CONCLUSIONS INTRODUCTION OBJECTIVES METHODS

CONCLUSIONS INTRODUCTION OBJECTIVES METHODS

RAS analysis of the PLANET study: Phase II trial of panitumumab (Pmab) plus FOLFOX4 or FOLFIRI
in subjects with wild-type (WT) KRAS colorectal cancer (CRC) and liver-limited disease (LLD)
A. Abad1*, B. Massuti2, C. Grávalos3, P. Escudero4, C. Guillén-Ponce5 , A. Gomez6, Mª J. Safont7, J. Gallego8, J. Sastre9, C. Pericay10, R. Dueñas11, C. López-López12, F. Losa13, M. Valladares14, E. González15, L. Robles3, L. Layos1, A. Carrato5, E. Aranda6
On behalf of the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD)
1.Germans Trias i Pujol Hospital –ICO, Badalona, Spain; 2. General Hospital, Alicante, Spain; 3. Doce de Octubre Hospital, Madrid, Spain; 4. Clínico Lozano Blesa Hospital, Zaragoza, Spain; 5. Universitario Ramón y Cajal Hospital, Madrid, Spain; 6. Maimonides Institute of Biomedical Research, IMIBIC, Spain, Reina Sofía Hospital, University of Córdoba. Spanish Cancer Network, (RTICC), Instituto de Salud Carlos III, Spain; 7. General Hospital, Valencia, Spain; 8. General Universitario de Elche Hospital, Alicante,
Spain; 9. Hospital Clínico San Carlos, Madrid; Center affiliated to the Red Temática de Investigación Cooperativa, RD06/0020/0021, Spain, Instituto Carlos III, Spanish Ministry of Science and Innovation, Madrid; 10. Sabadell Hospital, Corporación Sanitaria Parc Taulí, Barcelona, Spain; 11. Complejo Hospitalario de Jaén Hospital, Jaén, Spain; 12. Marqués de Valdecilla Hospital, Santander, Spain; 13. General de L´Hospitalet Hospital, Barcelona, Spain; 14. Complejo Hospitalario Universitario Hospital, La Coruña,
Spain; 15. Virgen de las Nieves Hospital, Granada, Spain; *actual address: Oncology Unit, Campus CIMA, Barcelona, Spain
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Exploratory Endpoint of the present subanalysis:
Response according to molecular biomarkers (RAS status)
Endpoints of the overall study:
Primary :
Objective response rate (ORR) over the entire Pmab+CT treatment period
Secondary :
Resection rate (R0+R1) of liver metastases
Time to resection
Progression-free survival (PFS)
Overall survival (OS)
Adverse Events (AEs) and peri-operative safety
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OBJECTIVES
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SD
Surgically non-resecable
Neoadjuvant treatment: 4
cycles
KRAS
Neoadjuvant treatment: 8 cycles
Evaluation of response every 4 cycles**
PR
100% (per-protocol)
Additional treatment cycles until progression or
resecability achieved. Evaluation of response every 4
cycles**
Exhaustive evaluation 4-8
weeks after resection
before initiation of
adjuvant treatment
Adjuvant treatment:
6 cycles
PROGRESSION
NRAS
Treatment
phase
R2
Adjuvant treatment until progression or resecability
achieved. Evaluation of response every 4 cycles**
ADDITIONAL SURGERY
PROGRESSION
Safety evaluation: 30±3 days after last treatment
Long term follow-up: every 3±1 months after safety evaluation (up to 36 months)
* Stratified by: prior adjuvant FOLFOX therapy; resectability of liver metastases
** After 4 cycles of neoadjuvant/adjuvant therapy, if PR ≥75% or nearly complete response and resection is feasible, the surgery
should be performed at that moment; PR= partial response; SD= stable disease
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METHODS
Phase II, open-label, randomized, multicentre, two-parallel-group study (Planet Study [TTD-0804], clinicaltrials.gov identifier NCT00885885)(Figure 1).
Tumour assessments (revised Response Evaluation Criteria in Solid Tumours [RECIST] criteria
version 1.1) were performed by investigators Q8W during the treatment phase.
In addition to the KRAS exon 2 (codons 12 and 13), the following RAS mutations were
determined in a central laboratory:
Exons 3 (codons 59 and 61) and 4 (codons 117 and 146) of KRAS
Exons 2 (codons 12 and 13), 3 (codons 59 and 61) and 4 (codons 117 and 146) of NRAS
Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were
analysed according to RAS status (mutant RAS / WT-RAS).
The primary analysis set included all randomized patients who received at least one dose of
panitumumab or chemotherapy.
Efficacy endpoints were reported using descriptive statistics, 95% CI, and Kaplan-Meier (KM)
plots.
