KRAS mCRC Research Articles

550P - Safety and Efficacy of Panitumumab (Pmab) Monotherapy in Recurrent or Progressive Metastatic Colorectal Cancer (Mcrc): Results from a Non-Interventional Study (Vectis)

ABSTRACT Aim: Pmab is an epidermal growth factor receptor (EGFR) inhibitor indicated for patients (pts) with wild-type RAS mCRC. EGFR inhibitors are associated with skin toxicity (ST) that is mild to moderate in severity for most pts (pts). VECTIS was designed to assess the safety and efficacy of pmab as monotherapy in daily practice with special reference to ST and its management. Methods: This was an open-label, prospective, non-interventional study of 632 pts who had EGFR-expressing wild-type KRAS mCRC and were receiving pmab monotherapy (6 mg/kg Q2W) according to the label at the time the study was initiated. The analysis includes data collected 2008-2013 from Hungary, Poland, Czech Republic, Slovakia, Slovenia, and Bulgaria. The observation period was limited to 18 cycles. The presence of non-zero correlation between best response and maximum ST was tested using chi-square test for non-zero correlation. Results: At time of reporting, 533/632 (84.3%) enrolled pts (64.6% males, median age 63.0 years) had experienced a total of 782 ST events, 43.2% Gr0-1, 56.8% Gr2-3. By the end of the study 29.2% of ST events had resolved; 2.0% had resolved with consequences; 24.2% were continued but improving; and 44.5% had not resolved. Overall, 69.8% of pts required therapeutic measures for ST. Of the 13 deaths that occurred, none was related to pmab. 5 pts have stopped pmab therapy due to adverse drug reactions including ST or other toxicity. Overall, 10.4% of pts have experienced tumor response (CR + PR), 58.9% have had disease control (CR + PR + SD), and 18.2% were reported to be free from progression (FFP) at the end of observation. A statistically significant positive correlation was observed between severity of ST and both best response (p = 0.0009) and tumor response (p = 0.0002). % (95% CI) Overall N = 632 ST Gr0-1 n = 273 ST Gr2-3 n = 359 CR + PR 10.4 (8.2, 13.1) 4.8 (2.6, 8.0) 14.8 (11.3, 18.9) CR + PR + SD 58.9 (54.9, 62.7) 53.8 (47.7, 59.9) 62.7 (57.4, 67.7) FFP 18.2 (15.3, 21.4) 13.6 (9.7, 18.2) 21.7 (17.6, 26.4) Conclusions: In clinical practice, pmab monotherapy was well tolerated and effective in pts who have recurrent or progressive mCRC with wild-type KRAS gene tumor status. Disclosure: R. Lakomy: has following interests to disclose: Advisory Board member - BMS, Research funding - BMS, GSK, Novartis, Roche, other relationship - remuneration from BMS (seminar presentation). no stock ownership; B. Piko: has following interests to disclose: Advisory board member - Roche, Bayer, Pfizer, other relationship - remunaration from Roche, Merck, Richter, Teva. No stock ownership, no research funding; Z. Mihaylova: has following interests to disclose: advisory board member - Lilly, Amgen, Merck, Sanofi. No stock ownership, no research funding, no other relationship; E. Pritzova: has following interests to disclose: research funding - Bayer, Pfizer, GSK. no stock, no advisory board member, no other relationship; L. Kvocekova: has folowing interests to disclose: stock - Amgen, other relationship - full time Amgen employee. no advisory board member, no research funding. All other authors have declared no conflicts of interest.

Hsa-miR-31-3p expression is linked to progression-free survival in patients with KRAS wild-type metastatic colorectal cancer treated with anti-EGFR therapy.

To identify microRNAs (miRNA) that predict response to anti-EGFR antibodies in patients with wild-type KRAS metastatic colorectal cancer (mCRC). miRNA profiling was performed in a training set of 87 patients with mCRC refractory to chemotherapy treated with anti-EGFR antibodies. This included 33 fresh-frozen (FF) and 35 formalin-fixed paraffin-embedded (FFPE) samples retrospectively collected and 19 prospectively collected FF samples. An independent validation cohort consisting of 19 FF and 26 FFPE prospectively collected samples from patients with mCRC treated with anti-EGFR antibodies was used to confirm our findings. After screening the expression of 1,145 miRNAs in FF samples from the training set, we identified that hsa-miR-31-3p expression level was significantly associated with progression-free survival (PFS). Statistical models based on miRNA expression discriminated between high and low risk of progression for both FF and FFPE samples. These models were confirmed in the validation cohort for both FF [HR, 4.1; 95% confidence interval (CI), 1.1-15.3; P < 0.04] and FFPE samples (HR, 2.44; 95% CI, 1.1-5.4; P = 0.028). The percentage of variation of RECIST criteria in the validation series was significantly associated with the expression level of hsa-miR-31-3p (r(2) = 0.49; P = 0.0035) and risk status determined by hsa-miR-31-3p expression level (P = 0.02, Kruskal-Wallis rank test). Nomograms were built and validated to predict PFS-depending on hsa-miR-31-3p expression level. Following in vitro studies, we identified 47 genes regulated by hsa-miR-31-3p. Hsa-miR-31-3p seems to be a new mCRC biomarker whose expression level allows for the identification of patients with wild-type KRAS mCRC who are more likely to respond to anti-EGFR therapy.

