Precision Medicine in Metastatic Colorectal Cancer: Relevant Carcinogenic Pathways and Targets-PART 1: Biologic Therapies Targeting the Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor

The survival of patients with metastatic colorectal cancer has improved dramatically in recent years, with overall survival exceeding 3 years in large randomized clinical trials. There are now several treatment options for patients with metastatic colorectal cancer. In addition to chemotherapy backbones utilizing fluoropyrimidine, oxaliplatin, and irinotecan combinations, biologic agents that target specific oncogenic pathways have contributed to the improved survival observed in this patient population. This class of medications includes epidermal growth factor receptor (EGFR)-targeted drugs (cetuximab and panitumumab) and vascular endothelial growth factor (VEGF)-targeted therapies (bevacizumab, ramucirumab, ziv-aflibercept, and regorafenib). Bevacizumab remains the only VEGF-targeted agent approved by the US Food and Drug Administration in the first-line metastatic setting. EGFR-directed treatment should be restricted to patients with extended RAS and BRAF wild-type tumors. Tumor sidedness may be a more powerful prognostic and predictive biomarker than tumor mutational profile. Patients with left-sided primary tumors derive greater benefit from EGFR-targeted therapies whereas patients with right-sided primary tumors benefit more from bevacizumab. Herein we review drugs that target the EGFR and VEGF pathways, focusing on patient selection, drug toxicities, and how to choose agents for first-line therapy.

Introduction

Colorectal cancer is a common malignancy and the second leading cause of cancer-related death in the United States.[1] Around one-fifth of patients have metastatic disease at the time of diagnosis, and their overall survival (OS) rate is only 13.5% at 5 years.[2] Nevertheless, the median OS of patients with metastatic colorectal cancer is currently 3 years, with results from large prospective clinical trials showing a continuing increase in survival rates.[3,4] Oncologists have an array of choices to consider in terms of possible combinations of cytotoxic and biologic drugs for patients with metastatic colorectal cancer.

For the purpose of this review, we define biologic therapies as pharmaceuticals that target specific carcinogenic pathways. Approved therapies include agents targeting the epidermal growth factor receptor (EGFR) and those targeting proteins essential to angiogenesis, including the vascular endothelial growth factor (VEGF) (Figure). Given the abundance of current therapeutic options for the treatment of colorectal cancer, there is often no single correct answer to the question of which therapies to select and how to sequence them. In this article, we will highlight the mechanisms of action of selected classes of biologic therapies, identify predictive biomarkers, and address how best to combine biologic agents with conventional cytotoxic chemotherapy.

The EGFR Pathway and Anti-EGFR Therapy

The ErbB family of receptor tyrosine kinases consists of the EGFR transmembrane glycoproteins Erbb1 (human epidermal growth factor receptor 1 [HER1]), HER2/neu (Erbb2), HER3 (Erbb3), and HER4 (Erbb4). EGFR is expressed in normal epithelial tissues and in several types of human cancers. Binding of EGF or other growth ligands to EGFR activates multiple downstream signal transduction pathways that promote cellular proliferation, including the RAS/RAF/MAPK/PI3K/AKT/mTOR pathways.[5] The anti-EGFR monoclonal antibodies cetuximab and panitumumab are approved by the US Food and Drug Administration (FDA) for use in patients with metastatic colorectal cancer who have KRAS wild-type tumors.[6,7]

Initially, EGFR expression was thought to be a positive predictive biomarker for response to anti- EGFR monoclonal antibodies, but work by Chung and colleagues published in 2005 demonstrated that EGFR-negative patients also have the potential to respond to cetuximab.[8] In subsequent studies by other investigators, published in 2008, KRAS mutations in exon 2 (codons 12 and 13), which are present in approximately 40% of patients with metastatic colorectal cancer, were found to confer de novo resistance to EGFR-directed therapies; this resistance is due to constitutive activation of the KRAS GTPase, which binds to and hydrolyzes guanosine triphosphate, bypassing the anti-EGFR effect on downstream signaling pathways.[9,10] Mutations in KRAS exons 3 and 4 and NRAS exons 2, 3, and 4 are also implicated in acquired resistance in patients treated with anti-EGFR monoclonal antibodies.[11,12] However, as far as predicting response to anti-EGFR therapy is concerned, extended RAS testing alone may not be sufficient to inform treatment decision making because mutations in PIK3CA (exon 20) and BRAF V600E have also been associated with low rates of response to anti-EGFR agents.[13] Therefore, the National Comprehensive Cancer Network (NCCN) recommends that all patients with metastatic colorectal cancer undergo tumor genotyping for KRAS, NRAS, and BRAF because anti-EGFR monoclonal antibodies should be administered only to patients with wild-type expression of these genes.[14]