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EXON 2
12 13
PR or SD
R0 or R1
EXON 1
Resecability not achieved
SURGERY
(4 to 6 weeks after last CT dose)
Any RAS mutation
(n=64 patients,
83.1% ascertainment*)
Individual RAS mutations
(n=64)
EXON 1
EXON 2
12 13
1.6% 0%
EXON 3
59 61
0%
0%
EXON 3
59 61
0% 3.1%
117 146
1.6%
10.9%
EXON 4
117 146
0% 0%
MutantRAS
17.2%
(n=11)
WT-RAS
82.8%
(n=53)
Table 1. Characteristics of the WT-RAS subgroup
Pmab-FOLFOX4 Pmab-FOLFIRI
(N = 27)
(N = 26)
Male, n (%)
23 (85.2)
18 (69.2)
Median age, years (min, max)
65 (32, 79)
60 (37, 78)
Median time since CCR diagnosis, months (Q1, Q3)
3.1 (1.5, 21.0)
1.6 (0.5, 27.0)
Technically resectable liver metastases
5 (18.5)
9 (34.6)
Prior surgery for primary tumor, n (%)
19 (70.4)
15 (57.7)
Prior adjuvant/neoadjuvant CT and/or radiotherapy, n (%)
4 (14.8)
3 (11.5)
Prior FOLFOX, n (%)
2 (7.4)
3 (11.5)
Efficacy according to RAS status
In the overall study population, ORR (not confirmed*) was noted in 70.1% patients (73.7%
(95% CI: 59.7-87.7) with Pmab-FOLFOX4 and 66.7% (51.9-81.5) with Pmab-FOLFIRI).
In the subgroup with RAS ascertainment, the ORR was 75.5% in WT-RAS patients (Figure
2) and 54.6% (25.1-84.0) in the Mutant (Mt)-RAS stratum.
After preoperative treatment, 52.8% of WT-RAS underwent surgical resection of liver
metastases. In the subgroup with of WT-RAS with non-resectable metastases (n=39), surgical
resection was possible in 53.8% of patients.
The R0+R1 resection rate in the WT-RAS subgroup was 39.6% (25.9% with P-FOLFOX4 and
53.8% with P-FOLFIRI)(Figure 2). Percentages of patients with R0 and R1 were 32.1% and
7.5%, respectively.
Higher ORR and longer PFS and OS were observed in WT-RAS versus Mutant-RAS patients in
the overall population (Figures 3 & 5), although differences were not significant, probably due
to small sample sizes.
There were no significant differences between P-FOLFOX4 and P-FOLFIRI within each of the
RAS strata, either (Mt-RAS: PFS p=0.699 / OS p=0.391; WT-RAS: Figures 4 & 6).
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*patients resected before response confirmation
(34.6-73.0)
n=14
(18.8-55.3)
n=10
50%
25.9%
39.6%
(26.4-52.8)
n=21
(9.4-42.4)
n=7
40%
30%
20%
1 00
P Wilcoxon=0.634
80
60
Median (95% CI), months:
40
WT-RAS/Pmab-FOLFOX4: 39.0 (26.4-NA)
WT-RAS/Pmab-FOLFIRI: 45.8 (32.8-51.5)
20
10%
0
Surgical resection Resection rate
(R0+R1)
1 00
10
20
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Safety (WT RAS population)
Peri-operative safety was similar (10.0% and 27.8% of patients who underwent surgery with
any adverse event (AE), p=0.536) (Table 2).
There was a trend toward less neutropenia and neuropathy with Pmab-FOLFIRI versus PmabFOLFOX4 in grade 3/4 adverse events (Table 3).
In the WT RAS population, 11 ( 40.7%) patients treated with Pmab-FOLFOX4 and 11 (42.3%)
treated with Pmab-FOLFIRI died, none of them due to an AE related to Pmab and/or CT.