Phase 1 study of biweekly (Q2W) anti-EGFR monoclonal antibody (mAb) mixture Sym004 in patients (pts) with metastatic colorectal cancer (mCRC) resistant to previous anti-EGFR treatment.

3551 Background: Preclinical models suggest that WT KRAS mCRC may retain EGFR dependency despite resistance developed to anti-EGFR mAb treatment (eg, cetuximab or panitumumab). Sym004 is the first-...

EGFR gene copy number as a predictive biomarker for resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer treatment: a meta-analysis.

The epidermal growth factor receptor (EGFR) inhibitors monoclonal antibodies (MoAbs) have already shown the therapeutic effectiveness in patients with metastatic colorectal cancer (mCRC). But many patients resist to the treatment. The aim of this meta-analysis was to assess EGFR gene copy number (GCN) as a candidate predictive biomarker for resistance to anti-EGFR MoAbs in mCRC treatment. Systematic computerized searches of the PubMed, EMBase and Cochrane Library were performed. The primary endpoint was objective response rate (ORR). The second endpoints included progression-free survival (PFS), and overall survival (OS). The pooled odd ratio (OR) and pooled sensitivity, specificity, and summary receiver operator characteristic (SROC) for ORR were estimated. The pooled hazard ratios (HR) for PFS and OS were also calculated. Fourteen studies with 1,021 patients were included. Increased EGFR GCN was associated with increased ORR (OR=6.905; 95% CI: 4.489-10.620). It was also found in wild-type KRAS mCRC patients, with the pooled OR of 8.133 (95% CI: 4.316-15.326). GCN has medium value for predicting ORR, with the pooled sensitivity of 0.79 (95% CI: 0.73-0.84), the pooled specificity of 0.59 (95% CI: 0.55-0.62). In wild-type KRAS mCRC patients, the sensitivity and the specificity were 0.80 (95% CI: 0.70-0.87) and 0.60 (95% CI: 0.53-0.66), respectively. Increased EGFR GCN was associated with increased PFS (HR=0.557; 95% CI: 0.382-0.732) and OS (HR=0.579; 95% CI: 0.422-0.737). This meta-analysis suggests that EGFR GCN represents a predictive biomarker for tumor response in mCRC patients treated with MoAbs regardless of KRAS mutation. mCRC patients with increased EGFR GCN are more likely to have a better response, PFS, and OS when treated with cetuximab or panitumumab.

Moving Forward With Expanding to an “All-RASMutational Analysis” in Metastatic Colorectal Cancer: BeyondKRASMutations

The advent of biologic agents such as those that target the epidermal growth factor receptor (EGFR) has favorably impacted outcomes for patients with metastatic colorectal cancer (mCRC). An important downstream component of EGFR is the RAS signaling pathway. RAS proteins mainly include KRAS and NRAS. Activating KRAS mutations occur in 30% to 50% of colorectal tumors, most commonly in exon 2 as point mutations in codon 12 followed by mutations in codon 13. NRAS mutations occur in 3% to 5% of colorectal tumors. Since initial approval of the EGFR-directed monoclonal antibodies cetuximab (2004) and panitumumab (2006) for clinical use in mCRC, strategies to improve selection of the appropriate patients have constantly been refined. In 2005, the first confirmation that immunohistochemical analysis for EGFR expression has no predictive value in selecting or excluding patients allowed the use of these agents to be expanded to all eligible patients. In November 2008, the NCCN Colorectal Panel recommended routine KRAS (exon 2 codons 12/13) mutational testing based on consistent findings from multiple retrospective analyses of large clinical trials confirming that KRAS mutational status had predictive value for the use of antiEGFR monoclonal antibodies in mCRC. This move effectively restricted the use of these agents to approximately 60% of all patients with nonmutated KRAS mCRC, sparing the remainder of patients the risk of toxicities and the cost in the absence of a clear benefit. After this restriction, early reports suggested a possible clinical benefit for cetuximab in patients with mCRC with KRAS G13D mutations. However, another report from 3 randomized trials failed to suggest a similar benefit from panitumumab in the presence of a KRAS G13D mutation. These inconsistent results, the absence of a clear biology, and the overall poor outcome associated with the KRAS G13D mutation made this finding inconsequential to actual clinical practice pending further clinical validation. The NCCN Colorectal Cancer Panel continues to recommend against the use of anti-EGFR therapy in patients with codon 13 mutations. More recent data suggest that testing for additional RAS mutations (KRAS exons 3 or 4 and NRAS exon 1, 2, 3, or 4) present in 16% of tumors previously identified as KRAS (exon 2 codons 12/13) wild-type may allow for further refinement. A predefined retrospective analysis of the large prospective randomized trial PRIME (FOLFOX4 [leucovorin, 5-FU, and oxaliplatin] +/– panitumumab in first-line treatment of mCRC) suggests that the presence of these additional RAS mutations predict for lack of benefit. Data from the large phase II randomized study PEAK (FOLFOX plus panitumumab vs FOLFOX plus bevacizumab in first-line treatment of mCRC) confirmed the results from PRIME. This initiated a label change clarifying that panitumumab in combination with oxaliplatin-based chemotherapy is not indicated in the treatment of patients with RAS (KRAS or NRAS) mutation-positive mCRC. Despite these preliminary findings, there was very little uptake for incorporating an all-RAS mutational analysis before using EGFR inhibitors in mCRC. Why the initial reluctance? In addition to the lack of available standardized testing to include all RAS mutations, additional confirmatory data from studies, especially those incorporating cetuximab or irinotecan (which remains the preferred chemotherapeutic backbone Tanios Bekaii-Saab, MD