Cetuximab

Cetuximab is a chimeric mouse/human immunoglobulin (Ig)G1 monoclonal antibody against EGFR. In the phase III CRYSTAL trial, the addition of cetuximab to FOLFIRI (leucovorin, fluorouracil [5-FU], and irinotecan) improved progression-free survival (PFS) compared with FOLFIRI alone.[15] Patients (N = 1,198) with previously untreated metastatic colorectal cancer that expressed EGFR by immunohistochemistry were randomized 1:1 to treatment with FOLFIRI plus cetuximab (at 400 mg/m² IV over 120 minutes on day 1, then 250 mg/m² weekly) or FOLFIRI alone. The primary endpoint of the study was median progression-free survival (PFS), which was shown to be longer with cetuximab (8.9 months vs 8.0 months; P = .048; Table), as was the objective response rate ORR (46.9% vs 38.7%; P = .004); however, median overall survival (OS) was not significantly different (19.9 months vs 18.6 months; P = .31). In a subsequent expanded analysis of 430 patients with tumors evaluable for extended RAS testing, adding cetuximab to the chemotherapy regimens of patients with RAS wild-type tumors led to significant improvements in median OS (28.4 months vs 20.2 months; P = .0024), as well as median PFS (11.4 vs 8.4 months; P < .001) and ORR (66.3% vs 38.6%; odds [OR], 3.11; 95% CI, 2.03–4.78; P < .001).[12] There was no corresponding improvement for patients with any RAS mutation. Cetuximab did cause more grade 3/4 adverse events, notably skin reactions (19.7% vs 0.2%), diarrhea (15.7% vs 10.5%), rash (8.2% vs 0%), and infusion reactions (2.5% vs 0%).[15]

In the phase II OPUS trial, 344 patients with previously untreated EGFR-positive metastatic colorectal cancer were randomized 1:1 to receive FOLFOX4 (oxaliplatin, leucovorin, and 5-FU) plus cetuximab (administered at the same dosing used in the previously described CRYSTAL trial) or FOLFOX4 alone.[16] The primary endpoint of the study was ORR, which was similar between treatment groups (46% [FOLFOX4 plus cetuximab] vs 36% [FOLFOX4 alone]; P = .064), but was significantly improved following FOLFOX4 plus cetuximab when patients with KRAS wild-type tumors only were singled out (61% with the combination vs 37% with FOLFOX4 alone; P = .011). The same pattern was seen for median PFS in patients with KRAS wild-type tumors only (7.7 months vs 7.2 months, respectively; P = .0163). However, in the KRAS-mutated population, median PFS was actually worse when cetuximab was incorporated into a FOLFOX4 regimen (5.5 months vs 8.6 months; P = .0192), indicating that RAS testing prior to treatment with an EGFR inhibitor is of the utmost importance. Among the most common grade 3/4 adverse events, rash was more common with cetuximab (11% with FOLFOX4 plus cetuximab vs 0.6% with FOLFOX4 alone), but rates of neutropenia (30% vs 34%) and diarrhea (8% vs 7%) were similar between the treatment groups.[16]

The phase III COIN trial again compared combination chemotherapy with a fluoropyrimidine and oxaliplatin, with or without cetuximab. In total, 1,630 patients with previously untreated metastatic colorectal cancer were randomized to receive chemotherapy (physician’s choice of capecitabine and oxaliplatin or FOLFOX4) plus cetuximab (at the standard approved dosing described previously) or chemotherapy alone.[17] Given the growing evidence that EGFR expression was not an effective biomarker for response to cetuximab, the revised primary endpoint was median OS in patients with KRAS wild-type tumors (729 patients). In this group, median OS was similar between treatment arms (17.0 months with chemotherapy plus cetuximab vs 17.9 months with chemotherapy alone; P = .67). In a subgroup of patients with tumors that expressed wild-type KRAS, as well as wild-type NRAS and BRAF, there was also no significant difference in median OS (19.9 months with chemotherapy plus cetuximab vs 20.1 months with chemotherapy alone; P = .86). Treatment that included cetuximab was associated with increased incidences of rash, nail changes, hand-foot syndrome, diarrhea, stomatitis, lethargy, anemia, and hypomagnesemia.

