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PRIME: Safety and efficacy of Vectibix® + FOLFOX in subgroups of patients with wild-type RAS mCRC

We now know that patients with wild-type RAS (wild-type KRAS and NRAS exons 2–4) mCRC may benefit from Vectibix® + FOLFOX.1,2 However, Vectibix® in combination with FOLFOX chemotherapy has shown a detrimental effect on survival in patients whose tumours carry mutated RAS.1

Further insights into the efficacy of this combination in the 1st line setting among patients with wild-type RAS mCRC were reported at the recent ASCO, WCGIC and ESMO congresses:

  • The 2014 American Society of Clinical Oncology (ASCO) Annual Meeting was held in Chicago, from 30 May 30 to 3 June 2014
  • The 16th World Congress on Gastrointestinal Cancer (WCGIC) was held in Barcelona, from 25 to 28 June 2014
  • The 2014 European Society for Medical Oncology (ESMO) was held in Madrid, from 26 to 30 September 2014

 

Three new analyses of the phase 3 PRIME trial – comparing Vectibix® + FOLFOX vs FOLFOX alone in the 1st line setting – were presented, focusing on outcomes in subgroups of patients with wild-type RAS mCRC:

 

Details about the prospective-retrospective analysis of outcomes among patients with wild-type RAS mCRC in the PRIME trial can be found in the Key data/PRIME section.

 

PRIME: Outcomes among patients with wild-type RAS/BRAF mCRC, stratified by baseline ECOG performance status3,4

In the prospective-retrospective analysis of outcomes among patients with wild-type RAS mCRC included in the PRIME trial, it was noted that the only subgroup of patients in which no Vectibix® treatment effect was observed was those with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, although the number of patients in this group was small (n=32).1 Also, BRAF mutations apparently conferred a worse prognosis, regardless of treatment group.1 Therefore, a further exploratory analysis was done to evaluate the efficacy of Vectibix® + FOLFOX among patients with wild-type RAS/BRAF mCRC, stratified by baseline ECOG PS.3,4 This analysis was done when ≥80% of patients in PRIME had had an overall survival (OS) event.

Of the 439 patients with wild-type RAS/BRAF mCRC included in the PRIME study, baseline ECOG PS had been recorded in 438. The Vectibix® + FOLFOX (n=222) and FOLFOX (n=216) treatment groups were well balanced with respect to sex, age and metastatic sites.3,4 In terms of ECOG PS, 411 of the 438 patients had PS 0–1 and 27 patients had PS 2 (5% vs 7%).

Among patients with wild-type RAS/BRAF mCRC with ECOG PS 0–1, the progression-free survival (PFS) and OS outcomes both favoured Vectibix® + FOLFOX.

PRIME: Outcomes among patients with wild-type RAS/BRAF mCRC and ECOG PS 0–13,4

PRIME: graphs of PFS and OS among patients with wild-type RAS/BRAF mCRC and ECOG PS 0–1

Adapted from Peeters et al.3 (a) PFS and (b) OS.

In patients with wild-type RAS/BRAF mCRC with ECOG PS 2, there were no significant differences in outcomes between the two treatment groups.3,4

PRIME: Outcomes among patients with wild-type RAS/BRAF mCRC and ECOG performance status 23,4

RAS/BRAF wild-type population with
ECOG PS 2
Vectibix® + FOLFOX FOLFOX
Number of patients 12 15
Median PFS (95% CI; months) 6.4 (2.7–14.6) 7.6 (3.7–11.1)
Hazard ratio (95% CI), p value 0.94 (0.38–2.31), descriptive p=0.891
Median OS (95% CI; months) 7.6 (4.6–28.7) 8.9 (5.3–13.0)
Hazard ratio (95% CI), p value 0.95 (0.41–2.21), descriptive p=0.904

 

As regards BRAF mutations, although patient numbers were small the analysis provides further support for the role of BRAF mutation as a poor prognostic factor.3,4

Conclusion

In the subgroup of patients with wild-type RAS/BRAF mCRC, the investigators concluded that the benefit of Vectibix® + FOLFOX is primarily confined to those with baseline ECOG PS of 0–1, and that this is an effective 1st line treatment option for these patients. Among patients with mutant BRAF mCRC and PS 0/1, the magnitude of the hazard ratio for median OS (HR=0.71) was similar to that in patients with RAS/BRAF mCRC and PS 0/1 (HR=0.69). However, the median OS was shorter in patients with BRAF mutated mCRC than in those with BRAF wild-type mCRC in both treatment groups, supporting the role of BRAF mutation as a poor prognostic factor.3,4

 

PRIME: Outcomes among patients with wild-type RAS mCRC, with non-liver limited disease (non-LLD)5,6

The 2014 ESMO guidelines recommend initial treatment with a very active combination regimen for patients with mCRC who have multiple metastases and for those with more limited disease.8 A recent exploratory analysis of data from PRIME observed a high median overall survival (OS) among patients with wild-type RAS mCRC and LLD who received Vectibix® + FOLFOX vs those receiving FOLFOX alone (40.7 months vs 32 months), although the difference between treatments did not achieve statistical significance.9 An exploratory analysis was therefore done to evaluate the treatment effect of Vectibix® + FOLFOX vs FOLFOX among patients with wild-type RAS mCRC and non-LLD.5,6 This analysis was done when ≥80% of patients in PRIME had had an OS event.