Analysis of KRAS/NRAS, PI3CA, and BRAF mutations in the phase II KSCC0901 study of cetuximab plus S-1 as third-line treatment for metastatic colorectal cancer in Japanese patients.

587 Background: Exploratory biomarker studies in the randomized phase III PRIME study suggested that patients with mCRC tumors harboring a mutation (MT) in KRAS or NRAS (beyond KRAS exon 2) do not respond to panitumumab-FOLFOX4 (2013 ASCO, JCO 31, #3511). We reported the efficacy and safety of S-1+. Cetuximab (Cmab) in wild-type (WT)-KRAS (exon 2) mCRC patients (pts) as third-line therapy (KSCC0901) (2012 ASCO, JCO 30, s3558). The full spectrum of characterized RAS (KRAS and NRAS), PI3CA, and BRAFMTs may affect efficacy in S-1+Cmab therapy in Japanese patients. Methods: An analysis was conducted to assess the treatment effect of S-1+Cmab, according to RAS (KRAS and NRAS), PI3CA, and BRAF MTs. The treatment protocol of KSCC0901 was as follows: weekly intravenous Cmab administration of 400 mg/m2 (day 1), 250 mg/m2/week (following day 1) and oral administration of 80 mg/m2/day S-1 on days 1–28 of each 42-day cycle. MTs in KRAS codons 12 and 13 (exon 2) were detected using direct sequencing according to the manufacturer’s instructions. MTs in KRAS codons 61 and 146, NRAS codons 12, 13 and 61, BRAF codon 600 and PIK3CA codons 542, 545, 546, and 1047 were detected using the multiplex PCR-Luminex method-based MEBGEN MT Kit (Medical and Biological Laboratories, Nagoya, Japan). Results: 35 pts were eligible for the analysis. Number of MT cases of KRAS, NRAS, BRAF, and PIK3CA were 4, 2, 2, and 5, respectively. One case had MTs of NRAS and PIK3CA. In 37 cases with WT KRASexon2 pts, median progression-free survival (mPFS) was 5.6 [95% CI: 4.4 – 5.7] months; median overall survival (mOS), 13.5 [8.5-16.5] months; and best overall response (ORR), 37.8%. In the all-WT subgroup 23 cases, mPFS was 5.6 [5.1-7.1] months; mOS, 13.5 [9.3-21.2] months; and best ORR, 47.8%. In 12 patients with any MT, mPFS was 4.0 [2.7-7.5] months; mOS, 5.5[2.9- ] months; and best ORR, 16.7%. Conclusions: These results suggest that also in Japanese patients receiving a Cmab containing regimen, RAS, BRAF and PIK3CA MT status beyond KRAS exon2 might predict non-responders to treatment. Clinical trial information: UMIN000002475.

Final results from a randomized phase 3 study of FOLFIRI ± panitumumab for second-line treatment of metastatic colorectal cancer

The study 20050181 demonstrated significant improvements in progression-free survival (PFS), objective response, and a nonsignificant trend toward increased overall survival (OS) with panitumumab-FOLFIRI versus FOLFIRI alone for second-line wild-type (WT) KRAS metastatic colorectal cancer (mCRC). Updated long-term data from a prespecified descriptive analysis are reported. Patients receiving one prior mCRC treatment were randomly assigned (1:1) to panitumumab (6.0 mg/kg)-FOLFIRI versus FOLFIRI every 2 weeks. Co-primary end points (PFS and OS) were prospectively analyzed by tumor KRAS status. One thousand one hundred and eighty-six patients were randomly assigned. In patients with WT KRAS tumors, panitumumab-FOLFIRI significantly improved PFS versus FOLFIRI [median 6.7 versus 4.9 months; hazard ratio (HR) 0.82 [95% confidence interval (CI) 0.69, 0.97]; P = 0.023]. A trend toward longer OS was observed (median 14.5 versus 12.5 months; HR 0.92 [95% CI 0.78, 1.10]; P = 0.37). Response rates improved from 10% to 36% (P < 0.0001). From post hoc analyses in patients receiving prior oxaliplatin-bevacizumab, panitumumab-FOLFIRI improved PFS (median 6.4 versus 3.7 months; HR 0.58 [95% CI 0.37, 0.90]; P = 0.014). PFS and OS appeared longer for worst-grade skin toxicity of 2-4, versus 0-1 or FOLFIRI. Safety results were as previously reported and consistent with the known toxicities with anti-epidermal growth factor receptor therapy. These data confirm the primary efficacy and safety findings of this trial and support panitumumab-FOLFIRI as a second-line treatment of WT KRAS mCRC.

