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Recent insights into outcomes and the impact of baseline covariates in the 181 trial

Further insights into the efficacy of the combination of Vectibix® + FOLFIRI in in the 2nd line setting, in patients with wild-type RAS mCRC, were reported at the recent ESMO congress.

  • The 2014 European Society for Medical Oncology (ESMO) was held in Madrid, from 26 to 30 September 2014

 

These analyses, based on data from the 181, phase 3 study of Vectibix® + FOLFIRI vs FOLFIRI alone in the 2nd line setting, focused on the following:

Details about the prospective-retrospective analysis of outcomes among patients with wild-type RAS mCRC in the 181 trial can be found in the Key data/additional studies/181 study.

181 trial: Tumour shrinkage and response outcomes during 2nd line treatment with Vectibix® + FOLFIRI vs FOLFIRI alone1

In the 1st line setting, Vectibix® + FOLFOX has been demonstrated to achieve higher objective response rate (ORR)3 and a higher rate of early tumour shrinkage (rates of ≥30% tumour shrinkage at week 8)4 vs FOLFOX alone among patients with wild-type RAS mCRC. Vectibix® + FOLFOX was also associated with numerically higher rates of surgical resection among patients with liver-limited disease, although statistical significance was not achieved.5

To examine the effects of Vectibix® + FOLFIRI vs FOLFIRI alone on tumour shrinkage and response among patients with wild-type RAS mCRC in the 2nd line setting, an exploratory analysis of the 181 study was conducted.1

The endpoints examined were ORR, median duration of response (DoR), median deepness of response (DpR) and mean % change in tumour load over time. DpR is the percentage tumour shrinkage (positive for tumour reduction and negative for tumour growth), and is defined as follows.1

  • If a patient experiences tumour reduction during treatment, then the DpR is the greatest percentage of tumour shrinkage observed vs baseline.
  • If a patient experiences tumour growth or no change, then the DpR is the percentage tumour shrinkage (vs baseline) at the time of disease progression if the patient experiences disease progression (not death). The value will be either 0 or negative by definition.
  • If a patient experiences neither tumour reduction nor disease progression then DpR was set to ‘missing’

 

Only those patients who fell into the first two categories were included in the DpR analysis.1

Of the 1186 patient initially randomised into the study,6 421 had RAS wild-type mCRC. In these patients, baseline demographics and disease characteristics were generally well balanced between treatment groups. However, primary rectal cancer was more common in the Vectibix® + FOLFIRI group (43% vs 31%), and primary colon cancer was more common in the FOLFIRI group (57% vs 69%). Also, more patients in the FOLFIRI group received subsequent therapy with an EGFR‐targeted monoclonal antibody.1

Overall, 411 patients were included in the ORR analysis, and 361 had data available at baseline and week 8 and so were included in the tumour shrinkage analysis. ORR and DpR were higher for Vectibix® + FOLFIRI vs FOLFIRI alone.1

181 trial: Best response, ORR, DoR and DpR among patients with wild-type RAS mCRC1

Vectibix® + FOLFIRI (n=208) FOLFIRI alone (n=213)
Best response (n [%])
Complete response 0 (0) 0 (0)
Partial response 83 (41) 21 (10)
Stable disease 78 (38) 117 (57)
Disease progression 29 (14) 48 (23)
Unevaluable/not done 14 (7) 21 (10)
ORR (n [%; 95% CI]) 83 (41%; 34–48) 21 (10%; 6–15)
DoR (months; median [95% CI]) [n] 7.7 (6.7–9.9) [83] 9.3 (6.1–12.8) [21]
DpR (%; median [Q1, Q3]) [n] 37 (13, 56) [50] 10 (–5, 26) [12]
p value 0.0001

 

Over the first 56 weeks of treatment, Vectibix® + FOLFIRI offered a consistent benefit over FOLFIRI alone in terms of mean percentage change from baseline in tumour load (sum of all target lesions).1

181 trial: Mean percentage change in tumour load (sum of all target lesions)* at each scheduled visit among patients with wild-type RAS mCRC1 181 trial: graph showing change in tumour load over time among patients with wild-type RAS mCRC

Adapted from Peeters et al.1 Tumour data at each scheduled visit are shown; following progression, patients were only followed up for survival and no further CT scans were taken. *Includes those patients evaluable for objective response who had baseline tumour shrinkage data.

