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New indication – Vectibix® + FOLFIRI in 1st line: What does this mean for patients with wild-type RAS mCRC?

The efficacy and safety of Vectibix® + FOLFOX in patients with wild-type RAS mCRC have been established in the phase 3 PRIME trial and in the phase 2 PEAK trial, versus FOLFOX alone and bevacizumab + FOLFOX, respectively.1,2 Both PRIME and PEAK are described in detail in the Key data section.

Vectibix® now has a licence extension for use with FOLFIRI to treat patients with wild-type RAS mCRC in the 1st line setting.3 To gain a sense of the efficacy that may be achieved with 1st line Vectibix® + FOLFIRI and how this compares to the efficacy of Vectibix® + FOLFOX, this hot topic:

 

Median OS of ≥40 months with 1st line Vectibix® + FOLFOX in three separate analyses

Exploratory retrospective analyses of PRIME have been conducted to explore the effects of Vectibix® + FOLFOX in subgroups of patients with wild-type RAS mCRC, providing further insight into the efficacy of this combination.4,5

One of the exploratory subset analyses of PRIME examined overall survival (OS) outcomes among patients who did/did not receive post-progression anti-VEGF treatment (Vectibix® + FOLFOX, n=55; FOLFOX alone, n=45). In patients receiving Vectibix® + FOLFOX in 1st line followed by bevacizumab + FOLFOX in 2nd line, a median OS of 40.0 months was observed.4

The second analysis compared outcomes (including OS) among patients receiving Vectibix® + FOLFOX vs FOLFOX alone among patients with liver-limited disease (LLD: Vectibix® + FOLFOX, n=48; FOLFOX alone, n=41).  A median OS of 40.7 months was observed among patients with LLD who received Vectibix® + FOLFOX in 1st line.5,6

A median OS in excess of 40 months was also observed with Vectibix® + FOLFOX among patients with wild-type RAS mCRC in the phase 2 PEAK study (in which no formal hypothesis testing was planned).2 Therefore, in total there are now three separate analyses that observed a median OS of 40 months or more with Vectibix® + FOLFOX in patients with wild-type RAS mCRC.2,4–6

Vectibix® + FOLFOX achieved a median OS of 40 months in three separate analyses

For reference, the median PFS values reported in in patients with wild-type RAS mCRC receiving Vectibix® + FOLFOX in PRIME and PEAK were 10.1 months and 13.0 months, respectively.1,2

20060314 (phase 2, single-arm study): Efficacy of 1st line Vectibix® + FOLFIRI

The recently reported 20060314 trial evaluated the efficacy of Vectibix® + FOLFIRI, and its findings in patients with wild-type RAS mCRC contributed to the Vectibix® licence extension.7,8

The 20060314 trial is a single-arm, phase 2 study that evaluated the effects of Vectibix® + FOLFIRI in patients with mCRC, which included a retrospective, descriptive analysis of outcomes by RAS status (wild-type [n=68] vs mutant [n=73]). The primary endpoint of the trial was objective response rate (ORR); a range of secondary endpoints were evaluated.8,9 (Complete details about the 20060314 study and its findings can be found in the Key data section.)

In terms of the primary endpoint, the ORR was 59% in the wild-type RAS group and 41% in the mutant RAS group (unadjusted OR=2.0; 95% CI: 1.0–4.2).7,8

The median progression-free survival (PFS), one of the secondary endpoints, favoured Vectibix® + FOLFIRI among patients with wild-type RAS mCRC versus those with mutations in the RAS genes (11.2 months; see Figure below).7,8

 Median PFS in 20060314 (phase 2 trial)

Adapted from Karthaus et al.

The ORR (primary endpoint) was 59% in the wild-type RAS group and 41% in the mutant RAS group (unadjusted odds ratio=2.0, 95% CI: 1.0–4.2).7,8

 

PLANET (phase 2 randomised study): Comparable efficacy with Vectibix® + FOLFOX and Vectibix® + FOLFIRI

Another trial – PLANET – directly compared Vectibix® + FOLFOX vs Vectibix® + FOLFIRI in patients with wild-type KRAS exon 2 mCRC who had liver-limited disease (LLD). PLANET is a phase 2 randomised study that included a protocol pre-defined analysis of outcomes among patients with wild-type RAS mCRC, as an exploratory endpoint. The primary endpoint of PLANET among patients with wild-type RAS mCRC and LLD (Vectibix® + FOLFOX, n=27; Vectibix® + FOLFIRI, n=26) was ORR, and a range of secondary endpoints were considered, including PFS and OS. Similar efficacy and safety results were obtained in the overall group with either Vectibix® + FOLFOX or Vectibix® + FOLFIRI schema.10 (Complete details about PLANET study and its findings can be found in the Key data section.)