Panitumumab Monotherapy as a Second-line Treatment in Metastasised Colorectal Cancer: A Single Centre Experience

AimsTo report our clinical experience of panitumumab monotherapy as a second-line treatment for patients with metastatic colorectal cancer (mCRC). Materials and methodsThis retrospective, descriptive study included a series of consecutive patients receiving panitumumab monotherapy (6 mg/kg 2 weekly) at a single centre in the Netherlands between June 2009 and November 2011. All patients had wild-type KRAS tumours, had progressed during first-line fluoropyrimidine-based therapy and were not candidates for, or refused, standard second-line therapy (usually irinotecan in the Netherlands). Prophylactic medication was given for epidermal growth factor receptor inhibitor-associated skin toxicities. ResultsThirty-one patients were treated during this period. The most commonly administered first-line mCRC regimen was capecitabine/oxaliplatin/bevacizumab (18/31 patients; 58.1%). Patients received a mean of 7.9 (range 1–18) panitumumab cycles. The median progression-free survival was 3.4 (95% confidence interval 2.4, 4.4) months. The median overall survival estimates were 11.4 (95% confidence interval 1.2, 21.6) months from the initiation of panitumumab monotherapy. Ten patients experienced partial responses according to Response Evaluation Criteria In Solid Tumors (RECIST; objective response rate: 32.3%); disease was controlled (objective response or stable disease) in 15 patients (48.4%). Carcinoembryonic antigen (CEA) responses (two consecutive ≥10% decreases from baseline) occurred in 11/29 patients (37.9%); all of whom had >50% decreases in CEA levels. All patients with an objective response at week 12 had CEA reductions at weeks 6 and 12. The only adverse events were grade 1/2 skin toxicities (61.3%) and gastrointestinal complaints (6.5%); three other patients (9.7%) experienced both skin and gastrointestinal complaints. ConclusionPanitumumab monotherapy seems to be a safe and active second-line treatment for patients with wild-type KRAS mCRC, with activity in line with that seen for irinotecan monotherapy, but with less toxicity. CEA may provide a useful early indicator of response to panitumumab.

A phase I/II study of decitabine in combination with panitumumab in patients with wild-type (wt) KRAS metastatic colorectal cancer

KRAS mutations are predictive of lack of response to monoclonal antibodies (mAb) against EGFR in metastatic colorectal cancer (mCRC). Most wild-type KRAS patients, however, are also resistant. Retrospective data suggest that EGFR silencing play a role in resistance to therapy. We conducted a study to evaluate the safety and efficacy of decitabine (a hypomethylating agent) in combination with panitumumab (mAb against EGFR) in mCRC patients. 20 patients with wild-type KRAS mCRC were included in this phase I/II study. Patients were treated with decitabine at 45 mg/m(2) IV over 2 h on day 1 and 15 and panitumumab 6 mg/kg IV over 1 h on day 8 and 22 every 28 days. Blood samples were collected at baseline, day 8, 15 and 22. Quantitative polymerase chain reaction was used to measure promoter-specific methylation in peripheral-blood cells (PBMCs). The most common adverse events were grade 1-2 (rash and hypomagnesemia); 3 (16 %) patients had grade III-IV neutropenia including one patient with neutropenic fever. Two of 20 patients (10 %) had a partial response. Both had previously received cetuximab. Ten patients had stable disease (3 of them longer than 16 weeks). Decreased methylation of the MAGE promoter was not evidenced in PBMCs. The combination of decitabine and panitumumab was well tolerated and showed activity in wild-type KRAS mCRC patients previously treated with cetuximab. Target modulation in surrogate tissues was not achieved and tumor biopsies were not available. Future studies evaluating hypomethylating agents in combination with EGFR mAb in patients with mCRC are warranted.

FOLFOXIRI in combination with panitumumab as first-line treatment in quadruple wild-type (KRAS, NRAS, HRAS, BRAF) metastatic colorectal cancer patients: a phase II trial by the Gruppo Oncologico Nord Ovest (GONO)

BackgroundThe FOLFOXIRI regimen developed by the Gruppo Oncologico Nord Ovest (GONO) demonstrated higher activity and efficacy compared with FOLFIRI in metastatic colorectal cancer (mCRC). Panitumumab is effective in some patients with KRAS codon 12–13 wild-type mCRC. KRAS codon 61, HRAS, NRAS, and BRAF V600E mutations might predict resistance to anti-epidermal growth factor receptor antibodies. Patients and methodsWe conducted a phase II study evaluating the combination of panitumumab (6 mg/kg on day 1) with a slightly modified GONO-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, and folinate 200 mg/m2 on day 1, followed by fluorouracil 3000 mg/m2 as a 48-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of wild-type KRAS, HRAS, NRAS (codon 12–13–61), and BRAF unresectable mCRC patients. Fluorouracil dose was reduced to 2400 mg/m2 after two of the first three patients reported grade 3–4 diarrhoea (in one case with febrile neutropenia). Induction treatment was scheduled for a maximum of 12 cycles, followed by panitumumab ± fluorouracil/folinate maintenance until progression. Primary end point was overall response rate (ORR). ResultsEighty-seven patients were screened and 37 were enrolled. Thirty-three patients achieved an objective response (ORR: 89%; 95% CI 75% to 96%). Sixteen patients (43%) underwent secondary surgery of metastases, and R0 resection was achieved in 13 cases (35%). At a median follow-up of 17.7 months, median progression-free survival was 11.3 months (95% CI 9.7–12.9 months). After amendment, most common grade 3–4 adverse events reported during induction treatment were neutropenia (48%; febrile neutropenia: 5%), diarrhoea (35%), asthenia (27%), stomatitis (14%), and skin toxic effect (14%). One treatment-related death was registered. ConclusionsAdding panitumumab to FOLFOXIRI is feasible decreasing the dose of fluorouracil and irinotecan to reduce the risk of diarrhoea. Activity and secondary resectability of metastases among Ras–BRAF wild-type patients are promising.