More patients in the Vectibix® + FOLFIRI vs FOLFIRI group had ≥30% tumour shrinkage at week 8 (37% vs 7%; difference 30%, 95% CI: 22–38). Tumour shrinkage of ≥30% at week 8 appeared to be associated with longer median PFS in both treatment groups vs <30% shrinkage.1

181 trial: Median PFS by tumour shrinkage at week 8 among patients with wild-type RAS mCRC1

Vectibix® + FOLFIRI (n=208) FOLFIRI alone (n=213)
 Week 8 tumour shrinkage (%) <30 ≥30 <30 ≥30
 n (%) 114 (63) 67 (37) 168 (93) 12 (7)
 Median PFS (months [95% CI]) 6.9 (5.4–8.0) 8.6 (7.3–11.3) 5.5 (3.9–6.7) 8.0 (3.5–NE)
 HR (95% CI) 0.66 (0.47–0.93); p=0.0182 0.51 (0.24–1.08); p=0.0797

NE, not evaluable.

Numerically more patients in the Vectibix® + FOLFIRI vs FOLFIRI alone group underwent surgical resection following treatment (any resection: 7 [3%] vs 2 [1%]; complete resection: 2 [1%] vs 2 [1%]).1

Conclusion

Among patients with wild-type RAS mCRC treated in the 2nd line setting, Vectibix® + FOLFIRI achieved a 30% improvement in ORR vs FOLFIRI alone. Also, more patients achieved ≥30% tumour shrinkage at week 8 with Vectibix® + FOLFIRI vs FOLFIRI alone. Early tumour shrinkage was apparently associated with improved PFS.1

The investigators concluded that, in these exploratory analyses, Vectibix® + FOLFIRI appeared to be associated with earlier and deeper responses than FOLFIRI alone in patients with wild-type RAS mCRC.1

181 trial: Impact of baseline covariates and prior therapy on efficacy during 2nd line treatment with Vectibix® + FOLFIRI vs FOLFIRI alone2

To examine the influence of baseline covariates and prior therapy on efficacy with Vectibix® + FOLFIRI vs FOLFIRI alone among patients with wild-type RAS mCRC in the 2nd line setting, an exploratory analysis of the 181 study was conducted.

Progression-free survival (PFS) and overall survival (OS) subgroup analyses in the wild-type RAS mCRC population were performed by:

  • randomisation stratification factors (Eastern Cooperative Oncology Group performance status [ECOG PS; 0/1 or 2], prior oxaliplatin exposure and prior bevacizumab exposure);
  • prespecified baseline covariates (age [<65 or ≥65 years] and BRAF status [wild-type or mutant]); and
  • other exploratory factors (body mass index [BMI] <30 or ≥30, location of metastases [liver only or other] and time to progression since completion of adjuvant therapy [≤6 months or >6 months]).

 

Of the 1186 patient initially randomised into the study,6 421 had RAS wild-type mCRC. In these patients, baseline demographics and disease characteristics were generally well balanced between treatment groups. However, primary rectal cancer was more common in the Vectibix® + FOLFIRI group (43% vs 31%), and primary colon cancer was more common in the FOLFIRI group (57% vs 69%). Also, more patients in the FOLFIRI group received subsequent therapy with an EGFR‐targeted monoclonal antibody.2

In the overall population of patients with wild-type RAS mCRC, median PFS was significantly longer in the Vectibix® + FOLFIRI vs FOLFIRI group (HR=0.70, 95% CI: 0.54–0.91; p=0.007). Median PFS improvements were seen for Vectibix® + FOLFIRI vs FOLFIRI in all prespecified subgroups. Improvements were also observed in all exploratory subgroups (based on the HRs reported) except for those whose time to disease progression since completing adjuvant therapy was >6 months.2

