Biological Therapy in Colorectal Cancer in the Era of Sidedness

Field: Medicine (Health Sciences)

colorectal cancer: colorectal cancerThe addition of the EGFR inhibitors, cetuximab or panitumumab, to chemotherapy in patients with KRAS exon 2 wild-type resulted in improvements in overall survival (OS) in two large randomized phase III clinical trials (J Clin Oncol 2010;28(31):4697-4705, J Clin Oncol 2011;29(15):2011-2019). Subsequent analysis confirmed that patients with exon 3, 4 KRAS mutations and exons 2, 3, and 4 NRAS mutations also do not derive a benefit from anti-EGFR therapy (N Engl J Med 2013;369(11):1023-1034, J Clin Oncol 2015;33(7):692-700). By limiting anti-EGFR therapy to patients with extended RAS wild-type tumors, statistically significant improvements in OS of 22 and 31 percent were noted with the addition of panitumumab to FOLFOX and cetuximab to FOLFIRI, respectively (N Engl J Med 2013;369(11):1023-1034, J Clin Oncol 2015;33(7):692-700). Second-line clinical trials also have confirmed an advantage for anti-EGFR therapy in response rate (RR) and progression-free survival (PFS) that is limited to the extended RAS wild-type colorectal cancer population, but an OS advantage did not reach statistical significance (Clin Cancer Res 2015;21(24):5469-5479). Patients with BRAF mutation, a poor prognosis subgroup comprising a predominantly right colon population, are also associated with lack of clinical benefit from anti-EGFR therapy (J Gastrointest Oncol 2016;7(5):687-704). Vascular endothelial growth factor (VEGF) inhibition, on the other hand, has been associated with improvements in clinical outcome that are independent of RAS status (J Clin Oncol 2015;33(16):1809-1824). The benefits of bevacizumab in PFS and OS have been noted in first- and second-line settings (N Engl J Med 2004;350(23):2335-2342, Lancet Oncol 2013;14(1):29-37). While the benefits of the VEGFR-2 inhibitor, ramucirumab, and VEGF-trap ziv-aflibercept have only been confirmed in second-line phase III clinical trials (J Clin Oncol 2012;30(28):3499-3506, Lancet Oncol 2015;16(5):499-508). While anti-angiogenic therapy has been cemented in the first-line settings of RAS-mutant and arguably BRAF-mutant patients, considerable debate has continued regarding biological class selection in RAS/BRAF wild-type patients. In this review, we highlight pertinent literature on right and left colon cancer and its impact on biological therapy recommendations in patients with advanced colorectal cancer. Differences in Right & Left Colon The right and left colons originate for distinct embryological origins. The right colon is derived from the midgut and extends from the cecum to the distal 1/3 of the transverse colon. The left colon is derived from the hindgut and extends distally from the end of the transverse colon (Dig Dis 1997;15(4-5):302-11). Biological differences between right and left colon exist in normal colonic tissue as well as the tumor level (Cancer Epidemiol Biomarkers Prev 2003;12(8):755-762, Ann Oncol 2014;25(10):1995-2001. Right colonic tumors are more likely to harbor microsatellite instability (MSI), exhibit a hypermutated profile, be associated with a RAS or a BRAF signature, have a serrated pathway, and have a JAK-STAT gene signature (Ann Oncol 2014;25(10):1995-2001, Nature 2012;487(7407):330-337). Left colonic tumors have an activated WNT and MYC pathways activation, and are associated with EGFR and HER2 upregulation. A clear difference in prognosis, favoring left colon over right has been established, especially in the stage IV setting, highlighting biological differences between these two subgroups (Ann Surg Oncol 2008;15(9):2388-2394, J Clin Oncol 2011;29(33):4401-4409, Dis Colon Rectum 2010;53(1):57-64, BMC Cancer 2016;16:554, Int J Colorectal Dis 2015;30(9):1173-1183, Lancet Oncol 2016;17(11):1480-1482, Eur J Cancer 2017;70:87-98). The difference in EGFR expression and activation level between left and right colons may explain recent clinical data confirming a divergence in outcome with anti-EGFR therapy in RAS wild type left versus right colons. Biological Therapy & Sidedness in the Front-Line Treatment of Metastatic Colorectal Cancer Sidedness and outcome has been investigated in clinical trials evaluating chemotherapy +/- anti-EGFR and in clinical trials comparing chemotherapy + anti-EGFR versus chemotherapy + bevacizumab. The CRYSTAL and PRIME trials reported on the outcome of first-line chemotherapy with or without cetuximab and panitumumab, respectively. On the CRYSTAL trial, adding cetuximab to chemotherapy significantly improved RR, PFS, and OS only in patients with left colonic tumors (OS summary in Table 1) (JAMA Oncol 2016; doi: 10.1001/jamaoncol.2016.3797). Similarly, improvements in RR, PFS, and OS were only noted in left colonic tumors on the PRIME clinical trial (Table 2) (Annals of Oncology 2016;27(6):15-42). These clinically relevant improvements strongly support the incorporation of either cetuximab or panitumumab in the front-line treatment of RAS wild-type left colon with metastatic disease. Similar trends have been demonstrated in the second-line setting