« All Hot Topics

PEAK final analysis: More support for median OS ≥40 with Vectibix® + FOLFOX

A previous hot topic covered evidence from three separate analyses showing that Vectibix®+FOLFOX can achieve a median OS of 40 months or more in patients with wild-type RAS mCRC. Two of these analyses, exploratory in nature, included subgroups of patients (both from the phase 3 PRIME study): patients with liver-limited disease and those receiving post-progression anti-VEGF.1,2 The third analysis – the primary analysis of the phase 2 PEAK study (no hypothesis testing planned) – included patients with wild-type RAS mCRC.3

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

Hot Topic Table

There is now further support from the final analysis of PEAK for the ability of Vectibix® + FOLFOX to achieve a median OS in excess of 40 months, among patients with wild-type RAS/BRAF mCRC.5

At the time of the primary analysis of PEAK (scheduled to be done when ~168 progression-free survival [PFS] events had occurred in the overall wild-type KRAS exon 2 group), approximately 41% of patients with wild-type RAS mCRC had died.3 In the final analysis approximately 68% of the wild-type RAS mCRC group had died, allowing a more mature assessment of efficacy.5

This hot topic summarises the results of

Final analysis: Efficacy outcomes

The median PFS (the primary endpoint of PEAK) in the wild-type RAS and in the wild-type RAS/BRAF subgroups was similar to that in patients with wild-type RAS in the primary analysis.5

The PFS data for the wild-type RAS/BRAF subpopulation are shown in the figure below. Among patients with wild-type RAS mCRC in the final analysis, the median PFS was 12.8 months with Vectibix® + FOLFOX (n=88) vs 10.1 months with bevacizumab + FOLFOX (n=82; HR=0.68, 95% CI: 0.48–0.96; p=0.029).5

PEAK final analysis: Median PFS among patients with wild-type RAS/BRAF mCRC

10427407 GRAPHS_v1c_02

Adapted from Rivera et al.5

As in the primary analysis, in the two subgroups the median OS suggested a trend toward improvement in the Vectibix® + FOLFOX arm in the final analysis, although statistical significance was not achieved.5

Among patients with wild-type RAS/BRAF mCRC, the median OS was 41.3 months with Vectibix® + FOLFOX (see diagram below). The median OS among patients with wild-type RAS mCRC in the final analysis was 36.9 months with Vectibix® + FOLFOX (n=88) vs 28.9 months with bevacizumab + FOLFOX (n=82; HR=0.76, 95% CI: 0.53–1.11; p=0.15).5

PEAK final analysis: Median OS among patients with wild-type RAS/BRAF mCRC

10427407 GRAPHS_v1d3

Adapted from Rivera et al.5

Tumour assessments beyond RECIST

In the final analysis of PEAK the objective response rate (ORR) was similar in the two treatment arms (65% with Vectibix® + FOLFOX vs 60% with bevacizumab + FOLFOX; p=0.86).5

The report went on to present additional analyses of tumour response, beyond RECIST, among patients with wild-type RAS mCRC. An assessment of tumour load (sum of the longest diameters of all target lesions) among patients with wild-type RAS mCRC appeared to favour Vectibix® + FOLFOX at all assessed time points, although confidence intervals were wide.5

PEAK final analysis: Percentage change from baseline in tumour load*

10427407 GRAPHS_v1d8

Adapted from Rivera et al.5 *Tumour load defined as sum of all target lesions. This analysis included patients with wild-type RAS mCRC evaluable for objective response who had baseline tumour shrinkage data.

It also found that duration of response (DoR) and depth of response (DpR) were significantly higher in the Vectibix® + FOLFOX arm versus the bevacizumab + FOLFOX arm. Time to response (TTR) was numerically greater in the Vectibix® + FOLFOX arm, but this did not achieve statistical significance.5

PEAK final analysis: Summary of response related efficacy results

Vectibix® + FOLFOX (n=88)  Bevacizumab + FOLFOX (n=82)*
Median DoR (months; 95% CI) 11.4 (10.0–16.3) 9.0 (7.6–9.5)
   HR (95% CI) 0.59 (0.39–0.88)
    p value 0.011
Median TTR (months; 95% CI) 2.3 (1.9–3.7) 3.8 (2.1–5.7)
  HR (95% CI) 1.19 (0.81–1.74)
  p value 0.37
Median DpR (%; Q1–Q3) 65.0 (45.7–89.5) 46.3 (29.5–63.3)
  p value 0.0018

Adapted from Rivera et al.5 *For DoR, TTR and DpR analysis, n=81 for the bevacizumab + FOLFOX. For treatment effect. p value from Wilcoxon test.

Early tumour shrinkage (ETS; assessed at week 8) was evaluated for two cut-off points: 30% and 20% tumour shrinkage. At both of these cut-off points, ETS was numerically higher in the Vectibix® + FOLFOX group, although significance was not achieved.5

PEAK final analysis: Rates of ETS

10427407 GRAPHS_v1c_0

Adapted from Rivera et al.5 *ETS assessable patients.

Irrespective of treatment, ETS was associated with longer PFS (≥30% vs <30%: median PFS 12.9 vs 9.8 months [HR=0.60, 95% CI: 0.42–0.87; p=0.0065]; ≥20% vs <20%: median PFS 13.0 vs 9.5 months [HR=0.55, 95% CI: 0.37–0.81; p=0.0029]).5

Conclusion

In the PEAK final analysis, PFS was significantly improved for patients with wild-type RAS mCRC receiving 1st line treatment with Vectibix® + FOLFOX vs bevacizumab + FOLFOX. For Vectibix® + FOLFOX versus bevacizumab + FOLFOX, the median OS was 8.0 months longer in the wild-type RAS mCRC group (36.9 vs 28.9 months; not significant). It was 12.4 months longer in the group with wild-type RAS/BRAF mCRC population, reaching 41.3 months with Vectibix® + FOLFOX (vs 28.9 months with bevacizumab + FOLFOX; not significant).5

While ORR was similar between the two treatment groups, the exploratory analysis detected differences between treatments in measures of tumour response beyond RECIST. Responses were apparently earlier, longer lasting and deeper in the Vectibix® + FOLFOX arm, although the difference in TTR did not achieve statistical significance.5

The results of the PEAK final analysis continue to support the efficacy of 1st Vectibix® + FOLFOX in patients with wild-type RAS mCRC.5

References

  1. Peeters M et al. Eur J Cancer 2013;49(suppl 4):abstract MC13–0024 (and poster).
  2. Peeters M et al. Eur J Cancer 2013;49(suppl 4):abstract MC13–0022 (and poster).
  3. Schwartzberg L et al. J Clin Oncol 2014;32:2240–2247.
  4. Douillard J-Y et al. Eur J Cancer 2015;51:1231–1242.
  5. Rivera F et al. Presented at ECC 2015; abstract 2014.
-->