Interim findings from this analysis revealed that the ORR was similar for the two regimens, at approximately 78% for Vectibix® + FOLFOX vs 73.1 for Vectibix® + FOLFIRI (see Figure below).7,10

PLANET (phase 2 randomised study): Objective response rate

Adapted from Abad et al.10

There was no significant difference between regimens in median OS (45.8 months with Vectibix® + FOLFIRI vs 39.0 months with Vectibix® + FOLFOX; see Figure below).10 This median OS of 45.8 months with Vectibix® + FOLFIRI is comparable to the ≥40 months median OS previously observed for Vectibix® + FOLFOX in three separate analyses.2,4–6

PLANET (phase 2 randomised study): Median OS

Adapted from Abad et al.10 *Wilcoxon test.

In this interim analysis of PLANET both regimens produced median PFS in excess of 10 months, with no significant difference between them (see Figure below).7,10

PLANET (phase 2 randomised study): Median PFS

Adapted from Abad et al.10 *Wilcoxon test.

PLANET (phase 2 randomised study): Adverse event profiles for Vectibix® + FOLFOX and Vectibix® + FOLFIRI compared

Broadly, the adverse event profiles of Vectibix® + FOLFOX and Vectibix® + FOLFIRI were similar among patients with wild-type RAS mCRC (see Table below). There was no significant difference between regimens in perioperative safety (10.0% and 27.8%, respectively; p=0.536). There was a trend toward less neutropenia and neuropathy with Vectibix® + FOLFIRI vs Vectibix® + FOLFOX in grade 3/4 adverse events. In the wild-type RAS population, 11 (40.7%) patients treated with Vectibix® + FOLFOX and 11 (42.3%) treated with Vectibix® + FOLFIRI died; none of these deaths were attributable to Vectibix® – or chemotherapy-related adverse events.10

Summary of adverse events reported in PLANET (phase 2 randomised study)

Adverse events (AEs; n [%]) Vectibix® combined with p value
FOLFOX
(n=27)
FOLFIRI
(n=26)
AE summary
Grade 3–4 22 (81.5) 20 (76.9) NR
Treatment-related grade 3–4 18 (66.7) 16 (61.5) NR
Fatal AEs 1 (3.7) 3 (11.5) NR
Treatment-related fatal AEs 0 0 NR
Serious AEs 6 (22.2) 7 (26.9) NR
Vectibix® and/or chemotherapy-related serious AE 0 0 NR
Perioperative AEs (in patients with surgery) 1 (10.0)* 5 (27.8)* 0.536
Grade 3/4* treatment-related adverse events
Neutropenia 7 (25.9) 2 (7.7) 0.077
Conjunctivitis 1 (3.7) 1 (3.8) 0.978
Diarrhoea 3 (11.1) 1 (3.9) 0.317
Asthenia 4 (14.8) 1 (3.8) 0.172
Neuropathy 5 (18.5) 0 0.051
Decreased appetite 2 (7.4) 0 0.157

Adapted from Abad et al.10 *Ten patients receiving Vectibix® + FOLFOX underwent surgical resection vs 18 of those receiving Vectibix® + FOLFIRI. NR, not reported.

Conclusion

Vectibix® is now licensed for use with FOLFOX or FOLFIRI in the 1st line setting to treat patients with wild-type RAS mCRC, based on an assessment by the EMA of data from multiple studies.7

References

  1. Douillard J-Y et al. N Engl J Med 2013;369:1023–1034.
  2. Schwartzberg L et al. J Clin Oncol 2014;32:2240–2247.
  3. Vectibix® Summary of Product Characteristics.
  4. Peeters M et al. EJC 2013;49(suppl 4):abstract MC13-0024 (and poster).
  5. Peeters M et al. EJC 2013;49(suppl 4):abstract MC13-0022 (and poster).
  6. Douillard J-Y et al. Eur J Cancer 2015 [Epub ahead of print].
  7. Vectibix® EPAR Variation II/65.
  8. Karthaus M et al. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P).
  9. Köhne CH et al. J Cancer Res Clin Oncol 2012;138:65−72.
  10. Abad A et al. Ann Oncol 2014;25(suppl 4):iv189 (poster 551P).

 

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