181 trial: Median PFS by subgroup2

Median PFS (months [95% CI]) HR (95% CI) Descriptive p value
Vectibix® + FOLFIRI (n=208) FOLFIRI (n=213)
 Randomisation stratification factors: ECOG PS
 0/1 6.7 (5.6–7.8) 4.9 (3.7–5.8) 0.71 (0.54–0.92) 0.0114
 2 3.1 (1.6–6.4) 2.5 (1.7–5.3) 0.68 (0.22–2.10) 0.5060
 Randomisation stratification factors: Prior bevacizumab
 Yes 6.7 (5.5–8.0) 3.7 (3.5–5.9) 0.65 (0.33–1.27) 0.2095
 No 6.1 (5.4–7.4) 4.6 (3.7–5.6) 0.72 (0.54–0.95) 0.0204
 Randomisation stratification factors: Prior oxaliplatin
 Yes 6.1 (4.8–7.4) 3.7 (3.3–4.9) 0.64 (0.47–0.86) 0.0035
 No 6.7 (5.6–9.2) 6.9 (5.2–9.2) 0.90 (0.55–1.47) 0.6803
 Prespecified baseline covariates: Age
 <65 years 6.4 (5.5–8.6) 4.6 (3.7–5.7) 0.64 (0.46–0.89) 0.0089
 ≥65 years 6.4 (4.5–7.4) 3.9 (3.3–7.1) 0.69 (0.45–1.04) 0.0770
 Prespecified baseline covariates: BRAF mutation
 Yes 2.5 (1.7–3.5) 1.8 (1.8–3.1) 0.69 (0.32–1.49) 0.3421
 No 6.9 (5.8–8.0) 5.5 (3.9–5.9) 0.68 (0.51–0.90) 0.0063
 Exploratory factors: BMI
 <30 6.4 (5.5–7.4) 4.1 (3.7–5.7) 0.72 (0.54–0.96) 0.0255
 ≥30 6.7 (4.1–9.9) 5.2 (3.7–9.1) 0.73 (0.38–1.40) 0.3406
 Exploratory factors: Location of metastases
 Liver only 7.5 (5.6–17.1) 5.2 (3.7–5.9) 0.45 (0.23–0.87) 0.0174
 Other 6.1 (5.4–7.3) 3.9 (3.7–5.6) 0.73 (0.54–0.98) 0.0336
 Exploratory factors: Time to disease progression*
 ≤6 months 5.7 (3.5–9.2) 3.8 (1.9–5.5) 0.58 (0.19–1.76) 0.3404
 >6 months 5.5 (3.7–8.3) 5.2 (3.5–NE) 1.42 (0.60–3.35) 0.4184

*After completion of adjuvant therapy.

In terms of median OS among patients with wild-type RAS mCRC overall, there was a trend toward improvement in the Vectibix® + FOLFIRI vs FOLFIRI group (HR=0.81, 95% CI: 0.63–1.03; p=0.08). Based on the HRs, improvements were seen in all subgroups other than in patients with a BMI ≥30 and in those whose time to disease progression since adjuvant therapy was >6 months.2