Similarly, the phase III NORDIC-VII trial randomized 571 patients with previously untreated metastatic colorectal cancer in a 1:1 ratio to receive the FLOX regimen (bolus 5-FU, leucovorin, and oxaliplatin) alone or with cetuximab.[18] There was no significant survival advantage following the addition of cetuximab to FLOX: median PFS (the primary endpoint) was 8.3 months in patients treated with FLOX and cetuximab vs 7.9 months in patients treated only with FLOX (P = .31), and median OS was 20.4 months vs 19.7 months, respectively (P = .67). ORR also remained essentially unchanged (49% vs 41%, respectively; P = .15). In the KRAS wild-type population, there was still no median OS benefit from the addition of cetuximab (22.0 months with FLOX and cetuximab vs 20.1 months with FLOX alone; P = .48). Therefore, cetuximab did not provide a survival benefit when added to the FLOX regimen.

Given the discordant findings between the CRYSTAL trial (which demonstrated improved median OS with the addition of cetuximab to FOLFIRI in RAS wild-type patients) and the COIN, OPUS, and NORDIC-VII trials (which did not demonstrate a survival benefit in this setting), it was concluded that cetuximab has the greatest efficacy in RAS wild-type patients when combined with irinotecan-based rather than oxaliplatin-based chemotherapy.[19] Confirmation of this theory requires further study of cetuximab administered together with irinotecan-based regimens as first-line treatment of patients with RAS wild-type metastatic colorectal cancer.

Panitumumab

The other FDA-approved anti-EGFR agent in metastatic colorectal cancer is panitumumab, a fully humanized IgG2 monoclonal antibody. The landmark phase III PRIME study randomized 1,183 patients with untreated metastatic colorectal cancer to receive FOLFOX4 plus panitumumab (with the latter administered at a dosage of 6 mg/kg IV over 1 hour, then 6 mg/kg over a 30-minute period every 2 weeks thereafter) or FOLFOX4 alone.[20] The primary endpoint was PFS, and patients were analyzed according to KRAS mutational status in a prospective manner. In the KRAS wild-type population, median PFS was significantly longer in patients treated with the panitumumab/chemotherapy combination (9.6 months vs 8.0 months with FOLFOX4 alone; P = .02). Although there was a trend toward increased median OS following chemotherapy plus panitumumab, this did not reach statistical significance (23.9 months vs 19.7 months with chemotherapy alone; P = .072). Conversely, median PFS was significantly shorter following administration of panitumumab to patients with KRAS-mutated tumors (7.3 months vs 8.8 months; P = .02) and, although median OS followed a trend similar to that of median PFS, there was no significant difference between treatment groups (median OS, 15.5 months with chemotherapy plus panitumumab vs 19.3 months with chemotherapy alone; P = .068).[20] Skin toxicity was common, affecting 96% of patients who received panitumumab, and 34% of patients had grade 3/4 skin toxicity. Only 2 patients (0.3%) had grade 3 infusion reactions; both subsequently received premedication therapy, enabling them to complete additional cycles of treatment with panitumumab.

In an updated analysis of the PRIME study, evaluating RAS and BRAF mutations, patients without RAS or BRAF mutations had significantly longer median PFS (10.8 months vs 9.2 months; P = .002) and median OS (28.3 months vs 20.9 months; P = .02) with panitumumab.[21] Patients with mutations of RAS or BRAF had inferior median PFS (7.3 months vs 8.0 months; P = .03) and median OS (15.3 months vs 18.0 months; P = .06) with the addition of panitumumab to their chemotherapy regimen. Therefore, administration of panitumumab in conjunction with FOLFOX4 is an effective first-line treatment option for patients with RAS and BRAF wild-type metastatic colorectal cancer only. Use of this combination should be avoided in patients whose tumors have RAS and BRAF mutations.

