A frequent quandary for oncologists is the selection of chemotherapy and biologic therapy for patients with metastatic colorectal cancer in second-line and higher treatment settings. While not approved by the US Food and Drug Administration (FDA) in the first-line setting, the vascular endothelial growth factor (VEGF)-targeting agents ziv-aflibercept and ramucirumab are appropriate treatment options in the second-line setting, as is continuation of first-line bevacizumab. Tumor RAS mutational status is helpful to determine which patients may benefit from epidermal growth factor receptor (EGFR)-directed therapies, and other novel biomarkers (BRAF, HER2, and mismatch repair deficiency) allow us to select patients who may benefit from biologic therapies that are FDA-approved for other malignancies. Maintenance therapy for patients with stable disease following first-line therapy is a unique clinical situation that warrants special attention. Immunotherapy has thus far been ineffective for patients with mismatch repair–proficient tumors, but novel combination strategies are being studied to break through this treatment barrier. Finally, several new biologic therapies with novel targets are under development and will likely contribute to the growing arsenal of treatment options for patients with metastatic colorectal cancer.
Second-Line Treatment Recommendations for Patients With Metastatic Colorectal Cancer
For patients with RAS-mutated tumors, we continue antiangiogenic therapy in the second line in combination with chemotherapy (typically either mFOLFOX6 [a modified regimen of leucovorin, 5-FU, and oxaliplatin] or FOLFIRI, switched from prior treatment in the first-line setting), using either bevacizumab or an alternative biologic therapy against VEGF. Continuation of treatment with bevacizumab after first disease progression is supported by the results of the phase III, multicenter, multinational ML18147 trial. If bevacizumab was not used in the first-line setting, its use in second-line therapy is supported by data from ECOG’s E3200 trial. The VELOUR and RAISE trials also support the use of ziv-aflibercept and ramucirumab, respectively, in combination with FOLFIRI in the second-line setting for FOLFIRI-naive patients.[2,9,10] There are no prospective head-to-head data comparing bevacizumab, ziv-aflibercept, and ramucirumab in the second-line setting; therefore, none of these agents can be recommended over another based on efficacy.
In patients with RAS wild-type tumors, our preferred approach to second-line treatment is to administer anti-EGFR therapy in combination with irinotecan-based chemotherapy (eg, FOLFIRI or irinotecan alone). The use of this regimen is supported by data from the EPIC trial, in which combination therapy with cetuximab and irinotecan was superior to irinotecan alone in terms of median OS in patients with EGFR-positive tumors. The administration of panitumumab plus irinotecan as second-line therapy is supported by the 20050181 trial and the PICCOLO trial, which investigated FOLFIRI and irinotecan monotherapy, respectively, in this setting.
Third-Line and Higher Treatment of Metastatic Colorectal Cancer
Once the aforementioned first- and second-line regimens have been exhausted, anti-EGFR monotherapy is a valid option for patients with RAS wild-type tumors who have not been treated previously with an anti-EGFR agent.[11,12] The phase III National Institute of Canada (NCIC) CO.17 study showed that adding cetuximab to best supportive care (BSC) in third-line treatment of patients with metastatic colorectal cancer improves survival. In this study, 572 patients with EGFR-positive metastatic colorectal cancer who had been previously treated with (or had contraindications to the use of) a fluoropyrimidine, irinotecan, and oxaliplatin were randomized in a 1:1 ratio to cetuximab plus BSC or BSC alone. Median OS was the primary endpoint of the study.
Patients who received cetuximab had improved median OS (6.1 months vs 4.6 months with BSC alone; P = .005) and a very slight improvement in median PFS (1.9 months vs 1.8 months; P < .001). There was a higher incidence of grade 3 or higher adverse events in the cetuximab group (78.5% vs 59.1% with BSC alone; P < .001). In a retrospective analysis of 394 patients with analyzable tumor samples from this trial, those with KRAS wild-type tumors who received treatment with cetuximab had significantly improved median OS (9.5 months vs 4.8 months; P < .001) and median PFS (3.7 months vs 1.9 months; P < .001). However, there was no survival advantage for patients with KRAS-mutated tumors who received cetuximab (median OS, 4.5 months with cetuximab vs 4.6 months without cetuximab, P = .9; median PFS, 1.8 months in both arms). Therefore, cetuximab monotherapy is a valid option in third-line metastatic colorectal cancer, although its use should also be restricted to patients with RAS wild-type tumors.