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Mutant RAS: 12.6 (3.7-24.9)
WT-RAS: 13.4 (9.9-18.6)
Table 2. Summary of adverse events (WT RAS population)
Pmab-FOLFOX4
(N = 27)
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P log-rank = 0.346
P Wilcoxon = 0.403
20
0
10
20
30
40
50
Time (months)
Figure 4. PFS by treatment in the WT-RAS subgroup
Grade 3-4, n (%)
Treatment-related Grade 3-4, n (%)
Fatal AEs, n (%)
Treatment-related fatal AEs, n (%)
Serious AE, n (%)
Pmab and/or CT-related serious AE, n (%)
Peri-operative AEs, n (%) (in patients with surgery)
Neutropenia, n (%)
Conjunctivitis, n (%)
Diarrhoea, n (%)
Asthenia, n (%)
Neuropathy, n (%)
Decreased appetite, n (%)
Median (95% CI), months:
WT-RAS/Pmab-FOLFOX4: 12.8 (6.2-22.0)
WT-RAS/Pmab-FOLFIRI: 14.8 (7.1-18.7)
80
60
40
P Wilcoxon = 0.675
0
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10
20
30
40
Time (months)
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CI: confidence interval; Mt: Mutant; NA: not achieved
Figure 5. Overall survival by RAS status
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Median (95% CI), months:
1 00
20 (76.9)
16 (61.5)
1 (3.7)
0
6 (22.2)
0
1 (10.0)
3 (11.5)
0
7 (26.9)
0
5 (27.8)
Pmab-FOLFIRI
(N = 26)
7 (25.9)
1 (3.7)
3 (11.1)
4 (14.8)
5 (18.5)
2 (7.4)
2 (7.7)
1 (3.8)
1 (3.9)
1 (3.8)
0
0
P-value
0.077
0.978
0.317
0.172
0.051
0.157
CONCLUSIONS
Despite the small sample size of the subgroup, patients with RAS mutations (KRAS,
NRAS) other than KRAS exon 2 show a clear trend to worse efficacy outcomes than
WT-RAS patients, without differences between Pmab-FOLFOX4 and Pmab-FOLFIRI, in
the first-line treatment of WT KRAS CRC.
In this selected population with liver-limited disease, panitumumab plus CT offers the
possibility of rapid overall response and potentially curative hepatic resection.
Similar efficacy and safety results were obtained in the overall group with either
Pmab-FOLFOX4 or Pmab-FOLFIRI schema.
Mutant RAS: 31.4 (13.7-NA)
WT-RAS: 44.7 (32.8-51.5)
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REFERENCES
1. Amado AG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26:1626-3
2. Douillard JY, Siena S, Cassidy J, et al. Final results from PRIME: randomized phase 3 study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol.
2014;25(7):1346-55
3. Douillard JY, Oliner KS, Siena S, et al. Panitumumab–FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer. N Engl J Med 2013; 369:1023-1034
4. Karnoub AE, Weinberg RA. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 2008;9:517-31.
5. Janakiraman M, Vakiani E, Zeng Z, et al. Genomic and biological characterization of exon 4 KRAS mutations in human cancer. Cancer Res 2010;70:5901-11.
6. Fernández-Medarde A, Santos E. Ras in cancer and developmental diseases. Genes Cancer 2011;2:344-58.
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ACKNOWLEDGEMENTS
The physicians listed below cared for the patients in this study. The authors thank them for their cooperation and support:
P log-rank = 0.621
P Wilcoxon = 0.724
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0
22 (81.5)
18 (66.7)
*There were no grade 5 AEs related to Pmab and/or CT
20
0
Pmab-FOLFIRI
(N = 26)
Table 3. Grade 3/4* treatment-related adverse events (WT RAS)
Pmab-FOLFOX4
(N = 27)
100
50
CI: confidence interval; Mt: Mutant; NA: not achieved
60
0
40
Time (months)
Median (95% CI), months:
80
0
EXON 4
*Ascertainment defined as percentage of patients with a known codon sequence result at all positions
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37.0%
60%
53.8%
52.8%
(39.4-66.3)
n=28
70%
Figure 1. Prevalence of RAS mutations (other than KRAS exon 2)
(every 14±3 days (+additional days needed to solve
toxicities);Pmab day 1 of each cycle)
Neoadjuvant treatment: 8 cycles
Evaluation of response every 4 cycles**
80%
(51.5-87.0)
n=18
Figure 3. Progression-free survival by RAS status
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Randomization 1:1* to:
Pmab+FOLFOX4 / Pmab+FOLFIRI
Surgically resecable
90%
ORR: Objective response rate (not confirmed*); *patients resected before response confirmation
Population characteristics and RAS ascertainment
In the PLANET study, 77 patients were analyzed (38 Pmab-FOLFOX4; 39 Pmab-FOLFIRI).
Their characteristics are shown in Table 1.
It was possible to determine the RAS status in 83.1% of the patients, from whom 82.8%
were WT-RAS and 17.2% were mutant RAS [WT KRAS (exon 2), mutant RAS (exons 3,4 of
KRAS or exons 2,3,4 of NRAS)] (Figure 1). No double mutations were observed.