The bottom line: anti-EGFR therapy improves outcomes in metastatic colorectal cancer

Overall, we conclude that the addition of EGFR inhibitors to chemotherapy in the first-line setting in patients with RAS and BRAF wild-type metastatic colorectal cancer improves patient survival and disease outcomes. Nevertheless, because these agents yield only marginal improvements in OS, treatments with greater efficacy are needed.

The VEGF Pathway and Anti-VEGF Therapy

Vascular endothelial growth factor A (VEGF-A) promotes endothelial cell proliferation and angiogenesis by binding to cell surface receptors (VEGFRs). Blocking the interaction between VEGF and VEGFRs inhibits growth of the microvasculature and impedes progression to metastatic disease.[22]

Bevacizumab

Bevacizumab, a recombinant humanized monoclonal antibody against VEGF-A, is FDA-approved for the treatment of multiple cancer types (including metastatic colorectal cancer, nonsquamous non–small-cell lung cancer [NSCLC], glioblastoma, metastatic renal cell carcinoma, cervical cancer, and platinum-resistant ovarian cancers).[23] Aside from its direct antiangiogenic effects, bevacizumab may also normalize tumor vasculature, thereby improving the delivery of cytotoxic chemotherapy to tumor tissue.[24]

Hurwitz and colleagues demonstrated that adding bevacizumab to combination treatment with the IFL regimen (irinotecan, bolus 5-FU, and leucovorin) improved survival in patients with metastatic colorectal cancer.[25] In their phase III trial, 813 patients with untreated metastatic colorectal cancer were randomized in a 1:1 ratio to IFL plus bevacizumab (with the latter administered at a dosage of 5 mg/kg IV every 2 weeks) or IFL plus placebo. OS, the primary study endpoint, was found to be significantly improved following therapy with bevacizumab (median OS, 20.3 months vs 15.6 months with placebo; P < .001). Significant improvement in median PFS was also seen following treatment with bevacizumab (10.6 months with IFL and bevacizumab vs 6.2 months with placebo; P < .001), as was ORR (44.8% vs 34.8%, respectively; P = .004). Patients who received bevacizumab were more likely to have grade 3/4 adverse events (84.9% vs 74.0% with placebo; P < .01)-notably, hypertension (11.0% vs 2.3% with placebo; P < .01) and, rarely, gastrointestinal perforation (1.5% vs 0% with placebo; P < .01). This study firmly established the combination of bevacizumab with cytotoxic chemotherapy as the standard of care in first-line treatment of metastatic colorectal cancer. Notably, in the large phase III TRIBE trial, which demonstrated an OS benefit with frontline treatment with FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, and irinotecan) compared with FOLFIRI, patients in both treatment arms received bevacizumab.[4,26] Results from this study showed that bevacizumab combined with irinotecan-based chemotherapy is an effective first-line treatment for patients with metastatic colorectal cancer, despite increased toxicities.

In a similar study, the phase III N01966 trial, 1,401 patients with untreated metastatic colorectal cancer were randomized in a 2 × 2 factorial fashion to receive combination treatment with CAPOX (capecitabine and oxaliplatin) or FOLFOX4, plus placebo or bevacizumab.[27] Patients who received bevacizumab had a significantly improved median PFS compared with those receiving placebo (9.4 months vs 8.0 months; P = .0023); however, there was no statistically significant improvement in median OS (21.3 months vs 19.9 months; P = .077) or ORR (47% vs 49%; P = .31). Nevertheless, bevacizumab combined with oxaliplatin and a fluoropyrimidine in the first-line setting is an appropriate treatment option.

In the phase III AVEX study, 280 patients (≤ 70 years of age) with untreated metastatic colorectal cancer were randomized in a 1:1 ratio to receive capecitabine plus bevacizumab or capecitabine alone.[28] PFS, the primary study endpoint, was found to be significantly improved in patients receiving bevacizumab (9.1 months) compared with those receiving chemotherapy alone (5.1 months; P < .0001). This was also the case for ORR (19% vs 10%, respectively; P = .04), although there was only a trend toward longer median OS (20.7 vs 16.8 months; P = .18). There were higher rates of grades 3 to 5 toxicities with bevacizumab, including venous thromboembolic events (8% vs 4%) and hand-foot syndrome (16% vs 7%). Although no OS benefit was demonstrated, given the significant PFS benefits reported, combination treatment with bevacizumab plus capecitabine is a reasonable option in older patients who have previously untreated metastatic colorectal cancer.