A randomized, placebo-controlled phase 2 study of ganitumab or conatumumab in combination with FOLFIRI for second-line treatment of mutant KRAS metastatic colorectal cancer

BackgroundTargeted agents presently available for mutant KRAS metastatic colorectal cancer (mCRC) are bevacizumab and aflibercept. We evaluated the efficacy and safety of conatumumab (an agonistic monoclonal antibody against human death receptor 5) and ganitumab (a monoclonal antibody against the type 1 insulin-like growth factor receptor) combined with standard FOLFIRI chemotherapy as a second-line treatment in patients with mutant KRAS mCRC. Patients and methodsPatients with mutant KRAS metastatic adenocarcinoma of the colon or rectum refractory to fluoropyrimidine- and oxaliplatin-based chemotherapy were randomized 1 : 1 : 1 to receive intravenous FOLFIRI plus conatumumab 10 mg/kg (Arm A), ganitumab 12 mg/kg (Arm B), or placebo (Arm C) Q2W. The primary end point was progression-free survival (PFS). ResultsIn total, 155 patients were randomized. Median PFS in Arms A, B, and C was 6.5 months (HR, 0.69; P = 0.147), 4.5 months (HR, 1.01; P = 0.998), and 4.6 months, respectively; median overall survival was 12.3 months (HR, 0.89; P = 0.650), 12.4 months (HR, 1.27; P = 0.357), and 12.0 months; and objective response rate was 14%, 8%, and 2%. The most common grade ≥3 adverse events in Arms A/B/C included neutropenia (30%/25%/18%) and diarrhea (18%/2%/10%). ConclusionsConatumumab, but not ganitumab, plus FOLFIRI was associated with a trend toward improved PFS. Both combinations had acceptable toxicity.

O-0012 - Updated Results of the Randomized Phase 2 Impact Trial: Maintenance with TLR-9 Agonist Mgn1703 Vs Placebo in Patients with Metastatic Colorectal Carcinoma (MCRC)

Background: The PRIME study reported significantly improved progression-free survival (PFS) and overall survival (OS) with panitumumab + FOLFOX vs FOLFOX in patients with WT RAS (exons 2, 3 and 4 of KRAS and NRAS) mCRC in a prospective-retrospective analysis (unpublished data). The PEAK study, presented here, was an estimation study of the treatment effect of FOLFOX6 + panitumumab or bevacizumab in 1st-line wild-type (WT) KRAS mCRC. Methods: This prospective-retrospective analysis was designed to assess the effect of FOLFOX6 + panitumumab or bevacizumab on PFS (primary endpoint) and OS in WT RAS (exons 2, 3 and 4 of KRAS and NRAS) mCRC in the PEAK study. WT KRAS exon 2 tumors were required for study entry. Transgenomic SURVEYOR/WAVE™ analysis and bidirectional Sanger sequencing were conducted independently in banked specimens to detect mutations in KRAS exon 3 (codons 59/61), exon 4 (codons 117/ 146); NRAS exon 2 (codons 12/13), exon 3 (codons 59/61), exon 4 (codons 117/146); BRAF exon 15 (codon 600). Results: Of the 285 WT KRAS (exon 2) mCRC patients randomized, 278 received treatment. The RAS ascertainment rate is currently 75%. For patients with WT RAS, treatment HRs (pmab:bev) were 0.63 (95% CI, 0.43-0.94; p = 0.02) for PFS and 0.55 (95% CI, 0.30-1.01; p = 0.06) for OS (Table). Worst grade 3-5 adverse event rates were consistent with the primary analysis. Conclusion: PFS and OS HRs favored panitumumab + FOLFOX6 relative to bevacizumab + FOLFOX6 in this 1st-line estimation study in WT RAS mCRC, suggesting that activating RAS mutations appear to be predictive for panitumumab treatment effect. Safety profiles for both arms were consistent with previously reported studies.

PD-0008 - Comprehensive Kras and Nras Mutation Analysis: Predictive Biomarkers in a Phase 3 Panitumumab Monotherapy Study of Metastatic Colorectal Cancer (Mcrc)

Background: In a hypothesis-generating biomarker analysis of the phase 3 randomized, monotherapy 20020408 study of panitumumab + best supportive care (BSC) vs BSC, the results suggested mutations in KRAS exon 3 and/or NRAS exons 2 and 3 were predictive of panitumumab treatment response (Peeters et al, 2013). In this retrospective, exploratory analysis, we evaluate if mutations in KRAS and/or NRAS exon 4 are predictive for panitumumab treatment and assess the treatment effect in patients with wild-type (WT) KRAS and NRAS mCRC tumors.

