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.
Maintenance therapy regimens for patients with stable metastatic colorectal cancer after induction chemotherapy often incorporate bevacizumab. In the phase III CAIRO3 trial, 558 patients with stable, partially responding, or completely responding metastatic colorectal cancer after CAPOX (capecitabine and oxaliplatin) plus bevacizumab were randomized 1:1 to receive maintenance capecitabine plus bevacizumab or just observation. Reinduction with CAPOX plus bevacizumab subsequently took place at the first sign of progression. The primary endpoint was time to second progression, PFS2, after reinduction. The maintenance group had longer median PFS2 (11.7 months vs 8.5 months; P < .0001), with a trend toward longer median OS (25.9 months vs 22.4 months; P = .06). There was a higher rate of grade 3/4 hand-foot syndrome in the maintenance group (23% vs 0%; P < .0001). The use of maintenance capecitabine plus bevacizumab is also supported by data from the phase III Arbeitsgemeinschaft Internistische Onkologie (AIO) 0207 trial, which compared maintenance therapy with capecitabine plus bevacizumab, bevacizumab alone, or observation. In this German trial, combination treatment with capecitabine and bevacizumab was again found to be an effective maintenance regimen; however, maintenance bevacizumab monotherapy does not appear to have clinical benefit, based on results from both the AIO 0207 trial and SAKK 41/06, a randomized, phase III, noninferiority trial conducted by the Swiss Group for Clinical Cancer Research.
Combination treatment with the VEGF inhibitor bevacizumab and the EGFR inhibitor erlotinib became another maintenance option following publication of results from the phase III DREAM OPTIMOX3 trial; it demonstrated a moderate median OS benefit for patients receiving this combination (24.9 months vs 22.1 months for patients treated with bevacizumab only; HR, 0.79; 95% CI, 0.63–0.99; P = .036). However, these findings did not hold for KRAS wild-type patients in the phase III Nordic ACT2 trial, and erlotinib is not approved by the FDA for use in colorectal cancer.
Finally, the addition of bevacizumab to trifluridine/tipiracil as maintenance therapy after induction with oxaliplatin- or irinotecan-based chemotherapy is under evaluation in our ongoing phase II ALEXANDRIA trial (ClinicalTrials.gov identifier: NCT02654639).
Use of Non–FDA-Approved Biologic Therapies in Selected Patient Populations
BRAF-mutated colorectal tumors
As mentioned previously, patients with BRAF mutations (usually V600E) have very low rates of response to EGFR-targeted therapy. However, these patients may benefit from the combination of a BRAF inhibitor and an anti-EGFR agent. The Southwest Oncology Group 1406 study randomized 99 patients with BRAF V600E–mutated, previously treated metastatic colorectal cancer 1:1 to irinotecan and cetuximab with or without the BRAF inhibitor vemurafenib at an oral dose of 960 mg daily. The primary endpoint of median PFS was significantly longer with vemurafenib (4.4 months vs 2.0 months; HR, 0.42; 95% CI, 0.26–0.66; P = .0002) at the expense of higher rates of grade 3/4 anemia (13% vs 0%), neutropenia (28% vs 7%), febrile neutropenia (11% vs 4%), diarrhea (22% vs 11%), nausea (15% vs 0%), and arthralgia (7% vs 0%). Therefore, the combination of vemurafenib, cetuximab, and irinotecan may be a valid second-line option in patients with BRAF-mutant metastatic colorectal cancer, although it is not without its limitations.
Approximately 5% of patients with KRAS wild-type metastatic colorectal cancer harbor HER2 amplification (defined by immunohistochemistry test scores of 3+, or 2+ with a HER2/chromosome enumeration probe 17 ratio above 2) that can be targeted by HER2-directed therapies.[26,27] In the phase II HERACLES trial, 27 patients with HER2-amplified, KRAS wild-type, chemotherapy-refractory metastatic colorectal cancer (including prior treatment with anti-EGFR agents) received the HER2-targeting agents trastuzumab (at 4 mg/kg IV followed by 2 mg/kg weekly) and lapatinib (at 1,000 mg daily by mouth). The ORR was 30% (95% CI, 14%–50%), which was again very high compared with ORRs for the FDA-approved third-line agents regorafenib (1.0%) and trifluridine/tipiracil (1.6%). Thus, combination HER2-directed therapy is effective in this rare patient population.
Mismatch repair–deficient (MMRd) tumors
An exciting recent discovery is that patients with MMRd tumors respond to checkpoint inhibition using the anti–programmed death 1 (PD-1) antibody pembrolizumab. This is apparently due to the accumulation of neoantigens that are recognizable by the patients’ T-cell repertoire. Le and colleagues evaluated treatment with pembrolizumab (10 mg/kg IV every 2 weeks) in 21 patients with MMRd metastatic colorectal cancer and 11 patients with MMR-proficient (MMRp) disease. Median PFS and OS were 2.2 months and 5.0 months, respectively, for patients with MMRp tumors, but these endpoints were not reached in patients with MMRd tumors (HR for progression, 0.1, P < .001; HR for death, 0.22, P = .05). Patients with MMRd metastatic colorectal cancer had a 40% ORR (95% CI, 12%–74%). These findings demonstrate that patients with MMRd tumors and higher tumor mutational load derive dramatic benefit from anti–PD-1 blockade.
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