Ziv-aflibercept

The antiangiogenic agent ziv-aflibercept traps the ligands VEGF-A, VEGF-B, and placental growth factor, preventing their interaction with VEGFR-1 and VEGFR-2[29] In the first-line setting, ziv-aflibercept plus modified FOLFOX6 (mFOLFOX6) did not improve survival when compared with mFOLFOX6 alone. The phase II AFFIRM trial randomized 236 patients with untreated metastatic colorectal cancer in a 1:1 ratio to receive mFOLFOX6 plus ziv-aflibercept or mFOLFOX6 alone. There was no difference in median PFS (the primary endpoint) for patients receiving the combination therapy (8.48 months ) compared with those receiving mFOLFOX6 alone (8.77 months; P > .05). The same was the case for ORR (49.1% vs 45.9%, respectively; P > .05).[30] A trial of first-line treatment with FOLFIRI with or without ziv-aflibercept (the MINOAS trial) is underway in Greece (ClinicalTrials.gov identifier: NCT02624726).

Ramucirumab

Ramucirumab is a fully humanized IgG1 monoclonal antibody that specifically blocks the ligand-binding site of VEGFR-2. It is FDA-approved for use in platinum-resistant NSCLC and gastric and gastroesophageal adenocarcinoma.[31] An open-label, single-arm phase II study of ramucirumab in combination with mFOLFOX6 chemotherapy in 48 patients with untreated metastatic colorectal cancer demonstrated a median PFS of 11.5 months, a median OS of 20.4 months, and an ORR of 58.3%. Adverse events included grade 3/4 neutropenia (41.6%), hypertension (16.7%), and neuropathy (12.5%).[32] No randomized phase III data on ramucirumab in the first-line treatment of metastatic colorectal cancer have been published, and this agent is not FDA-approved for use in the first-line setting.

Combination Biologic Therapy

The combination of anti-EGFR and anti-VEGF biologic therapies should be avoided. The phase IIIB PACCE trial randomized 1,053 patients with untreated metastatic colorectal cancer in a 1:1 ratio to receive chemotherapy (a fluoropyrimidine plus oxaliplatin or irinotecan) with bevacizumab and panitumumab or chemotherapy plus bevacizumab only.[33] The addition of panitumumab increased toxicity and actually decreased median PFS (oxaliplatin cohorts: 10.0 months vs 11.4 months; irinotecan cohorts: 10.1 months vs 11.7 months;) and median OS (oxaliplatin cohorts: 19.4 months vs 24.5 months; irinotecan cohorts: 20.7 months vs 20.5 months). These findings persisted in the KRAS wild-type subpopulation. Patients receiving panitumumab also had a lower relative dose intensity of bevacizumab and chemotherapy than those who did not receive panitumumab, likely contributing to the survival outcomes. Similarly, the phase III CAIRO2 trial randomized 755 patients with untreated metastatic colorectal cancer in a 1:1 ratio to CAPOX plus bevacizumab and cetuximab or CAPOX plus bevacizumab alone (with PFS as the primary endpoint).[34] Patients who received both biologic therapies had inferior median PFS (9.4 months vs 10.7 months with bevacizumab alone; P = .01) and a trend toward inferior median OS (19.4 months vs 20.3 months, respectively; P = .16). ORR was similar between the two arms (52.7% vs 50.0%; P = .49). Within the group of patients who received dual biologic therapy, those with KRAS wild-type tumors fared better than those with KRAS-mutated tumors (median OS, 21.8 months vs 17.2 months, respectively; P = .06), although the study data do not support the use of both biologic therapies even in KRAS wild-type patients (in whom median OS was 22.4 months with bevacizumab vs 21.8 months with cetuximab and bevacizumab; P = .64).

