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.
Colorectal cancer is a common malignancy and the second leading cause of cancer-related death in the United States. 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. 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. 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. 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. 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.
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. 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). 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%).
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. 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.
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. 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. 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. 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.
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. 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). 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. 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.
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