Analysis of KRAS/NRAS mutations in PEAK: A randomized phase II study of FOLFOX6 plus panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC).

3631 Background: PEAK estimated the tx effect of FOLFOX6 with pmab or bev in 1st-line WT KRAS mCRC. The PRIME study showed significantly improved progression free survival (PFS) and overall survival (OS) with pmab + FOLFOX vs FOLFOX in pts with WT RAS (KRAS/NRAS exons 2, 3, 4) mCRC in a prospective-retrospective analysis (unpublished data). Methods: This prospective-retrospective analysis of PEAK was designed to assess the effect of pmab + FOLFOX6 or bev + FOLFOX6 on PFS (primary endpoint) and OS in WT RAS (KRAS/NRAS exons 2, 3, 4) mCRC. Pts were required to have WT KRAS exon 2 tumors. Bidirectional Sanger sequencing and Transgenomic SURVEYOR/WAVE analysis were independently conducted to detect mutations in KRAS exon 3 (codons 59/61), exon 4 (codons 117/146); NRAS exon 2 (codons 12/13), exon 3 (codons 59/61), exon 4 (codons 117/146); BRAF exon 15 (codon 600) in banked specimens. Results: 285 WT KRAS (exon 2) mCRC patients (pts) were randomized, 278 received tx. The current RAS ascertainment rate is 75%. Tx HRs (pmab:bev) for pts with WT RAS were 0.63 (95% CI, 0.43-0.94; p = 0.02) for PFS and 0.55 (95% CI, 0.30-1.01; p = 0.06) for OS (Table). The incidence of worst grade 3-5 adverse events was consistent with the primary analysis. Updated OS and BRAF results will be presented. Conclusions: In this 1st-line estimation study in WT RAS mCRC, PFS and OS HR favored pmab + FOLFOX6 relative to bev + FOLFOX6, suggesting that activating RAS mutations appear to be predictive for pmab tx effect. The safety profile for both arms was consistent with previously reported studies. Clinical trial information: NCT00819780. [Table: see text]

Overall survival (OS) analysis from PRIME: Randomized phase III study of panitumumab (pmab) with FOLFOX4 for first-line metastatic colorectal cancer (mCRC).

3620 Background: The primary and final analyses of PRIME demonstrated that pmab + FOLFOX4 significantly improved progression-free survival (PFS) vs FOLFOX4 alone for first-line treatment of patients (pts) with wild-type (WT) KRAS exon 2 mCRC. Methods: Pts were randomized 1:1 to pmab 6.0 mg/kg every 2 weeks + FOLFOX4 or FOLFOX4 alone and had no prior chemotherapy for mCRC, ECOG performance status ≤ 2, and tumor tissue for biomarker testing. The primary endpoint was PFS by central assessment. Secondary endpoints included OS, objective response rate, and safety. KRAS exon 2 tumor status was determined by a blinded central lab prior to the primary analysis. This exploratory analysis of updated survival (&gt;80% OS events) estimated the treatment effect of pmab + FOLFOX4 compared with FOLFOX4 alone on OS by KRAS exon 2 status. Previous analyses in pts with WT KRAS exon 2 tumor status reported OS with an event rate of 54% of pts in the primary analysis and 68% of pts in the final analysis. Results: 1183 pts were randomized and received treatment: 593 pts in the pmab + FOLFOX4 arm and 590 pts in the FOLFOX4 alone arm. The KRAS exon 2 ascertainment rate was 93%, consistent with the primary analysis. 535/656 pts (82%) with WT KRAS exon 2 mCRC had an OS event at the time of this analysis. Results are shown (Table). Conclusions: In this updated analysis, an improvement in OS was observed in pts with WT KRAS exon 2 mCRC treated with pmab + FOLFOX4 vs FOLFOX4 alone (p = 0.03). Median OS was reduced in pts with mutant (MT) KRAS mCRC (p = 0.16) and is consistent with previous analyses. Updated efficacy and safety results will be presented. KRAS testing is critical to select appropriate pts with mCRC for treatment with pmab. Clinical trial information: NCT00364013. [Table: see text]

Prospective analysis of the early modulation of plasma amphiregulin (AR) during treatment with cetuximab and irinotecan in irinotecan-refractory metastatic colorectal cancer (mCRC) patients (pts).