Neoadjuvant Therapy in Resectable Metastatic Colorectal Cancer With Liver Metastases

Can biologic agents be added to chemotherapy in order to increase the chance of rendering liver metastases resectable? Starting with cetuximab in this setting, evidence of benefit is lacking. The phase III New EPOC trial randomized 272 patients with KRAS exon 2 wild-type metastatic colorectal cancer and potentially resectable liver metastases to chemotherapy (FOLFOX, CAPOX, or FOLFIRI) plus cetuximab or chemotherapy alone in a 1:1 ratio.[35] Patients who received cetuximab actually had inferior median PFS (14.1 months vs 20.5 months; P = .030), with a trend toward inferior median OS (39.1 months vs not reached at point of follow-up; P = .16) and similar liver resection rates (87% vs 93%), although this study should possibly take place in pan-RAS/BRAF wild-type patients, and perhaps in patients with only left-sided tumors (see section on tumor sidedness in this article). There was a trend toward improved PFS with cetuximab in patients who received FOLFIRI, but there were only 26 patients in this group. Regardless, neoadjuvant cetuximab is not recommended in this setting.

The phase II OLIVIA trial validated the use of neoadjuvant bevacizumab for patients with initially unresectable liver metastases. Eighty patients were randomized in a 1:1 ratio to treatment with FOLFOXIRI plus bevacizumab or mFOLFOX6 plus bevacizumab.[36] The resection rate was higher following therapy with FOLFOXIRI plus bevacizumab (61% vs 49%), as were the rate of R0 resection (49% vs 23%), ORR (81% vs 62%), and median PFS (18.6 months vs 11.5 months). Although this study did not compare chemotherapy plus bevacizumab against chemotherapy alone and thus cannot address the contribution made by adding bevacizumab to chemotherapy in this setting, these findings support the safety of bevacizumab plus chemotherapy in the neoadjuvant setting prior to liver resection.

Selection of Biologic Therapies in the First Line

Given the panoply of biologic therapies from which to choose, how does the treating oncologist select which agent and which chemotherapy backbone to use? As discussed, EGFR-directed therapies should be restricted to patients with RAS and BRAF wild-type tumors, and not all biologic therapies are approved for the first-line treatment of patients with metastatic colorectal cancer. For patients with RAS-mutated tumors, bevacizumab remains the biologic agent of choice in the first-line setting, and can be administered in combination with capecitabine, CAPOX, FOLFOX, FOLFIRI, or FOLFOXIRI.[3,28,34,37]

For patients with RAS wild-type tumors, choosing the most appropriate first-line treatment regimen is more complicated. Is it better to use a VEGF-targeting agent or an EGFR-targeting agent in the first-line treatment of patients with RAS wild-type tumors? In the phase III German Arbeitsgemeinschaft Internistische Onkologie FIRE-3 trial, 592 patients with untreated KRAS exon 2 wild-type metastatic colorectal cancer were randomized 1:1 to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab.[38] Adverse events were as expected, including more grade 3/4 skin reactions with cetuximab (26% vs 2% with bevacizumab). The primary endpoint of ORR was very similar between the groups (62% vs 58%; P = .18), as was median PFS (10.0 months vs 10.3 months; P = .55). However, median OS was greater following cetuximab than following bevacizumab therapy (28.7 months vs 25.0 months; P = .017). In a subgroup analysis of patients with RAS wild-type tumors, median OS favored the cetuximab arm (33.1 months vs 25.0 months; P = .0059), although median PFS (10.3 months vs 10.2 months; P = .77) and ORR (65.3% vs 58.7%; P = .18) were similar between the treatment arms.[39] Radiologic review showed that cetuximab was superior to bevacizumab in terms of the frequency of early tumor shrinkage (68.2% vs 49.1%, respectively; P = .0005) and median depth of response (–48.9% vs –32.3%; P < .0001),[39] indicating again that RAS wild-type tumors are particularly responsive to first-line FOLFIRI plus cetuximab.[39,40]

KEY POINTS

All patients with metastatic colorectal cancer should undergo testing for KRAS, NRAS, and BRAF status and microsatellite instability/mismatch repair status.
The addition of epidermal growth factor receptor inhibitors to chemotherapy in the first-line setting in patients with RAS and BRAF wild-type metastatic colorectal cancer improves survival.
Patients with right-sided primary colon tumors have worse overall survival and derive less benefit from cetuximab (even if their tumors are KRAS wild-type) than patients with left-sided tumors.
While great strides have been made, many patients still do not reap an overall survival benefit from currently available biologic therapy. Therefore, additional novel therapies and combination approaches are needed.

