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.
While progression-free survival (PFS) has increased in patients treated in the first-line setting, patients with metastatic colorectal cancer will inevitably become resistant or intolerant to first-line therapy. Thankfully, a variety of second- and third-line treatment options exist. Traditionally, if oxaliplatin was used in the first-line chemotherapy regimen, it is substituted with irinotecan in the second line, and vice versa. If treatment targeting the epidermal growth factor receptor (EGFR) is not used in the first-line setting, then initiating EGFR-directed therapy in the second line, especially in combination with irinotecan, is a good option. Alternatively, continuing antiangiogenic therapy with the vascular endothelial growth factor (VEGF) inhibitor bevacizumab after progression or switching to a different antiangiogenic agent in the second-line setting are also established treatments. Third-line therapy typically consists of anti-EGFR therapy (if not used previously), the oral multikinase inhibitor regorafenib, or combination treatment with the cytotoxic pyrimidine analog trifluridine and the thymidine phosphorylase inhibitor tipiracil. Herein we review the evidence for use of biologic agents in the second-line setting and beyond. We also discuss off-label indications for biologics in selected patient populations, as well as biologics currently under development.
Second-Line Anti-EGFR Therapy
The combination of irinotecan and cetuximab was explored as second-line treatment in the phase III EPIC trial: 1,298 patients with EGFR-positive metastatic colorectal cancer with disease progression on first-line fluorouracil (5-FU) and oxaliplatin were randomized in a 1:1 ratio to receive cetuximab plus irinotecan (at 350 mg/m2 every 3 weeks) or irinotecan alone. Although there was no significant difference in the primary endpoint of median overall survival (OS; 10.7 months with cetuximab vs 10.0 months with irinotecan alone; P = .71), there were significant improvements in median PFS (4.0 months vs 2.6 months; P < .001) and objective response rate (ORR; 16.4% vs 4.2%; P < .0001), despite the fact that the patient population was not KRAS wild-type–enriched. Thus, it can be concluded that irinotecan plus cetuximab is an acceptable second-line regimen in the treatment of patients with metastatic colorectal cancer, particularly in those with KRAS wild-type tumors.
To evaluate panitumumab in the second-line setting in combination with irinotecan, the phase III PICCOLO trial used three treatment arms: irinotecan, irinotecan with panitumumab, and irinotecan with ciclosporin. A year and a half after its initiation, the trial was amended to restrict randomization to the panitumumab arm to patients with KRAS wild-type tumors only, and in this review we report on results from the irinotecan vs irinotecan plus panitumumab portion of the trial (since irinotecan plus ciclosporin was found to be noninferior to irinotecan monotherapy). PICCOLO enrolled patients with KRAS wild-type metastatic colorectal cancer who had not received any anti-EGFR therapy and had progressed on fluoropyrimidine-based chemotherapy. Thus, 460 patients were randomized 1:1 to receive irinotecan (at 350 mg/m2 every 3 weeks) alone or in combination with panitumumab (at 9 mg/kg every 3 weeks). The primary endpoint, median OS, was found to be similar in both treatment groups (10.4 months with irinotecan plus panitumumab vs 10.9 months with irinotecan monotherapy; P = .91). However, significant improvements in median PFS (hazard ratio [HR], 0.78; P = .015) and ORR (odds ratio [OR], 4.12; P < .0001) were observed with the addition of panitumumab to irinotecan. At 12 weeks post treatment with panitumumab, 33% of patients had a partial response (PR) and 1% had a complete response (CR), whereas only 12% of patients who did not receive panitumumab with irinotecan had a PR (and none had a CR). Grade 3 and higher adverse events that were more common with panitumumab included diarrhea (29% vs 18%), skin toxicity (19% vs 0%), lethargy (21% vs 11%), infection (19% vs 10%), and hematologic toxicity (22% vs 12%). Still, there was no OS benefit to adding panitumumab to irinotecan in second-line treatment of patients with KRAS wild-type metastatic colorectal cancer, despite an initial improvement in disease response.
The phase III 20050181 trial (ClinicalTrials.gov identifier: NCT00339183) had a similar focus: does the addition of panitumumab to second-line FOLFIRI (5-FU, leucovorin, and irinotecan) improve PFS and OS in KRAS wild-type metastatic colorectal cancer? In this trial, 1,186 patients who had disease progression on prior fluoropyrimidine-based chemotherapy were randomized 1:1 to receive FOLFIRI plus panitumumab (at 6 mg/kg every 2 weeks) or FOLFIRI alone. PFS and OS were coprimary endpoints. Median PFS was significantly longer when panitumumab was added to chemotherapy (6.7 months vs 4.9 months; P = .023) and there was a trend toward longer median OS with panitumumab (14.5 months vs 12.5 months; P = .37). OS may have been confounded by a higher rate of subsequent anti-EGFR therapy in patients in the FOLFIRI arm (34% vs 12%). ORR was superior in the panitumumab arm (36% vs 10%; P < .0001). Despite the lack of clear OS benefit, given the PFS results from the PICCOLO and 20050181 trials, irinotecan, particularly in the FOLFIRI regimen, plus panitumumab is a valid second-line treatment option for patients with KRAS wild-type metastatic colorectal cancer.
