METASTATIC COLORECTAL CANCER: TUMOR MUTATIONAL ANALYSIS AND ITS IMPACT ON CHEMOTHERAPY SUMA SATTI, MD INTRODUCTION Second leading cause of cancer related death in the United States. 136,830 cases in 2014 50,310 will die of the disease. 1
CURRENT APPROACHES IN TREATMENT Combination cytotoxic chemo is the backbone. First line: doublet cytotoxic combinations of FOLFOX, FOLFIRI, XELOX, FOLFOXIRI Angiogenesis and EGFR targeting agents have improved clinical outcomes and also added further complexity to treatment decisions. TARGETING ANGIOGENESIS IN MCRC 2
TARGETING ANGIOGENESIS IN MCRC CONCLUSION FOR ANGIOGENESIS IN FIRST LINE AVF 2107 (phase III, IFL plus Avastin): Superior RR, PFS and OS The remaining trials revealed Superior PFS and not OS. Discrepancy in OS may be partly attributed to continuation of Avastin after first progression in the experimental arm of AVF2107. 3
CONCLUSION FOR ANGIOGENESIS IN FIRST LINE Avastin has become an acceptable standard across all firstline 5FU based treatments. Maintenance chemo (after Induction chemo) is recommended with 5FU and Avastin. Scheduled treatment breaks after first line combination therapy are associated with a shorter progression free survival. TARGETING ANGIOGENESIS IN SECOND-LINE AND SUBSEQUENT LINE SETTINGS 4
CONCLUSIONS FOR ANGIOGENESIS IN SECOND AND SUBSEQUENT LINE SETTINGS ECOG 3200: FOLFOX +Bev vs FOLFOX with increased RR, PFS and OS with addition of Bev. ML18147: evaluated utility of Bev beyond progression with improved PFS and OS. VELOUR (Aflibercept vs Placebo in Combination with FOLFIRI after progression on FOLFOX): Modest improvement in PFS and OS with significant toxicity limits use. 5
CONCLUSIONS FOR ANGIOGENESIS IN SECOND AND SUBSEQUENT LINE SETTINGS Regorafenib in chemo refractory settings: reduced progression with modest improvement in OS. Real but modest value for continuation of angiogenesis inhibition Bev in first and second line Ziv-Aflibercept in second line with FOLFIRI Regorafenib in chemo refractory TARGETING EGFR IN FIRST-LINE SETTINGS 6
TARGETING EGFR IN FIRST-LINE SETTINGS TARGETING EGFR IN FIRST-LINE SETTINGS COIN (continuous versus intermittent chemo FOLFOX or XELOX with excessive toxicity negated any benefit) and Nordic (unconventional 5FU dosing): Negative trials PRIME (FOLFIRI and panitumumab): improved PFS and OS (The PFS benefits in PRIME were in line with FOLFOX on Coin and do not suggest a differential impact of Panitumumab over Cetuximab in a FOLFOX setting) CRYSTAL (FOLFIRI and Cetuximab): improved RR, PS and OS in all groups (KRAS wt, RAS wt, BRAF mutants). 7
TARGETING EGFR IN SECOND LINE SETTINGS Three randomized phase III clinical trials: all demonstrated improved RR and PFS, but no OS advantage. Reasons? EPIC was conducted before KRAS was a predictive marker and was thus underpowered to test an OS end point in KRAS wt PICCOLO and 20050181 were powered to address PFS in a KRASwt. Lack of OS may be due to salvage EGFR regimens 8
TARGETING EGFR IN CHEMOTHERAPY REFRACTORY SETTINGS ASCO UPDATE 2015 RAS mutational testing of colorectal carcinoma tissue should be performed in a CLIA-certified laboratory for all patients who are being considered for anti-egfr monoclonal antibody therapy. Mutational analysis should include KRAS and NRAS codons 12, 13 of exon 2; 59, 61 of exon 3; and 117 and 146 of exon 4. The weight of current evidence indicates that anti-egfr monoclonal antibody therapy (currently cetuximaband panitumumab) should only be considered for treatment of people with mcrc who are identified as having tumors with no mutations detected after such extended RAS mutation analysis. 9
BRAF (V600E) MUTATIONS ~5% of mcrc. More aggressive phenotype, Chemotherapy resistance Inferior OS No improvement in OS when anti EGFR therapy is used whether as monotherapy or in combination with chemo FOLFOXIRI and Bev (Phase II) : RR 73%, PFS 9.2mo, OS 24.1 mo TRIBE (FOLFOXIRI and Bev, Phase III) improved PFS and OS ANTI EGFR THERAPY VERSUS BEV IN RAS-WT MCRC: FIRST-LINE FIRE 3: FOLFIRI +Cetuximabvs FOLFIRI + Bev: No improvement in RR and PFS but improved OS in favor of FOLFIRI +Cetuximab PEAK: FOLFOX + Panintumamabvs FOLFOX+ Bev: Improved PFS and OS CALGB 80405: FOLFOX or FOLFIRI with Cetuximabor Bev: No difference in PFS or OS. Recent Update on CALGB: Increased RR in RAS-wt and KRAS-wt Also increased resectability with Cetuximab 10