WT KRAS (exon 2) CCRm patients with liver-only metastases
69.2%
(62.1-93.5) 73.1% (63.9-87.1)
n=21 (56.0-90.1)
n=40
n=19
ORR
RESULTS
Figure 1. Study scheme
75.5%
TOTAL WT RAS (n=53)
0%
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77.8%
100%
Pmab-FOLFIRI (n=26)
Figure 6. Overall survival by treatment in the WT-RAS subgroup
Percentage free of event
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Pmab-FOLFOX4 (n=27)
Percentage free of event
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Main inclusion criteria:
>18 years of age
WT KRAS CRC
Liver-only metastases fulfilling one of the following criteria:
≥4 liver metastases
at least 1 metastasis >10 cm in diameter
Liver metastases technically not resectable (vascular compromise and/or location
in which complete resection is impossible and/or 25-30% of healthy liver would not
remain functional after resection)
Patients with recurrence after adjuvant treatment with 5-fluorouracil/folinic acid or
capecitabine or an oxaliplatin-based regimen or with recurrence after surgical treatment
and/or radiotherapy without adjuvant systemic treatment or with de novo diagnosis
No major contra-indication to liver surgery
Karnofsky performance status ≥ 70%
Adequate bone marrow function, hepatic and renal function and magnesium levels.
Main exclusion criteria:
Prior anti-EGFr antibody therapy or treatment with small molecule EGFr tyrosine kinase
inhibitors.
Hormonal therapy, immunotherapy or experimental or approved proteins/antibodies (eg,
bevacizumab) ≤ 30 days before inclusion
Surgery (not including diagnostic biopsy or central venous catheter placement) and/or
radiotherapy in the 4 weeks prior to inclusion
Significant cardiovascular disease including unstable angina or myocardial infarction within
12 months before initiating study treatment or a history of ventricular arrhythmia
Percentage free of event
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It is well known that patients with KRAS mutations in exon 2 do not respond to
panitumumab (Pmab) 1,2, but more negative predictive markers are needed to improve the
benefit–risk balance of this drug.
Recently, it was confirmed that other activating mutations in KRAS and NRAS, members of
the RAS oncogene family, predict a lack of response to panitumumab3. For this reason,
there was a label change in Europe to restrict the indication to WT-RAS patients.
The locations of the activating mutations in both genes are at codons 12, 13, 61, 117, and
146. All of them result in increased levels of guanosine triphosphate–bound RAS proteins4,5.
In CRC, these mutations are mutually exclusive, probably due to similar functionality of
KRAS and NRAS genes6.
Using data from a phase II, open-label trial of Pmab added to standard CT regimens, we
performed a protocol-predefined subanalysis to explore the effect of RAS mutations other
than KRAS exon 2 mutations in the efficacy of Pmab-FOLFIRI or Pmab-FOLXOX4, as firstline treatment of WT KRAS CRC patients with liver-only metastases.
Percentage free of event
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Figure 2. Response rate and resectability in the WT-RAS subgroup
ELIGIBILITY CRITERIA
Percentage of patients (95% CI)
INTRODUCTION
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10
Study Chairs: Alfredo Carrato (H.U. Ramon y Cajal), Albert Abad (H. Trias i Pujol Badalona; actual address: Oncology Unit, Campus CIMA, Barcelona)
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Time (months)
CI: confidence interval; NA: not achieved
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F. Losa (H. General de L'Hospitalet (L´Hospitalet de Llobregat))
F. Rivera, C. López-López (H. Marqués de Valdecilla (Santander))
J. Gallego (H. General Universitario de Elche (Alicante))
J. Sastre (H. Universitario Clínico San Carlos (Madrid))
M. Valladares (C. H. Universitario (La Coruña))
Mª J. Safont (H. General Universitario (Valencia))
P. Escudero (H. C. Universitario Lozano Blesa (Zaragoza))
R. Dueñas (H. Ciudad de Jaén)
TTD Data Center: I Ruiz de Mena and S. Rodríguez; Statistics and Data Management: TFS: R. Dosantos; Monitoring: TFS: E. Molina and N. Escalona; Medical Writing: TFS: N. Valveny;
Financial Support: Amgen S.A.
A. Abad, JL Manzano (ICO. H. Germans Trias i Pujol (Badalona))
A. Carrato, C. Guillén-Ponce (H. Ramón y Cajal (Madrid))
B. Massuti, A.Yuste (H. General Universitario (Alicante))
C. Grávalos, L. Robles (H. 12 de Octubre (Madrid))
C. Pericay (C. S. Parc Taulí (Barcelona))
E. Aranda, A. Gómez (H. Universitario Reina Sofía (Córdoba))
E. González (H. Virgen de las Nieves (Granada))
Presented at the 2014 European Society of Medical Oncology Meeting, September 26-30, 2014, Madrid, Spain; Abstract # 7823
Corresponding author: Albert Abad, email: [email protected]