Second-Line Antiangiogenic Therapy
In the second-line setting, the Eastern Cooperative Oncology Group (ECOG) E3200 trial showed an OS benefit after adding bevacizumab to FOLFOX4 (oxaliplatin, 5-FU, and leucovorin). In this trial, 829 patients with metastatic colorectal cancer previously treated with a fluoropyrimidine and irinotecan were randomized in a 1:1:1 ratio to receive FOLFOX4 plus bevacizumab, FOLFOX4 alone, or bevacizumab alone. Bevacizumab prolonged median OS (the primary study endpoint) when added to FOLFOX4 (12.9 months vs 10.8 months with FOLFOX4 alone; P = .0011). Following the addition of bevacizumab to FOLFOX4, improvements were also seen in median PFS (7.3 months vs 4.7 months; P < .001) and ORR (22.7% vs 8.6%; P < .0001). The effects of treatment with bevacizumab monotherapy were substandard, and included a median OS of 10.2 months, a median PFS of 2.7 months, and an ORR of 3.3%. There were significantly more grade 3/4 adverse events among patients treated with FOLFOX4 plus bevacizumab compared with those treated with FOLFOX4 alone, with higher reported rates of hypertension (6.2% vs 1.8%; P = .008), bleeding (3.4% vs 0.4%; P = .011), vomiting (10.1% vs 3.2%; P = .01), and neuropathy (16.3% vs 9.2%; P = .011). Most episodes of bleeding occurred in the gastrointestinal tract, although 2 patient deaths were attributed to central nervous system hemorrhage (1 patient in each bevacizumab arm). Results of the E3200 trial indicate that the combination of bevacizumab with FOLFOX4 is effective in second-line treatment of metastatic colorectal cancer, despite the increased toxicities observed.
Continuation of bevacizumab in the second-line setting after progression on bevacizumab in the first line is also supported by prospective data. In the BRiTE trial, an observational study of 1,445 patients, those who received first-line bevacizumab beyond progression had significantly improved median OS (31.8 months) compared with patients who received post-progression treatment without bevacizumab (19.9 months; P < .001 compared with continuation of bevacizumab, in multivariate analysis) or no treatment (12.6 months).
Along these lines, the phase III ML18147 trial enrolled 820 patients with metastatic colorectal cancer who had progressed on first-line treatment with a fluoropyrimidine, bevacizumab, and either irinotecan or oxaliplatin. Patients were randomized in a 1:1 ratio to receive chemotherapy consisting of a fluoropyrimidine and irinotecan or oxaliplatin (with a switch of chemotherapy depending on the first-line treatment) with or without bevacizumab in the second-line setting. The primary endpoint of median OS was significantly improved following continuation of bevacizumab in second-line treatment compared with halting bevacizumab therapy completely (11.2 months vs 9.8 months; P = .0062). This was also the case for median PFS (5.7 months vs 4.1 months; P < .0001). Grades 3 to 5 adverse events such as bleeding (2% vs < 1%), gastrointestinal perforation (2% vs < 1%), and venous thromboembolic events (5% vs 3%) were slightly more common in the patients who were treated with bevacizumab plus chemotherapy, compared with patients who received chemotherapy alone.
Other second-line antiangiogenic treatment options include ziv-aflibercept and ramucirumab. In the phase III VELOUR trial, 1,226 patients with metastatic colorectal cancer who had progressed on first-line oxaliplatin-based chemotherapy (with or without bevacizumab) were randomized in a 1:1 ratio to treatment with FOLFIRI plus ziv-aflibercept (4 mg/kg IV every 2 weeks) or FOLFIRI plus placebo. The primary endpoint of OS was improved in patients who received treatment including ziv-aflibercept (13.5 months vs 12.1 months with FOLFIRI alone; P = .0032), as were median PFS (6.9 months vs 4.7 months; P < .0001) and ORR (19.8% vs 11.1%; P < .001).
There were higher rates of grade 3/4 adverse events with ziv-aflibercept, including diarrhea (19.3% vs 7.8% without ziv-aflibercept), stomatitis (13.7% vs 5.0%), infections (12.3% vs 6.9%), hand-foot syndrome (2.8% vs 0.5%), neutropenia (36.7% vs 29.5%), complicated neutropenia (5.7% vs 2.8%), thrombocytopenia (3.3% vs 1.7%), proteinuria (7.9% vs 1.2%), hypertension (19.3% vs 1.5%), bleeding (2.9% vs 1.7%), arterial thromboembolic events (1.8% vs 0.5%), and venous thromboembolic events (7.9% vs 6.3%). Based on results of the VELOUR trial, ziv-aflibercept with FOLFIRI is an accepted second-line regimen for the treatment of metastatic colorectal cancer, despite the higher rates of toxicities.
