OverviewExons examinedOS
The 181 study
An overview of the 181 study
Background
- Biomarker analyses from the 1st line PRIME (phase 3) and PEAK* (phase 2) studies in patients with mCRC demonstrated that additional activating mutations in RAS genes beyond KRAS exon 2 (exons 2–4 of both KRAS and NRAS) predicted a lack of response to Vectibix®1,2
- Studies with Vectibix® in subsequent lines of therapy with chemotherapy backbones other than FOLFOX have yet to be analysed by RAS tumour status3
- A prospective-retrospective analysis of the 181 study was done to compare the treatment effect of Vectibix® + FOLFIRI vs FOLFIRI alone in patients with wild-type RAS mCRC, and preliminary outcomes data have been reported3
*PEAK is a phase 2 study, in which no formal hypothesis testing was planned.
Methods
Adapted from Peeters et al.3
- The primary objective of this prospective-retrospective analysis was to evaluate the treatment effect of Vectibix® + FOLFIRI vs FOLFIRI alone on PFS and OS in patients with wild-type RAS in the primary analysis population3
- Banked patient tumour specimens characterised as wild-type KRAS exon 2 by an investigational use only assay (Therascreen® KRAS Mutation Kit by QIAGEN; Roche LightCycler) were selected for analysis3
- Standard bidirectional Sanger sequencing and WAVE-based SURVEYOR® Scan Kits (Transgenomic) were performed separately3
References:
- Douillard J-Y et al. N Engl J Med 2013;369(11):1023–34.http://www.nejm.org/ doi / full /10.1056 / NE JMoa 13052 75 [last accessed September 2017].
- Rivera F et al. Int J Colorectal Dis 2017;32(8):1179-90. https://www.ncbi.nlm.nih.gov/pubmed/28424871. [last accessed September 2017].
- Peeters M et al. J Clin Oncol 2010; 28:4706 -13.
181 study – exons examined
Prevalence of RAS mutations within the wild-type KRAS (exon 2) subset: Preliminary data
Adapted from Peeters et al.1 *The KRAS (exon 2) data are from the overall population.
- Tumour RAS ascertainment rate: 85%1
References:
- Peeters M et al. Clin Canc Res 2015; 21(24):5469-79.
181 study – OS in patients with wild-type RAS mCRC
OS in patients with wild-type RAS mCRC: Preliminary data
Adapted from Peeters et al.1
- In the patient population with wild-type RAS mCRC, Vectibix® + FOLFIRI achieved a median OS of 16.2 months, which was 2.3 months longer than with FOLFIRI alone (difference not statistically significant)1
References:
- Peeters M et al. Clin Canc Res 2015; 21(24):5469-79.
PFSSafetyPFS in mutant RAS
181 study – PFS in patients with wild-type RAS mCRC
PFS in patients with wild-type RAS mCRC: Preliminary data
Adapted from Peeters et al.1
- Vectibix® + FOLFIRI achieved a median PFS of 6.4 months – a median of 1.8 months longer than with FOLFIRI alone – in the patient population with wild-type RAS mCRC1
References:
- Peeters M et al. Clin Canc Res 2015; 21(24):5469-79.
