Precision Medicine in Metastatic Colorectal Cancer: Relevant Carcinogenic Pathways and Targets-PART 2: Approaches Beyond First-Line Therapy, and Novel Biologic Agents Under Investigation

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.

Introduction

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.[1] 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.[1] 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.[2]

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).[3] 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).[4] 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.[5] 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.[6] 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%.[6] 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).[7]

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.[8] 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.[9] 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%).[9] 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.[10] 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.

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.[8] 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.[6] 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.[1] The administration of panitumumab plus irinotecan as second-line therapy is supported by the 20050181 trial[5] and the PICCOLO trial,[4] 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.[11] 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).[11] 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).[13] 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.[2]

Panitumumab monotherapy was evaluated in the third-line setting in a phase III trial by Van Cutsem et al.[12] 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.[14] 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.[15] 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.[16] 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.[14] 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%),[14] compared with rates seen with regorafenib (1.0%)[16] and trifluridine/tipiracil (1.6%).[19] Thus, if obtaining an objective response is important, then anti-EGFR therapies should be favored over treatment with regorafenib or trifluridine/tipiracil.

Maintenance Therapy

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.[20] 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.[21] 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[21] and SAKK 41/06, a randomized, phase III, noninferiority trial conducted by the Swiss Group for Clinical Cancer Research.[22]

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).[23] 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.[24]

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.[25] 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.

HER2-amplified tumors

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).[26] 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%)[16] and trifluridine/tipiracil (1.6%).[19] 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.[28] 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.[28] 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.

Novel Biologic Therapies Under Development

Ensituximab

Ensituximab is a chimeric immunoglobulin (Ig)G1 monoclonal antibody against the polypeptide MUC5AC, a member of the mucin gene family that is aberrantly glycosylated in colorectal and pancreatic tumors and absent in the normal adult colon and pancreas.[29] Ensituximab functions via antibody-dependent cellular cytotoxicity and spares noncancerous colon and pancreas tissues.[30] In a phase I study of treatment-refractory patients who had received third-line and higher chemotherapy, Beg and colleagues found the maximum tolerated dose to be 3 mg/kg IV every 2 weeks (dose-limiting toxicities at 4 mg/kg were grade 3/4 anemia and hyperbilirubinemia).[31] Of 11 evaluable patients, 5 had stable disease (4 with colorectal cancer and 1 with pancreatic cancer), and 6 had progressive disease. The phase II portion of this study (QUILT-3.019) is ongoing (ClinicalTrials.gov identifier: NCT01040000).

Nimotuzumab

Nimotuzumab, a humanized IgG1 monoclonal antibody against EGFR, is a potent radiosensitizer lacking the dermatologic and gastrointestinal toxicities associated with cetuximab and panitumumab.[32] In a single-arm phase II study, nimotuzumab at 400 mg IV weekly was safely combined with capecitabine-based chemoradiation in the treatment of 21 patients with locally advanced rectal cancer.[32] Four patients (19%) had a pathologic CR. This approach has not been evaluated in a randomized controlled trial.

Urelumab

Urelumab is a fully humanized IgG4 monoclonal antibody agonist of CD137 (4-1BB); the latter is an immune costimulatory molecule that induces cytokine production and cytotoxic T-cell activation.[33] The maximum tolerated dose was 0.1 mg/kg IV, administered every 3 weeks; transaminitis was the main dose-limiting toxicity, and no immune-mediated adverse events were observed.[34] A phase I study of cetuximab and urelumab in advanced colon cancer and head and neck squamous cell cancers (ClinicalTrials.gov identifier: NCT02110082), and a phase I/II study of urelumab administered in combination with the anti–PD-1 antibody nivolumab for the treatment of solid tumors and non-Hodgkin lymphoma (ClinicalTrials.gov identifier: NCT02253992) are ongoing.

Varlilumab

Varlilumab is a fully humanized IgG1 monoclonal antibody that behaves as a CD27 agonist. CD27, an immune costimulatory molecule found on the T-cell surface, binds to CD70 on antigen-presenting cells and promotes T-cell proliferation and survival.[35] A phase I trial of varlilumab in select cancer types is ongoing (ClinicalTrials.gov identifier: NCT01460134).

Imalumab

Imalumab is a first-in-human fully humanized monoclonal antibody against anti-oxidized migration inhibitory factor, which is implicated in tumor angiogenesis, proliferation, and stromal inflammation. In a phase I study, imalumab administered at a dose of 10 mg/kg IV weekly was determined to be the recommended phase II dose and schedule (the only dose-limiting toxicity was hypersensitivity pneumonitis, observed in 1 patient).[36] A phase II trial of imalumab in combination with 5-FU/leucovorin and panitumumab (if RAS wild-type) is ongoing (ClinicalTrials.gov identifier: NCT02448810).

Atezolizumab and cobimetinib

There is an important ongoing effort to identify therapies that can render MMRp colorectal tumors sensitive to immune checkpoint inhibition. Combination therapy with the anti–programmed death ligand 1 monoclonal antibody atezolizumab and the oral MEK inhibitor cobimetinib leads to upregulation of major histocompatibility complex class I on tumor cells and T-cell infiltration into the tumor.[37] A phase IB study of the combination included 23 patients (22 KRAS-mutant patients and 1 KRAS wild-type patient) with metastatic colorectal cancer. Dose expansion occurred at the dosages of atezolizumab, 800 mg IV every 2 weeks, and cobimetinib, 60 mg by mouth daily.[37] The ORR of 17% was considerably higher than that reported in the medical literature, which showed a 0% ORR following pembrolizumab monotherapy in patients with MMRp colorectal cancer.[28] Combination therapy with atezolizumab and cobimetinib is under investigation in a phase III trial (ClinicalTrials.gov identifier: NCT02788279) in which patients with refractory metastatic colorectal cancer are randomized 1:1:1 to the combination, to atezolizumab monotherapy, or to regorafenib (with the last being the standard of care).

Conclusion

The standard of care for patients with previously treated metastatic colorectal cancer involves sequencing combinations of chemotherapy backbones with biologic therapies. Maintenance therapy often consists of low-dose chemotherapy in combination with a biologic agent. Beyond RAS mutational status, novel biomarkers are playing important roles, especially in later lines of therapy. Broader use of genomic tumor profiling has elucidated rare but actionable mutations suitable for off-label use. Checkpoint inhibitors, currently limited to treatment of MMRd tumors, hold promise for use in metastatic colorectal cancer. Much research is ongoing to bring this treatment option to patients with MMRp tumors. It is hoped that, in the near future, biologic agents now under development may yield meaningful clinical outcomes for patients with metastatic colorectal cancer.

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.

References:

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.