Of the 505 patients in PRIME who had wild-type RAS mCRC, 416 (82%) had non-LLD. The Vectibix® + FOLFOX (n=205) and FOLFOX (n=211) treatment groups were well balanced with respect to baseline sex, age and metastatic sites. Overall, 82% of patients had liver involvement, and 21% had more than three metastatic sites (median 3, range 1–6).5,6

As in the overall population of patients with wild-type RAS mCRC included in PRIME, the progression-free survival (PFS) and OS in patients with wild-type RAS mCRC and non-LLD favoured treatment with Vectibix® + FOLFOX. For comparison, the subgroup with LLD receiving Vectibix® + FOLFOX also had longer PFS (11.3 months vs 9.9 months) and OS (40.7 months vs 33.4 months) than did those receiving FOLFOX alone, although these findings did not achieve statistical significance in this exploratory analysis.5,6

PRIME: Outcomes among patients with wild-type RAS mCRC, with non-LLD5,6

PRIME: graphs of PFS and OS among patients with wild-type RAS mCRC, with disease not confined to the liver

Adapted from Douillard et al.5,6 (a) PFS and (b) OS.

The investigators also estimated 3-year OS in the patients with wild-type RAS mCRC.5,6

PRIME: 3-year survival rates among patients with wild-type RAS mCRC stratified by LLD and non-LLD5,6

3-year OS (%) among patients with wild-type RAS mCRC Vectibix® + FOLFOX FOLFOX
Non-LLD 31% 23%
LLD 52% 37%
Overall population 33% 24%

Conclusion

This post-hoc analysis suggests that the PFS and OS benefits previously reported for 1st line Vectibix® + FOLFOX vs FOLFOX treatment in the overall PRIME population (patients with wild-type RAS mCRC) are also observed in patients with non-LLD. The investigators concluded that Vectibix® + FOLFOX is an effective 1st line treatment for patients with wild-type RAS mCRC, irrespective of whether metastases are limited to the liver or are more extensively distributed, and is superior to FOLFOX alone in these patients.5,6

 

PRIME: Impact of baseline age on efficacy and safety7

The incidence of CRC increases with age.10 Despite this, older patients are often excluded from clinical trials, and so evidence-based data for the efficacy and safety of many cancer treatments in older patients are lacking.11,12 The available data from retrospective analyses and newer trials conducted in elderly patients suggest that they can achieve similar treatment benefits to younger patients.11-15

An exploratory analysis of efficacy and safety data from PRIME was conducted, stratifying patients by baseline age. The analysis was done when ≥80% of patients in PRIME had had an overall survival (OS) event, and it included only those patients with wild-type RAS mCRC. Objective response rate (ORR), progression-free survival (PFS), OS and safety were assessed by baseline age subgroup (<65 years, ≥65 to ≤75 years, >75 years and ≥65 years).7

A total of 505 patients with wild-type RAS mCRC were included in the analysis; their median age was 61 years, and more than 60% of patients were <65 years old at baseline. Baseline demographics and disease characteristics were well balanced between treatment groups and across age subgroups.7

ORRs were higher among patients with wild-type RAS mCRC receiving Vectibix® + FOLFOX vs FOLFOX alone overall and in all of the age subgroups assessed except for those aged >75 years. However, only 32 patients aged >75 years were evaluable for response (16 for Vectibix® + FOLFOX and 16 for FOLFOX).7

PRIME: ORRs and best responses among patients with wild-type RAS mCRC, stratified by age7

Age subgroup ORR
(%; 95% CI)
Best response (n [%])
CR PR SD PD NE
<65 years
Vectibix® + FOLFOX (n=158) 65 (57–73) 1 (1) 100 (65) 39 (25) 10 (6) 5 (3)
FOLFOX (n=158) 47 (39–55) 1 (1) 72 (46) 55 (35) 20 (13) 7 (5)
≥65 to ≤75 years
Vectibix® + FOLFOX (n=79) 57 (45–68) 0 (0) 44 (57) 22 (29) 6 (8) 5 (6)
FOLFOX (n=76) 45 (34–57) 0 (0) 34 (45) 31 (41) 7 (9) 3 (4)
≥65 years
Vectibix® + FOLFOX (n=95) 53 (42–63) 0 (0) 49 (53) 29 (31) 8 (9) 7 (8)
FOLFOX (n=94) 46 (36–57) 0 (0) 42 (46) 36 (40) 9 (10) 4 (4)
>75 years
Vectibix® + FOLFOX (n=16) 31 (11–59) 0 (0) 5 (31) 7 (44) 2 (13) 2 (13)
FOLFOX (n=18) 50 (25–75) 0 (0) 8 (50) 5 (31) 2 (13) 1 (6)
Overall
Vectibix® + FOLFOX (n=253) 60 (54–67) 1 (<1) 149 (60) 68 (27) 18 (7) 12 (5)
FOLFOX (n=252) 47 (40–53) 1 (<1) 114 (46) 91 (37) 29 (12) 11 (4)