181 study – safety
Summary of adverse events according to RAS mutation status: Preliminary data
| Adverse event (n [%]) |
Wild-type RAS | Mutant RAS | ||
| Panitumumab + FOLFIRI (n=207) | FOLFIRI alone (n=213) | Panitumumab + FOLFIRI (n=298) | FOLFIRI alone (n=292) | |
| Any adverse event | 207 (100) | 211 (99) | 296 (99) | 281 (96) |
| Worst grade of 3 | 114 (55) | 78 (37) | 137 (46) | 100 (34) |
| Worst grade of 4 | 41 (20) | 35 (16) | 50 (17) | 44 (15) |
| Worst grade of 5 | 8 (4) | 13 (6) | 21 (7) | 17 (6) |
| Any serious adverse events | 94 (45) | 67 (31) | 110 (37) | 90 (31) |
| Adverse event leading to permanent discontinuation of any study drug | 50 (25) | 25 (12) | 56 (19) | 33 (11) |
| Not serious | 30 (15) | 19 (9) | 40 (13) | 14 (5) |
| Serious | 24 (12) | 8 (4) | 19 (6) | 20 (7) |
| Adverse event (n [%]) |
Wild-type RAS | |
| Panitumumab + FOLFIRI (n=207) | FOLFIRI alone (n=213) | |
| Any adverse event | 207 (100) | 211 (99) |
| Worst grade of 3 | 114 (55) | 77 (36) |
| Worst grade of 4 | 41 (20) | 35 (16) |
| Worst grade of 5 | 8 (4) | 13 (6) |
| Any serious adverse events | 94 (45) | 67 (31) |
| Adverse event leading to permanent discontinuation of any study drug | 50 (25) | 25 (12) | Not serious | 30 (15) | 19 (9) | Serious | 24 (12) | 8 (4) |
| Adverse event (n [%]) |
Mutant RAS | |
| Panitumumab + FOLFIRI (n=298) | FOLFIRI alone (n=292) | |
| Any adverse event | 296 (99) | 281 (96) |
| Worst grade of 3 | 137 (46) | 100 (34) |
| Worst grade of 4 | 50 (17) | 44 (15) |
| Worst grade of 5* | 21 (7) | 17 (6) |
| Any serious adverse events | 110 (37) | 90 (31) |
| Adverse event leading to permanent discontinuation of any study drug | 56 (19) | 33 (11) |
| Not serious | 40 (13) | 14 (5) |
| Serious | 19 (6) | 20 (7) |
Adapted from Peeters et al.1,2
- Adverse events were similar to those reported in the Vectibix® + FOLFIRI arm of patients with wild-type KRAS (exon 2) mCRC, and no new safety signals were identified1
References:
- Peeters M et al. Clin Canc Res 2015; 21(24):5469-79.
- Peeters M et al. Poster presented at the Gastrointestinal Cancers Symposium; 16−18 January 2014; San Francisco, CA.
181 study – PFS in patients with mutant RAS mCRC
PFS in patients with wild-type KRAS (exon 2) mCRC with additional KRAS/NRAS mutations: Preliminary data
Adapted from Peeters et al.1
- In the patient population with wild-type KRAS (exon 2) mCRC with additional KRAS/NRAS mutations, there was no significant difference between Vectibix® + FOLFIRI and FOLFIRI alone in median PFS1
The combination of Vectibix® with oxaliplatin-containing chemotherapy is contraindicated for patients with mutant RAS mCRC or for whom RAS mCRC status is unknown. Evidence of wild-type RAS (KRAS and NRAS) status is required before initianting treatment with Vectibix®.2
References:
- Peeters M et al. Clin Canc Res 2015; 21(24):5469-79.
- Vectibix® Summary of Product Characteristics.
Summary
181 study – conclusions
Conclusions
- In patients with wild-type RAS mCRC, Vectibix® + FOLFIRI achieved a significantly longer median PFS compared with FOLFIRI alone (6.4 vs 4.6 months; HR=0.70, 95% CI: 0.54–0.91, p=0.007)1
- In patients with wild-type RAS mCRC, Vectibix® + FOLFIRI also achieved a longer median OS compared with FOLFIRI alone (16.2 vs 13.9 months), although this did not achieve statistical significance (HR=0.81, 95% CI: 0.63–1.03, p=0.08)1
- Improvements were seen in the treatment effect on PFS and OS in patients with wild-type RAS mCRC vs those with wild-type KRAS exon 2 mCRC1
- Patients with mCRC harbouring any mutation in RAS are unlikely to benefit from the addition of Vectibix® to FOLFIRI, as was observed in patients with mutant KRAS exon 2 mCRC1
Consistent with the findings of other prospective-retrospective analyses in the 1st line setting,2,3 the results of this prospective-retrospective analysis in the 2nd line setting support RAS testing to identify potential candidates for Vectibix® treatment.
References:
- Peeters M et al, Clin Canc Res 2015;21(24):5469-79.
- Douillard J-Y et al. N Engl J Med 2013;369(11):1023–34. http://www. nejm.org/ doi / full / 10.1056/ NEJMoa 1305275 [last accessed September 2017].
- Rivera F et al. Int J Colorectal Dis 2017;32(8):1179-90. https://www.ncbi.nlm.nih.gov/pubmed/28424871. [last accessed September 2017].