In contrast, the Cancer and Leukemia Group B (CALGB)/Southwest Oncology Group (SWOG) 80405 study showed no difference in median OS between cetuximab and bevacizumab in the first-line setting.[41] In this phase III study, 1,137 patients with untreated KRAS exon 2 wild-type metastatic colorectal cancer were randomized in a 1:1 ratio to cetuximab or bevacizumab in combination with either FOLFIRI or mFOLFOX6 (patient’s and physician’s choice, with 73.4% deciding on treatment with mFOLFOX6). The primary endpoint, median OS, was the same between the treatment groups (29.0 months for both cetuximab and bevacizumab; P = .34), as was median PFS (10.45 months vs 10.84 months). As noted, the majority of patients received oxaliplatin (not irinotecan), and EGFR-targeting agents may be more effective in combination with irinotecan than with oxaliplatin. Nevertheless, both regimens are reasonable choices in the first-line setting.

The phase II PEAK study randomized 285 patients with KRAS exon 2 wild-type untreated metastatic colorectal cancer to mFOLFOX6 plus panitumumab or mFOLFOX6 plus bevacizumab.[42] The primary endpoint of median PFS was not significantly improved with panitumumab (10.9 months vs 10.1 months; P = .353), but median OS was significantly improved (34.2 months vs 24.3 months; P = .009). OS may have been confounded by the effects of subsequent treatment regimens (since most patients subsequently received anti-EGFR and/or anti-VEGF agents). However, given the demonstrated improvements in median OS, mFOLFOX6 plus panitumumab is an appropriate first-line treatment for patients with metastatic colorectal cancer.

Tumor Sidedness as a Prognostic and Predictive Marker

The right side of the colon (extending from the cecum to the proximal two-thirds of the transverse colon) and the left side of the colon (incorporating the distal transverse to sigmoid colon and rectum) arise from different embryological origins (midgut and hindgut, respectively) and have different dominant blood supplies (superior mesenteric and inferior mesenteric arteries, respectively). Results from the FIRE-3, CRYSTAL, CALGB/SWOG 80405, and National Cancer Institute of Canada CO.17 trials, as well as Surveillance, Epidemiology, and End Results program database analyses, demonstrate that patients with right-sided tumors have worse OS and derive less benefit from cetuximab (even if their tumors are KRAS wild-type) than patients with left-sided tumors.[43-46]

For example, patients in the CALGB/SWOG 80405 study with KRAS wild-type left-sided tumors had a median OS of 37.5 months with cetuximab and 32.1 months with bevacizumab, whereas patients with KRAS wild-type right-sided tumors had a median OS of 16.4 months with cetuximab and 24.5 months with bevacizumab (hazard ratio [HR] for cetuximab 1.97; P < .0001; HR for bevacizumab 1.26; P < .0001).[45] These findings suggest that anti-EGFR therapies should be avoided in patients with right-sided tumors, and that bevacizumab should be used instead. The underlying biological differences between right colon, left colon, and rectal tumors are likely the cause of these differences in response, but more research is necessary to better characterize the differences.[47] Although these trials were conducted in the first-line metastatic setting, it may be possible to extrapolate their findings regarding tumor sidedness to later lines of therapy. At a minimum, these study results should be prospectively validated, and future trials in metastatic colorectal cancer should stratify patients based on tumor sidedness.

Conclusion

In our practice, we favor the use of mFOLFOX6 or CAPOX plus bevacizumab in the first-line RAS wild-type setting, saving irinotecan and EGFR-directed therapy for later lines of treatment. We also favor using bevacizumab for patients with right-sided colon primaries and anti-EGFR therapies for patients with left-sided primaries.

Biologic therapies remain integral to the treatment of patients with metastatic colorectal cancer. We are now better able to tailor these therapies to individual patients and thus optimize their treatment response. Bevacizumab is the most versatile biologic anticancer agent because it is effective regardless of RAS mutational status. Anti-EGFR therapy should be used in patients with RAS wild-type tumors and may be reserved for later lines of therapy. Combination biologic therapy should be avoided outside the context of a clinical trial. While great strides have been made, many patients still do not experience an OS benefit; additional novel therapies and combination approaches are needed.

Financial Disclosure:Dr. Salem serves as a speaker for, and consultant to, Genentech. The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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