CR, complete response; NE, not evaluable; PD, disease progression; PR, partial response; SD, stable disease.

PFS was significantly longer in the overall population of patients with wild-type RAS mCRC who received Vectibix® + FOLFOX vs FOLFOX (11.1 months vs 8.7 months; HR=0.74, 95% CI: 0.61–0.89; p=0.0015) and among those aged <65 years (12.9 months vs 8.7 months; HR=0.65, 95% CI: 0.51–0.82; p=0.0004).7

PRIME: Summary of PFS hazard ratios among patients with wild-type RAS mCRC stratified by age7

PRIME: forest plot of PFS hazard ratios among patients with wild-type RAS mCRC, stratified by age

Adapted from Douillard et al.7

As for PFS, OS was significantly longer in the overall population of patients with wild-type RAS mCRC who received Vectibix® + FOLFOX vs FOLFOX (26.0 months vs 20.2 months; HR=0.76, 95% CI: 0.63–0.92; p=0.0057) and among those aged <65 years (25.8 months vs 21.2 months; HR=0.74, 95% CI: 0.58–0.94; p=0.0158).7

PRIME: Summary of OS hazard ratios among patients with wild-type RAS mCRC stratified by age7

PRIME: forest plot of OS hazard ratios among patients with wild-type RAS mCRC, stratified by age

Adapted from Douillard et al.7

No new safety signals were identified in any of the age subgroups. The incidence of serious and treatment-related serious adverse events (AEs) appeared to increase with increasing age, especially in the Vectibix® + FOLFOX group. Trends were less clear in the FOLFOX4 group. In the Vectibix® + FOLFOX group overall, diarrhoea was the most common serious AE (9%) and the most common serious treatment-related AE (9%). This was also the most common serious AE and serious treatment-related AE in all of the age subgroups assessed. In the FOLFOX group overall, vomiting was the most common serious AE (4%) and the most common serious treatment-related AE (3%). Vomiting was also among the most common serious and serious treatment-related AEs in all of the age subgroups assessed.7

Conclusion

In these exploratory analyses, Vectibix® + FOLFOX offered efficacy benefits over FOLFOX among patients with wild-type RAS mCRC overall and in the subgroups of patients aged <65 years, ≥65 to ≤75 years, and ≥65 years. Analysis of efficacy in patients aged >75 years was limited by patient numbers, and more research is needed to assess treatment benefit in these patients. In patients receiving Vectibix® + FOLFOX, the incidence of serious AEs and treatment-related serious AEs appeared to increase with increasing age.7

Chronological age alone should not exclude a patient from treatment, although elderly patients should be carefully monitored and early intervention provided in the event of toxicity.7

 

References

  1. Douillard J-Y et al. N Engl J Med 2013;369:1023–1034.
  2. Schwartzberg LS et al. J Clin Oncol 2014;32:2240–2247.
  3. Peeters M et al. J Clin Oncol 2014;32(suppl):5s, abstract 3557 (and poster).
  4. Peeters M et al. Ann Oncol 2014;25(suppl 2): ii87–ii88, abstract P-0236 (and poster).
  5. Douillard J-Y et al. J Clin Oncol 2014;32(suppl):5s, abstract 3550 (and poster).
  6. Douillard J-Y et al. An Oncol 2014;25(suppl 2):ii6, abstract PD-0004 (and poster).
  7. Douillard JY, et al. Ann Oncol 2014; 25(suppl 4): iv187, abstract 547P (and poster).
  8. Van Cutsem E, et al. Ann Oncol 2014 [in press].
  9. Peeters M et al. EJC 2013;49(Suppl 4): abstract MC13-0022 (and poster).
  10. Kordatou Z, et al. Ther Adv Med Oncol 2014;6:128–140.
  11. Cassidy J, et al. J Cancer Res Clin Oncol 2010;136:737–743.
  12. Leo S, et al. J Gastrointest Cancer 2013;44:22–32.
  13. Jehn CF, et al. Br J Cancer 2012;106:274–278.
  14. Folprecht G, et al. J Clin Oncol 2008;26:1443–1451.
  15. Hung A, Mullins CD. Oncologist 2013;18:54–63.
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