ANTI EGFR THERAPY VERSUS BEV IN RAS-WT MCRC: FIRST-LINE Why the difference between FIRE-3, PEAK and CALGB: Unclear Hypothesis: Lifetime exposure to anti-egfr therapy is superior to Bev Robust improvement in OS when anti EGFR agents are added to modern combination chemo vs modest impact with Bev The sequence of anti-egfr therapy vs Bev may have little relevance as long as patients are exposed to anti-egfr therapy in their treatment lifetime FUTURE DIRECTIONS IN CRC 11
IMPROVING PATIENT SELECTION Identify suitable candidates for anti EGFR therapy by excluding RAS-mut and BRAF-mut Sanger sequencing: poor sensitivity and requires 20% mutant RAS to confirm presence of mutation PCR can detect lower frequency RAS mutations (1-10%) Digital PCR: more sensitive, can detect RAS and BRAF mutations at mut:wt RAS DNA ratio of 0.01% Tumors with mut:wt RAS DNA ratio less than 1% had RRs to anti EGFR similar to those of RAS-wt tumors. Ratios above 10% had no response to anti EGFR therapies. Right sided colon tumor: have higher rate of BRAF, more MSI high, display CpG island methylator phenotype Retrospective analysis: Shortened PFS with CpG island methylator phenotype-high, RAS-wt/BRAF-wt tumors treated with anti EGFR therapy 12
Increased expression of epiregulin (EREG) is associated with RAS-wt tumor and better prognosis MicroRNA tumor profiling with increased mir-31 expression as a marker of resistance to Cetuximab and poor outcome in RAS-wt tumors Other potential predictive markers of EGFR resistance: PIK3CA mutations, HER2 amplification, HER3 overexpression and MET amplification TARGETING MECHANISMS OF RESISTANCE BRAF inhibitor in BRAF mutant mcrc with only 5% RR and median time to progression of less than 4 months Resistance to BRAF inhibitors could be due to EGFR phosphorylation, KRAS activation and downstream CRAF an ERK activation Ongoing trials are evaluating EGFR, BRAF and MEK inhibitors with or without Irinotecan 13
HOW ABOUT ANTI-EGFR RESISTANCE IN RAS AND BRAF-MUTANT TUMORS? Resistance to anti-egfr therapy is due to emergence of RAS and BRAF mutations while on Cetuximab and Panintumamab Majority of patients with RAS and RAF-wt tumors will test positive for one or more KRAS, NRAS or BRAF mutations in their cdna on repeat tumor biopsy at the time of EGFR resistance RAS mutations were present before anti-egfr treatment and their emergence is a result of clonal selection induced by anti EGFR therapy MOLECULAR HETEROGENEITY IN CRCAND THE FUTURE OF DRUG DEVELOPMENT 16% have WNT pathway alterations 19%: ERBB family gene amplification or mutation MSI-H tumors are hypermutated and are associated with lymphocyte infiltration and PD-1 and PDL-1 overexpression 3% have HER2 amplification (also KRAS wild type and anti- EGFR resistance) 2% c-met amplification 1% ALK/ROS fusion rearrangements 14
CONCLUSION All patients with mcrc should be tested for RAS (KRAS and NRAS) and BRAF at diagnosis Treatment should be based on molecular phenotype, performance stats, age and goals of treatment Future new therapeutics for RAS-mut, BRAF, PIK3CA mutations, HER2 amplification and MSI Modes of resistance to anti-egfr therapy in patients with RAS-wt and BRAF-wt population Identify subgroups who benefit from aggressive surgical intervention RAS WT and BRAF WT Excellent performance status RAS WT and BRAF WT Limited performance status or elderly CONCLUSION FOLFOX or XELOX or FOLFIRI +/- Bev FOLFOX or FOLFIRI +/- EGFR therapy FOLFOXIRI +/-Bev Xeloda or 5Fu/Lv +/- Bev FOLFOX or FOLFIRI +/- anti EGFR therapy FOLFOX or FOLFIRI +/- Bev Consider dose mod: eliminate 5FU bolus RAS MT Excellent performance status RAS MT Limited performance status or elderly FOLFOXIRI +/- Bev FOLFOX or FOLFIRI +/- Bev FOLFOX or FOLFIRI or XEX +/- Bev Xeloda or 5Fu/Lv +/- Bev BRAF MT Excellent performance status BRAF MT Limited performance status or elderly Favor FOLFOXIRI +/- Bev FOLFOX or FOLFIRI or XELOX +/- Bev Clinical trials Xeloda or 5Fu/Lv +/- Bev FOLFOX or FOLFIRI or XELOX +/- Bev Clinical trials, dose mod 15
QUESTIONS? 16