3602 Background: The potential role of AR tissue levels in the prediction of benefit from anti-EGFRs in mCRC pts was suggested by retrospective series. Preclinical and preliminary clinical experiences showed a modulation of plasma EGFR ligands during the treatment with cetuximab. Previous data by our group evidenced that a significant increase of plasma AR occurred one hour after the administration of cetuximab and higher increases were associated with worse clinical outcome in KRAS and BRAFwt irinotecan-refractory mCRC pts receiving cetuximab and irinotecan. Methods: We designed a prospective confirmatory study in the same setting of mCRC pts. To detect a HR for PFS of 2.3 for pts with high AR levels one hour after the administration of cetuximab (1hr-AR) compared to those with low levels, with two-sided a=0.05 and b=0.2, 45 events were required. The median value was adopted as cut-off. Plasma AR levels were assessed by means of validated ELISA kits. Results: Forty-nine KRAS and BRAFwt pts were included. A significant early increase of AR levels was observed (median increase +24.7%; median levels of baseline AR and 1hr-AR: 18.06 and 24.06 pg/mL, respectively; Wilcoxon signed rank test, p&lt;0.0001). At a median follow-up of 20.4 mos, median PFS and OS were 4.6 and 12.1 mos, respectively. No differences in PFS or OS were observed according to 1hr-AR levels (median PFS 5.5 vs 4.6 mos, HR: 0.76 [95%CI:0.40-1.32], p=0.322; median OS: 15.6 vs 13.4 mos, HR:0.77 [95%CI:0.36-1.62], p=0.485). Conclusions: This prospective experience confirms that AR early increases one hour after the administration of cetuximab. Underlying biological mechanisms should be investigated. Nevertheless, this modulation of AR does not predict clinical outcome. Our work underlines the need to prospectively validate retrospective findings in independent series, to assess their reliability. Clinical trial information: 2008-003160-19.

Analysis of NRAS mutation as poor prognostic indicator and predictor of resistance to anti-EGFR monoclonal antibodies (anti-EGFRs) in metastatic colorectal cancer (mCRC) patients (pts).

3613 Background: NRAS belongs to RAS family. NRAS mutations are mutually exclusive with KRAS and BRAF mutations and contribute to the activation of Ras/Raf/MAPK pathway. Previous experiences evaluated the prognostic/predictive role of NRAS mutations suggesting a poorer prognosis and resistance to anti-EGFRs for NRASmutant (mut) mCRC pts. The aim of the present study was to confirm such preliminary findings in a large cohort of mCRC pts. Methods: Data on KRAS (codons 12, 13 and 61) and BRAF-V600E mutational status of mCRC pts referred to our pathology from '09 to '12 were collected. NRAS mutational status (codons 12, 13 and 61) was evaluated in KRAS and BRAF wt pts. OS was calculated from date of diagnosis of metastatic disease. Data on response and PFS according to RECIST were collected for NRASmut irinotecan-refractory pts treated with anti-EGFRs +/- irinotecan. Results: 774 mCRC pts were included. KRAS/BRAF mutations were found in 384 (50%)/69 (9%) cases. NRAS was mut in 47 (15%) out of 318 KRAS and BRAF wt pts. NRAS mut pts had significantly shorter OS in comparison to KRAS-BRAF-NRAS wt pts (HR=0.60 [0.29-0.99] p=0.045). BRAF mut pts had significantly worse OS in comparison to NRAS mut pts (HR=1.75 [1.073-2.87] p=0.03). No difference was observed between NRAS mut and KRAS mut pts (HR=0.86 [0.51-1.43] p=0.61). 18 pts out of 47 NRAS mut pts received anti-EGFRs in advanced lines. 8 pts (7 cetuximab-based, 1 panitumumab monotherapy) were evaluable according to RECIST criteria and therefore eligible for the present analysis. None of them responded and only 1 SD was observed. Pooling our results with available data on anti-EGFRs’ activity in NRASmut pts in advanced lines of treatment (De Roock, 2010; Peeters, 2013; Andrè, 2012), only 1 response is described out of 35 treated pts (2,9%). Conclusions: Our data demonstrate that NRAS mutations have a relevant incidence in KRAS and BRAF wt mCRC pts. Present results are consistent with previous experiences and confirm that NRAS mutations affect prognosis of mCRC patients and predict lack of response to anti-EGFRs. Further insights into NRAS mut mCRC biology and prospective validation are warranted.

Cost-effective analysis of the use of EGFR inhibitors (E) for wild-type (WT) KRAS unresectable metastatic colorectal cancer (mCRC).

6552 Background: Patients (pts) with unresectable WT KRAS mCRC benefit from fluoropyrimidines (FP), oxaliplatin (O), irinotecan (I), bevacizumab (Bev) and E. The most cost-effective strategy to combine them remains unclear. Methods: A Markov model was constructed for a hypothetical cohort of pts with mCRC to examine the costs and outcomes of 3 treatment strategies: (A): 1st line (1L) Bev+FP+O/I, 2nd line (2L) FP+I/O, 3rd line (3L) E, (B): 1L Bev+FP+O/I, 2L FP+I/O, 3L E+I, and (C): 1L E+FP+O/I, 2L Bev+FP+I/O, 3L best supportive care (BSC). Efficacy and probability data of the treatments were obtained from clinical trials identified through a systematic review of the literature. Resource utilization data were derived from a chart review of 65 consecutive pts treated at Odette Cancer Centre (OCC) since 2009 and from the literature. Utilities were obtained by surveying oncologists (n= 24) across Canada using EQ-5D. Costs were obtained from the Ontario Ministry of Health and Long/Term Care, Ontario Case Costing Initiative, OCC and the literature. The analysis was conducted from the Canadian public healthcare system perspective over a 5 year time horizon with a 5% discount in 2012 Canadian dollars (CAD$) for cost and outcome. Incremental cost-effectiveness analyses were conducted comparing costs and outcomes of the 3 strategies. One way and probabilistic sensitivity analyses (SA) were conducted (n=10,000). Results: All 3 strategies appeared to be of relatively similar efficacy clinically, but C is more expensive than A or B by &gt;45% (see Table). The model is primarily driven by the acquisition cost of drugs. B is most cost-effective when the willingness-to-pay (WTP) threshold &gt;$120,000/QALY. SA showed that C would be cost-effective only when the progression-free survival of E is better than Bev in 1L with hazard ratio &lt;0.24 at WTP of $150,000/QALY. Conclusions: 1L use of E followed by 2L Bev in mCRC is not cost-effective at the current pricing of E relative to Bev. [Table: see text]