181 trial: Median OS by subgroup2

Median OS (months [95% CI]) HR (95% CI) Descriptive p value
Vectibix® + FOLFIRI (n=208) FOLFIRI (n=213)
 Randomisation stratification factors: ECOG PS
 0/1 16.5 (14.7–20.1) 14.8 (12.3–16.9) 0.79 (0.62–1.02) 0.0736
 2 4.3 (2.8–6.6) 4.4 (2.5–14.9) 0.85 (0.32–2.26) 0.7413
 Randomisation stratification factors: Prior bevacizumab
 Yes 23.8 (15.7–29.9) 12.5 (9.1–17.3) 0.45 (0.23–0.88) 0.0185
 No 15.2 (13.6–19.0) 14.5 (11.9–16.5) 0.89 (0.69–1.16) 0.4055
 Randomisation stratification factors: Prior oxaliplatin
 Yes 15.7 (13.0–19.0) 12.4 (10.3–15.3) 0.74 (0.56–0.99) 0.0391
 No 20.2 (14.5–22.1) 16.6 (13.0–27.2) 0.99 (0.63–1.57) 0.9777
 Prespecified baseline covariates: Age
 <65 years 15.7 (14.1–20.0) 15.0 (12.2–17.9) 0.84 (0.61–1.15) 0.2704
 ≥65 years 18.7 (13.3–21.3) 12.2 (9.8–15.3) 0.74 (0.50–1.09) 0.1236
 Prespecified baseline covariates: BRAF mutation
 Yes 4.7 (2.8–9.0) 5.7 (3.5–7.3) 0.64 (0.32–1.28) 0.2061
 No 18.7 (15.7–20.3) 15.4 (13.0–17.9) 0.83 (0.64–1.07) 0.1545
 Exploratory factors: BMI
 <30 16.1 (14.2–20.1) 12.4 (10.8–15.1) 0.74 (0.56–0.96) 0.0267
 ≥30 16.6 (12.6–20.8) 22.3 (13.6–23.8) 1.15 (0.63–2.08) 0.6525
 Exploratory factors: Location of metastases
 Liver only 21.6 (16.5–24.0) 16.5 (14.8–23.7) 0.65 (0.36–1.20) 0.1717
 Other 15.4 (13.3–19.0) 12.4 (10.5–14.9) 0.79 (0.60–1.04) 0.0883
 Exploratory factors: Time to disease progression*
 ≤6 months 20.0 (11.4–NE) 13.0 (6.6–NE) 0.64 (0.23–1.78) 0.3924
 >6 months 15.7 (8.3–21.3) 14.7 (10.3–27.2) 1.24 (0.57–2.68) 0.5847

*After completion of adjuvant therapy. NE, not evaluable.

More patients experienced grade 3/4 adverse events in the Vectibix® + FOLFIRI group than in the group receiving FOLFIRI alone, irrespective of patient subgroup. Within treatment groups, the incidence of grade 3/4 adverse events was generally similar between the respective subgroups for each baseline factor.2

Conclusion

Vectibix® + FOLFIRI generally produced consistent PFS benefits vs FOLFIRI alone across all prespecified subgroups assessed in patients with wild-type RAS mCRC receiving 2nd line treatment. Similar observations were made in the OS subgroup analyses. However, based on the HRs, outcome improvements were not observed in patients with a BMI ≥30 (median OS) or those whose time to disease progression since adjuvant therapy was >6 months (median OS and PFS).2

Patients with an ECOG PS of 2 appeared to have similar median OS in the Vectibix® + FOLFIRI vs FOLFIRI group, although numbers were small in this patient subgroup and so firm conclusions cannot be drawn from these data. Also, in alignment with previous observations, BRAF mutations were associated with poor prognosis, irrespective of 2nd line treatment received, but were not predictive of lack of benefit from treatment.2

The investigators concluded that Vectibix® + FOLFIRI was generally effective across prespecified subgroups, further supporting the efficacy of this combination in patients with wild-type RAS mCRC.2

References

  1. Peeters M, et al. Ann Oncol 2014; 25:(suppl 4): iv186–iv187, abstract 546P (and poster).
  2. Peeters M, et al. Ann Oncol 2014; 25:(suppl 4): iv187–iv188, abstract 548P (and poster).
  3. Vectibix® European Public Assessment Report; 27 June 2013.
  4. Douillard J-Y et al. Ann Oncol 2013;24(suppl 4):iv32–iv33.
  5. Peeters M et al. EJC 2013;49(Suppl 4): abstract MC13-0022 (and poster).
  6. Peeters M et al. J Clin Oncol 2010;28:4706–4713.
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