with FOLFIRI plus panitumumab versus FOLFIRI (Table 1) (Annals of Oncology 2016;27(6):15-42).Table 1Table 2.Sidedness plays an important role in the choice of biological therapy when comparing anti-EGFR treatment with bevacizumab in RAS wild-type patients. The FIRE-3 clinical trial randomized 592 patients with KRAS wild-type metastatic colorectal cancer to FOLFIRI plus bevacizumab versus FOLFIRI plus cetuximab (Lancet Oncol 2014;15(10):1065-1075). While this study failed its primary endpoint of investigator-evaluated RR, significant improvements in OS were noted in favor of cetuximab. In a post-hoc analysis, the cetuximab-treated arm had an improved OS over the bevacizumab-treated arm in the left colon population (38.3 vs. 28 months; HR=0.63, p=0.02), but opposite trends were noted in right colonic tumors (18.3 vs. 23 months; HR 1.44, p=0.28). CALGB 80405, a randomized clinical trial of chemotherapy (FOLFOX or FOLFIRI) with cetuximab versus bevacizumab in the first-line treatment of KRAS wild-type metastatic colorectal cancer, confirmed similar findings (J Clin Oncol 2014;32:abst LBA4). No difference in PFS or OS was noted between biological arms in the overall population (J Clin Oncol 2014;32:abst LBA4). However, a significant biological interaction was noted between sidedness and clinical outcome (J Clin Oncol 2016;34:(suppl;abstr 3504). Significant improvements in OS were noted in favor of cetuximab (39.3 vs. 32.7 months; HR=0.77, p=0.04) in the left colonic tumors while cetuximab was associated with an inferior PFS (7.5 vs. 10.2 months; HR = 1.64, p = 0.006) and OS (13.7 vs. 29.2 months; HR=1.36, p=0.10) in right colonic tumors (Table 1) (J Clin Oncol 2016;34:(suppl; abstr 3504). The CRYSTAL, PRIME, FIRE-3, and CALGB 80405 studies point to a new direction in the integration of biological therapy in the front-line treatment of RAS wild-type colorectal cancer (Figure 1). In left colonic tumors, anti-EGFR therapy may provide a superior outcome over bevacizumab when combined with doublet chemotherapy. Right-sided tumors are not likely to derive any benefit from anti-EGFR therapy and post a trend to an inferior outcome when compared to bevacizumab. Similar trends have been described in second-line treatment of colorectal cancer based on the limited analysis reported from the 181 clinical trial (Annals of Oncology 2016;27(6):15-42). Biological Therapy & Sidedness in the Treatment of Refractory Metastatic Colorectal Cancer In an updated analysis, CO.17, a phase III study of cetuximab versus best supportive care in chemotherapy-resistant metastatic colon cancer reported on patient outcome by tumor location in the KRAS wild-type patient population (Table 2) (Eur J Cancer 2015;51(11):1405-1414). Cetuximab significantly improved PFS and OS only in patients with left-sided tumors. Only 56 patients with right colon cancer were subject to analysis in this study and, despite a lack of a PFS in this cohort, a non-significant trend of benefit in OS favored the cetuximab arm (Eur J Cancer 2015;51(11):1405-1414). Additional series of retrospective cases have also reported on lack of response in RAS wild-type right colonic cancers to anti-EGFR therapy (Oncologist 2016;21(8):988-994). In addition, prior studies also reported limited benefits in RAS and BRAF wild-type irinotecan-refractory metastatic colorectal cancer patients who were treated with cetuximab plus irinotecan (Lancet Oncol 2010;11(8):753-762). One can, therefore, conclude that the clinical benefits of anti-EGFR therapy are limited, if at all existent, in right colon cancer—irrespective of line of therapy. Nevertheless, one cannot exclude definitively the presence of a small subgroup or right colon cancer patients with potential benefit from anti-EGFR therapy. If this group exists, it is still to be defined. HER-2 Amplifications & Biological Therapy While left colonic RAS/BRAF wild-type tumors appear to derive significant benefit from anti-EGFR therapy, this by no means indicates that all patients with such a profile will benefit substantially from this strategy. Indeed, up to 6 percent of patients with RAS/BRAF wild-type tumors exhibit HER-2 amplifications, approximately >80 percent of which may occur in the left colon/rectum (J Pathol 2016;238(4):562-570, Oncotarget 2017; doi:10.18632/oncotarget.15030, PLoS One 2014;9(5):e98528). HER-2 amplified RAS/BRAF wild-type colorectal tumors have been associated with preclinical and clinical resistance to anti-EGFR therapy (Cancer Discov 2011;1(6):508-253, Lancet Oncol 2016;17(6):738-746). Indeed, none of the HER-2 amplified patients who participated on the HERACLES trial had a response on prior anti-EGFR therapy (Lancet Oncol 2016;17(6):738-746). In addition, a retrospective analysis of RAS/BRAF HER-2 amplified colorectal tumors treated with anti-EGFR therapy noted a significantly shorter time to progression in comparison to non-HER-2 amplified RAS/BRAF wild-type patients (J Clin Oncol 2016;34:(suppl; abstr 3517)). In contrast, dual HER-2 targeting with trastuzumab plus lapatinib or trastuzumab plus pertuzumab has been associated with promising clinical activity in this