Panitumumab monotherapy was evaluated in the third-line setting in a phase III trial by Van Cutsem et al. This study enrolled 463 patients with metastatic colorectal cancer whose tumors had at least 1% EGFR expression; patients had to have progressed on treatment with a fluoropyrimidine, oxaliplatin, and/or irinotecan and to have had no prior anti-EGFR therapy. They were randomized in a 1:1 ratio to receive BSC with or without panitumumab. Although median PFS (the primary endpoint) was not significantly improved following treatment with panitumumab (8.0 weeks vs 7.3 weeks with BSC only), there was a significant reduction in the risk of progression (HR, 0.54; P < .0001). A few patients had an objective response (ORR, 10% vs 0%; P < .0001), but OS was similar between the study groups (HR, 1.00; P = .81). Panitumumab monotherapy is a palliative option for patients with refractory metastatic colorectal cancer.
Panitumumab and cetuximab were compared head-to-head in the third-line phase III ASPECCT trial. In this study, 1,010 patients with KRAS wild-type metastatic colorectal cancer who had no prior anti-EGFR therapy and prior progression on fluoropyrimidine-based chemotherapy, and/or intolerance to oxaliplatin and irinotecan, were randomized 1:1 to receive panitumumab (at 6 mg/kg every 2 weeks) or cetuximab (at 400 mg/m2 then 250 mg/m2 weekly). The primary study endpoint was noninferior OS. Median OS was indeed similar between the two treatment groups (10.4 months with panitumumab vs 10.0 months with cetuximab; P = .0007 for noninferiority), as was the ORR (22.0% with panitumumab vs 19.8% with cetuximab). Rates of grade 3/4 skin toxicity (13% with panitumumab vs 10% with cetuximab) were also similar. Grade 3/4 hypomagnesemia was more common with panitumumab (7% vs 3% with cetuximab), and infusion reactions were less common (< 0.5% vs 2%, respectively). Therefore, based on these results it can be concluded that panitumumab monotherapy is noninferior to cetuximab in third-line treatment of KRAS wild-type metastatic colorectal cancer, with marginally less toxicity and a less frequent infusion schedule.
Results from an ongoing phase I/II study of panitumumab in combination with trifluridine/tipiracil for patients with metastatic colorectal cancer refractory to standard chemotherapy and anti-VEGF therapy (APOLLON, ClinicalTrials.gov identifier: NCT02613221) are anticipated and may provide treatment options for this group of patients.
Regorafenib is an oral multikinase inhibitor that inhibits multiple angiogenic and oncogenic targets, including KIT, RET, RAF1, BRAF, VEGFR1–3, TIE2, DDR2, Trk2A, EphA, platelet-derived growth factor, and fibroblast growth factor receptor. The phase III CORRECT trial evaluated regorafenib in patients with metastatic colorectal cancer refractory to all approved treatments. A total of 760 patients were randomized 2:1 to regorafenib (at 160 mg daily for 21 out of 28 days) or placebo. Median OS (the primary endpoint) was improved in patients treated with regorafenib compared with placebo (6.4 months vs 5.0 months, respectively; P = .0052). Median PFS was also slightly longer (1.9 months vs 1.7 months; P < .0001), but ORR was very low, and any difference between the two treatment groups did not reach significance (1.0% vs 0.4%; P = .19). Regorafenib is approved by the US Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer refractory to fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF agents, and (in KRAS wild-type patients) anti-EGFR therapy. We recommend a starting dose of 80 to 120 mg daily prior to escalating to 160 mg daily, with frequent reassessment for potential toxicities (including hand-foot syndrome, hepatotoxicity, and hypertension).[17,18] Alternative dosing at 120 mg daily for 21 out of 28 days is being prospectively studied in multiple ongoing trials in metastatic colorectal cancer (ClinicalTrials.gov identifiers: NCT02402036, NCT02466009, NCT02835924, and NCT02368886).
In patients not previously treated with EGFR-directed therapies, we generally favor the use of panitumumab over cetuximab because of the lower risk of infusion reactions, as reported in the ASPECCT trial. Regorafenib monotherapy is the other US Food and Drug Administration (FDA) approved biologic therapy used with some success in the third-line setting. However, much higher ORRs in the third-line setting have been seen in patients treated with cetuximab (22.0%) and panitumumab (19.8%), compared with rates seen with regorafenib (1.0%) and trifluridine/tipiracil (1.6%). Thus, if obtaining an objective response is important, then anti-EGFR therapies should be favored over treatment with regorafenib or trifluridine/tipiracil.
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