In the phase III RAISE trial, 1,072 patients with metastatic colorectal cancer who had progressed on first-line chemotherapy were randomized to FOLFIRI plus ramucirumab (at 8 mg/kg IV every 2 weeks) or FOLFIRI plus placebo. The primary endpoint of median OS was improved with ramucirumab (13.3 months vs 11.7 months; P = .0219), a significant difference that was also demonstrated for median PFS (5.7 months vs 4.5 months; P = .0005) but not ORR (13.4% vs 12.5%; P = .63). Grade 3/4 adverse events that were more common in patients treated with ramucirumab in combination with FOLFIRI included neutropenia (38% vs 23% with FOLFIRI alone), febrile neutropenia (3% vs 2%), hypertension (11% vs 3%), diarrhea (11% vs 10%), and fatigue (12% vs 8%). Results of the RAISE study suggest that ramucirumab with FOLFIRI is an appropriate treatment option for patients with metastatic colorectal cancer who have progressed on first-line combination treatment with a fluoropyrimidine, oxaliplatin, and bevacizumab.
1. Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:2311-9.
2. National Comprehensive Cancer Network. NCCN Guidelines. Colon Cancer. Version 1.2017. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed June 9, 2017.
3. Middleton GW, Brown SR, Gwyther SJ, et al. Ciclosporin in combination with irinotecan for chemoresistant advanced colorectal cancer - results of PICCOLO, a large randomised trial with prospective molecular stratification. Eur J Cancer. 2011;47:S420-S421.
4. Seymour MT, Brown SR, Middleton G, et al. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013;14:749-59.
5. Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:4706-13.
6. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25:1539-44.
7. Grothey A, Sugrue MM, Purdie DM, et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol. 2008;26:5326-34.
8. Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14:29-37.
9. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30:3499-506.
10. Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16:499-508.
11. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040-8.
12. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25:1658-64.
13. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:757-65.
14. Price TJ, Peeters M, Kim TW, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014;15:569-79.
15. Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129:245-55.
16. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303-12.
17. Grothey A, George S, van Cutsem E, et al. Optimizing treatment outcomes with regorafenib: personalized dosing and other strategies to support patient care. Oncologist. 2014;19:669-80.
18. Weinberg BA, Marshall JL, Salem ME. Trifluridine/tipiracil and regorafenib: new weapons in the war against metastatic colorectal cancer. Clin Adv Hematol Oncol. 2016;14:630-8.
19. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372:1909-19.
20. Simkens LH, van Tinteren H, May A, et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015;385:1843-52.
21. Hegewisch-Becker S, Graeven U, Lerchenmuller CA, et al. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol. 2015;16:1355-69.
22. Koeberle D, Betticher DC, von Moos R, et al. Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06). Ann Oncol. 2015;26:709-14.
23. Tournigand C, Chibaudel B, Samson B, et al. Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2015;16:1493-505.
24. Hagman H, Frodin JE, Berglund A, et al. A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial. Ann Oncol. 2016;27:140-7.
25. Kopetz S, McDonough SL, Morris VK, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). J Clin Oncol. 2017;35(suppl):abstr 520.
26. Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17:738-46.
27. Valtorta E, Martino C, Sartore-Bianchi A, et al. Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Mod Pathol. 2015;28:1481-91.
28. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509-20.
29. Bara J, Chastre E, Mahiou J, et al. Gastric M1 mucin, an early oncofetal marker of colon carcinogenesis, is encoded by the MUC5AC gene. Int J Cancer. 1998;75:767-73.
30. Patel SP, Bristol A, Saric O, et al. Anti-tumor activity of a novel monoclonal antibody, NPC-1C, optimized for recognition of tumor antigen MUC5AC variant in preclinical models. Cancer Immunol Immunother. 2013;62:1011-9.
31. Beg MS, Azad NS, Patel SP, et al. A phase 1 dose-escalation study of NEO-102 in patients with refractory colon and pancreatic cancer. Cancer Chemother Pharmacol. 2016;78:577-84.
32. Jin T, Zhu Y, Luo JL, et al. Prospective phase II trial of nimotuzumab in combination with radiotherapy and concurrent capecitabine in locally advanced rectal cancer. Int J Colorectal Dis. 2015;30:337-45.
33. Yonezawa A, Dutt S, Chester C, et al. Boosting cancer immunotherapy with anti-CD137 antibody therapy. Clin Cancer Res. 2015;21:3113-20.
34. Segal NH, Logan TF, Hodi FS, et al. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res. 2016 Oct 18. [Epub ahead of print]
35. Ramakrishna V, Sundarapandiyan K, Zhao B, et al. Characterization of the human T cell response to in vitro CD27 costimulation with varlilumab. J Immunother Cancer. 2015;3:37.
36. Mahalingam D, Patel MR, Sachdev JC, et al. First-in-human, phase I study assessing imalumab (Bax69), a first-in-class anti-oxidized macrophage migration inhibitory factor (oxMIF) antibody in advanced solid tumors. J Clin Oncol. 2015;33(suppl):abstr 2518.
37. Bendell JC, Kim TW, Goh BC, et al. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J Clin Oncol. 2016;34(suppl):abstr 3502.