population based on two prospectively conducted trials (Lancet Oncol 2016;17(6):738-746, J Clin Oncol 2017;35:(suppl 4S; abstract 676)). The upcoming SWOG S1613 trial will randomize patients with RAS/BRAF wild-type and HER-2 amplified colorectal cancer patients to a combination of cetuximab plus irinotecan versus trastuzumab plus pertuzumab. This study will shed additional light on the role of anti-EGFR therapy and HER-2 targeting therapy in this unique subgroup of patients. Study Summaries The OS benefits noted with anti-EGFR therapy over bevacizumab in left-sided RAS/BRAF wild-type tumors on the FIRE-3 and CALGB 80405 studies in the first-line setting support the early integration of cetuximab or panitumumab in the first-line treatment in this subgroup of patients (Figure 1). While these studies have compared cetuximab to bevacizumab in the setting of FOLFOX or FOLFIRI backbones, we have no head-to-head studies for these biologicals in the setting of FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, irinotecan). Given the superiority of FOLFOXIRI-BV over FOLFIRI-BV across different molecular subgroups of metastatic colorectal cancer, FOLFOXIRI-BV remains an appropriate first-line regimen in good performance, younger patients, irrespective of RAS or BRAF status (Lancet Oncol 2015;16(13):1306-1315). BRAF-mutated colon cancers, while representing a very small portion of left colon cancers, are not known to benefit from anti-EGFR therapies and can be considered for FOLFOXIRI-BV based on subgroup analysis of the TRIBE trial (Lancet Oncol 2015;16(13):1306-1315). BRAF-mutated tumors appear also to benefit from combinations of BRAF inhibitors and anti-EGFR therapy, with or without chemotherapy (J Gastrointest Oncol 2016;7(5):687-704). Given the poor prognosis of patients with BRAF mutations, they should be considered early on for appropriate clinical trials.Figure 1:: First-Line Treatment Algorithm and Pertinent Molecular SubtypesIn view of the limited (or lack of) activity of anti-EGFR therapy in RAS wild-type right colonic tumors (irrespective of BRAF status), these patients should not receive anti-EGFR therapy in the first- and second-line settings, especially given the proven benefits from bevacizumab in first- and second-line settings (Figure 1) (JAMA Oncol 2016; doi: 10.1001/jamaoncol.2016.3797). In addition, chemotherapy-refractory RAS wild-type right colon cancers do not appear to benefit significantly from salvage anti-EGFR therapy based on recent data from CO.17 and other retrospective series. However, one must acknowledge the limitations of the above analysis due to a small number of or right colonic cancers analyzed and possible imbalance in patients' characteristic on post-hoc analysis. Therefore, there is a possible small benefit from anti-EGFR therapy in a yet to be defined molecularly-distinct right colonic RAS/BRAF wild-type colorectal cancer population. Indeed, a trend towards improvement in OS with cetuximab monotherapy in KRAS wild-type right colonic tumors as well as trends in improved response rate on the CRYSTAL and PRIME in right colonic tumors support such a possibility. Given the lack of viable options upon progression on cytotoxic chemotherapy in RAS/BRAF wild-type right colonic cancers, physicians should weigh the risks and financial toxicity versus the small potential benefits of anti-EGFR in such settings. Finally, we must acknowledge the complexity of colorectal cancer beyond sidedness, RAS, and BRAF. HER-2 amplified colorectal cancers appear to be a select group of patients with increased resistance to anti-EGFR therapy and with sensitivity to HER-2 dual targeting. The early identification of these patients may be beneficial in helping physicians determine optimal biological therapy sequencing and consider appropriate clinical trials. In addition, 4 percent of metastatic colorectal cancers harbor microsatellite instability (MSI-H) leading to a hypermutated profile and sensitization to immunotherapy, particularly with PD-1 targeting. Nivolumab has been associated with a response rate of 31 percent, a disease control rate of 69 percent, and a 12-month PFS rate of 48 percent in MSI-H colorectal cancer (J Clin Oncol 2017;35:(suppl 4S; abstract 519)). In addition, in an updated analysis of their single center experience, Le and colleagues reported on 28 patients with MSI-H colon cancer treated with pembrolizumab (J Clin Oncol 2016;34:(suppl; abstr 103)). The response rate in this cohort was 50 percent and the 2-year PFS was 61 percent. These preliminary data confirm the utility of PD-1 targeting in MSI-H patients and support the rationale for the NCCN recommendation to integrate pembrolizumab or nivolumab in MSI-H metastatic colorectal cancer. Given the limited available data on the biological activity of anti-EGFR therapy (RAS/BRAF wild-type) in MSI-H patients, specific treatment sequencing recommendations in this subgroup of patients are not well-defined. MARWAN FAKIH, MD, is Professor of Medical Oncology and Section Chief, Gastrointestinal Oncology, City of Hope Comprehensive Cancer Center, Duarte, Calif.Marwan Fakih, MD: Marwan Fakih, MD