CRYSTAL7,8 ≥ 18 years of age
  • Histologically confirmed adenocarcinoma of colon or rectum
  • ECOG status 0 – 2
  • First occurrence of metastatic disease that could not be resected for curative purposes
  • Immunohistochemical evidence of tumour EGFR expression
  • Previous exposure to an EGFRI or irinotecan-based chemotherapy
  • Previous chemotherapy for mCRC
  • Adjuvant treatment that was terminated ≤ 6 months previously
  • Treatment with any experimental drug ≤ 30 days previously
  • Previous radiotherapy or surgery (excluding previous diagnostic biopsy) or any investigational drug in the 30-day period before the start of treatment of the trial
FIRE-39,10 18-75 years
  • Histologically confirmed mCRC
  • ECOG status 0 – 2
  • At least one measurable lesion by RECIST v1.0
  • KRAS exon 2 WT tumours
  • No surgery in 4 weeks prior to study start
  • Known or suspected brain metastases
  • Previous treatment with EGFRI or bevacizumab
  • Previous chemotherapy for mCRC (excluding adjuvant therapy terminated ≥ 6 months previously)
  • Treatment with any experimental drug ≤ 30 days previously
  • Clinically relevant coronary heart disease
  • MI within the past 12 months
  • Risk of uncontrolled arrhythmia
  • Acute or subacute intestinal obstruction
  • History of IBD or chronic diarrhoea

Demographics*

Study 3145,6 CRYSTAL7,8 FIRE-39,10
Sex, male 80% 61% 73%
Median age 62 60 64
ECOG status
0 or
1 - 96% 		2 - 4%
0 - 54% 1 - 43% 2 - 3%
0 - 54% 1 - 45% 2 - 2%
Primary tumour Colon – 58%
Rectum – 42% 		Colon – 60%
Rectum – 38%
Colon or rectum – 2% 		Colon – 60%
Rectum – 36%
Colon or rectum – 4%
Unknown – 1%
Metastatic sites Liver only – 38%
Liver and other – 48%
Other only – 14% 		Liver only – 24%
At one or two sites – 88% 		Liver – 85%
Liver only – 36%
Liver not affected – 14%
Previous treatment Adjuvant - NR Adjuvant – 22.5% Surgery – 86%
Adjuvant – 19%
Radiotherapy – 12%
Ethnicity White – 96%
Other Number of metastatic sites: Tumour location:
left – 80%
right – 19%
1 - 43% 2 - 32% ≥ 3 – 25%
*The demographics presented are for the EGFR-treated arm of each study, prior to the RAS analysis, as some of the studies did not report the demographics of the RAS WT population

RAS testing and endpoints

Study 3145,6 CRYSTAL7,8 FIRE-39,10
RAS testing Tumour mutational status assessed using DxS kit that utilised allele-specific, real-time PCR
  • KRAS exon 2 Bi-directional Sanger sequencing
  • KRAS exons 3 – 4 all codons
  • NRAS exons 2 – 4 all codons
  • BRAF exon 15
 Tumour mutations assessed using PCR clamping and melting curve method
  • KRAS exon 2 Additional mutations-BEAM technology
  • KRAS exon 3 – 4 all codons
  • NRAS exon 2 – 4 all codons
≥ 5% mutant allele cut-off was used to call mutations
 Tumour mutations assessed using pyrosequencing
  • KRAS exon 2 – 4 all codons
  • NRAS exon 2 – 4 all codons
Endpoints (original study) KRAS WT patients
  • Primary: ORR
  • Secondary: duration of response, PFS, time to progression, DCR, safety
 All mCRC patients
  • Primary: PFS
  • Secondary: OS
 KRAS WT patients
  • Primary: ORR
  • Secondary: OS, PFS, safety, secondary resection of liver metastases
RAS WT analysis endpoints Exploratory RAS status analysis Post hoc retrospective analysis of RAS WT patients
  • Primary objective to assess treatment impact in RAS mutant patients
 Post hoc exploratory analysis of RAS WT patients
  • Endpoints: ORR, PFS, OS, early tumour shrinkage, depth of response, duration of response, time to response

Clinical trial results

Outcomes (WT RAS)
ORR, % PFS, months OS, months
FOLFIRI + panitumumab
Study 3145,6 59.0 11.2 NR
FOLFIRI + cetuximab
CRYSTAL7,8 66.3 11.4 28.4
FIRE-39,10 65.3 10.3 33.1

Abbreviations

AE, adverse event; CI, confidence interval; BORR, best overall confirmed response rate; DCR, disease control ratio; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; HR, hazard ratio; IBD, inflammatory bowel disease; mCRC, metastatic colorectal cancer; MI, myocardial infarction; NGS, next generation sequencing; NR, not reported; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PCR, polymerase chain reaction; RECIST, Response Evaluation Criteria in Solid Tumours; WT, wild-type.

References

  1. NICE. Cetuximab and panitumumab for previously untreated metastatic colorectal cancer (TA439).
  2. Douillard J-Y et al. Journal of Clinical Oncology 2010;31: 4697–4705.
  3. Douillard J-Y et al. N Engl J Med 2013;369:1023–1034.
  4. Douillard JY et al. Ann Oncol 2014: 25: 1346–55.
  5. Köhne CH et al. J Cancer Res Clin Oncol 2012;138:65-72.
  6. Karthaus M et al. Br J Cancer 2016;115:1215-1222.
  7. Van Cutsem E et al. N Engl J Med 2009;360:1408–1417.
  8. Van Cutsem E et al. J Clin Oncol 2015;33:692–700.
  9. Heinemann V et al. Lancet Oncol 2014;15:1065–1075.
  10. Stintzing S et al. Lancet Oncol 2016;17:1426–1434.