Choice of sequential biologic therapies in metastatic colorectal cancer (mCRC): A cost comparison analysis for wild-type KRAS mCRC patient population in Brazil.

e14679 Background: Colorectal cancer is the third most common cancer and the second leading cause of cancer-related death in Brazil. Metastatic disease affects up to 50% of patients resulting in 5-year survival of less than 10%. Therefore, there is an increasing interest about the best treatment options, mainly regarding biologics and their sequencing across first line (1L) and second line (2L) treatment of mCRC. Modern series show that the probability of a patient receives 1L, 2L and a third line (3L) therapy is approximately 99%, 70% and 40%, respectively. In addition, in 2012, the ML 18147 study demonstrated the benefit of sequential use, 1L and 2L, of bevacizumab (bev) based combination in mCRC and considering this emerging data, it is important to understand the implications in terms of costs for the Brazilian private healthcare system. Methods: A costing tool was developed to compare the sequencing costs of 1L → 2L regimens used for treatment of wild-type KRAS mCRC patients. Dosing schedules were derived from labels, clinical trials and expert opinion. Analysis was performed from a private payer perspective and included drug-acquisition and administration costs only. Sequences in the ML18147 study (1L bev 5mg/kg+FOLFOX → 2L bev 5mg/kg+FOLFIRI and 1L bev 5mg/kg+FOLFIRI→2L bev 5mg/kg+FOLFOX) were compared to another frequently used sequence in Brazil where bev is replaced by cetuximab(cet) in 1L (1L cet 400-250mg/m2+ FOLFIRI → 2L bev 5 mg/Kg + FOLFOX). Results: Average costs per patient per month were Brz 21,285.50 for sequences with bev in 1L and 2L and Brz 24,191.68 when bev is replaced by cet in 1L. The average cost savings per patient for the entire treatment were Brz 28,767 (1L bev 5mg/kg + FOLFOX → 2L bev 5mg/kg + FOLFIRI vs 1L cet + FOLFIRI → 2L bev + FOLFOX) and Brz 29,938 (1L bev 5mg/kg + FOLFIRI → 2L bev 5mg/kg + FOLFOX vs1L cet + FOLFIRI → 2L bev + FOLFOX). Conclusions: Sequential use of bev in 1L and 2L mCRC according to the ML18147 study protocol is less costly compared to another sequence of biologics that starts with cet in 1L followed by bev in 2L. Resources savings with sequential bev have the potential to optimize 3L treatment strategy for wild-type kras mCRC patients in Brazil.

Hsa-miR-31-3p expression in FFPE tumor samples as a predictor of anti-EGFR response in patients with metastatic colorectal cancer.

3562 Background: In metastatic colorectal cancer (mCRC), KRAS mutations are associated with resistance to anti-EGFR antibodies. To identify, in wild-type KRAS mCRC patients, markers that predict response to anti-EGFR antibodies, we focused on miRNAs. Methods: Expression profile of 1145 miRNAs was done on 84 colorectal tumors and 5 normal colon mucosae. Correlations between miRNAs expression level and survival were based on frozen samples of a training set from a retrospective series of 33 patients treated by cetuximab and irinotecan and of two validation set from prospective collections of 38 patients treated by cetuximab or panitumumab based chemotherapy or by panitumumab and irinotecan as third-line, using an adjusted Cox proportional hazards model. Validation on FFPE samples was done on 39 patients treated with panitumumab and irinotecan as third-line. Results: A predictive signature of 11 miRNA linked to the PFS was identified (p&lt;0.01) but only one, hsa-miR-31-3p, exhibited significant different expression level between tumor from bad prognosis and good prognosis from the training set. We tested expression of this miRNA on the training set, and found a HR of 1.9 CI95% [1.1-2.9]. In validation set, the prognostic impact of hsa-miR-31-3p the HR was estimated to 1.9 CI95% [1.1-3.1]. Using multivariate model obtained from the training set to the two validation set, we predict the PFS of the patients (accuracy of prediction: AUC = 0.77). We classified the validation set according to a free PFS score (P=0.005) with a specificity of 62% CI95% [38%-82%] and a sensitivity of 82% CI95% [56%-96%] for the prediction model. A nomogram, established taking into account hsa-miR-31-3p expression level, predicted the progression risk (P&lt;0.0001). Confirmation of the predictive value of hsa-miR-31-3p expression on survival risk progression was done on FFPE sample (p=0.0006). Conclusions: This is the first tool to select individual patients with a wild-type KRAS tumor for anti-EGFR therapy from frozen or FFPE samples.