A Review of Selected Presentations From the 2018 American Society of Clinical Oncology Gastrointestinal Cancers Symposium • January 18-20, 2018 • San Francisco, California
Regorafenib Dose Optimization Study (ReDOS): Randomized Phase II Trial to Evaluate Dosing Strategies for Regorafenib in Refractory Metastatic Colorectal Cancer—An ACCRU Network Study
Regorafenib is an oral multikinase inhibitor that targets the receptor tyrosine kinases involved in angiogenesis and oncogenesis. In phase 3 trials of patients with previously treated metastatic colorectal cancer, regorafenib improved overall survival (OS).1,2 However, the use of regorafenib has been associated with toxicities, such as hand-foot skin reaction and fatigue. In an effort to reduce toxicities while maintaining efficacy, the randomized phase 2 ReDOS trial (Regorafenib Dose Optimization Study) compared a fixed dose of regorafenib vs a dose-escalated regimen in patients with metastatic colorectal cancer.3 Patients in arm A received regorafenib at 80 mg/day, with weekly dose escalation up to 160 mg/day in the absence of significant drug-related toxicities. Patients in arm B received the standard dose of regorafenib at 160 mg/day. Both arms received regorafenib for 21 days during each 28-day cycle. In addition to the regorafenib dose randomization, patients within each regorafenib arm were randomly assigned to receive clobetasol either preemptively or to treat hand-foot skin reaction. The primary endpoint was the proportion of patients who completed 2 treatment cycles and initiated treatment cycle 3.
Among 123 patients, evaluable data were available for 54 patients in the escalated-dose arm and 62 patients in the standard-dose arm. Patient demographics were evenly balanced between the 2 arms. The 116 patients had a median age of 61 years (range, 53-68 years), and 61.2% were male. All patients had a performance score of 0 or 1. The primary tumor had been resected in 69.8% of patients, and two-thirds of patients had 3 or more metastatic sites. KRAS was mutated in 47% of patients, wild type in 44%, and of unknown status in 9%.
The trial met its primary endpoint, with 43% of patients in the escalated-dose arm entering the third treatment cycle vs 24% in the standard-dose arm (P=.028). Escalation of regorafenib was also associated with an improved OS (9.0 months vs 5.9 months; P=.094; Figure 1). Median progression-free survival (PFS) was 2.5 months for the escalated-dose arm vs 2.0 months for the standard-dose arm (P=.553; Figure 2). Overall quality of life decreased more in the standard-dose arm compared with the escalated-dose arm, particularly at week 2 of treatment cycle 1. In the escalated-dose arm, 18.5% of patients discontinued treatment owing to adverse events (AEs), side effects, or other complications, compared with 9.7% of patients in the standard-dose arm. However, patients in the escalated-dose arm had lower rates of grade 3/4 toxicity, including fatigue (13.0% vs 17.7%), hand-foot skin reaction (14.8% vs 16.1%), and hypertension (7.4% vs 14.5%). The results support the use of regorafenib dose escalation in patients with previously treated metastatic colorectal cancer. Outcomes with preemptive vs reactive clobetasol will be presented at a later date.
References
1. Grothey A, Van Cutsem E, Sobrero A, et al; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312.
2. Li J, Qin S, Xu R, et al; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16(6):619-629.
3. Bekaii-Saab T, Ou FS, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)—an ACCRU Network study [ASCO GI abstract 611]. J Clin Oncol. 2018;36(suppl 4S).
Nivolumab + Ipilimumab Combination in Patients With DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer: First Report of the Full Cohort From CheckMate-142
The DNA mismatch repair (dMMR) system is defective in approximately 4% of patients with metastatic colorectal cancer. The defect confers high microsatellite instability (MSI-H) and decreases benefit from conventional chemotherapy.1,2 The multicenter, open-label, nonrandomized, phase 2 CheckMate 142 trial (An Investigational Immuno-Therapy Study of Nivolumab, and Nivolumab in Combination With Other Anti-Cancer Drugs, in Colon Cancer That Has Come Back or Has Spread) was designed to evaluate nivolumab, alone or in combination with other therapies, in patients with dMMR/MSI-H metastatic or recurrent colorectal cancer. Eligible patients had progressed on, or were intolerant of, at least 1 prior line of therapy, including a fluoropyrimidine and oxaliplatin or irinotecan. After a median follow-up of 12.0 months, 74 patients treated with nivolumab monotherapy in the CheckMate 142 trial demonstrated an objective response rate (ORR) of 31.1%, as assessed by the investigators.3
One cohort of the CheckMate 142 trial investigated the combination of nivolumab plus ipilimumab. These 2 checkpoint inhibitors synergistically promote T-cell antitumor activity.4-6 Patients in the monotherapy cohort received nivolumab at 3 mg/kg every 2 weeks. Those in the combination cohort received 4 doses of nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks, followed by nivolumab at 3 mg/kg every 2 weeks. Among the 119 patients in the nivolumab-plus-ipilimumab cohort, the median age was 58 years (range, 21-88 years), and 59% were male. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Forty-five percent of patients had stage IV disease, and 40% had received 3 or more prior lines of therapy.
In the combination analysis, the median follow-up was 13.4 months among patients treated with nivolumab plus ipilimumab followed by nivolumab.3 The investigator-assessed ORR was 55%, and an add-itional 31% of patients had stable disease. The median follow-up was also 13.4 months in the cohort of patients treated with nivolumab monotherapy. These patients exhibited an ORR of 31%, and 38% of patients had stable disease.3 In the combination cohort, the median time to response was 2.8 months (range, 1-14 months), and responses were durable. Responses occurred irrespective of expression of programmed death ligand 1 (PD-L1), mutation status of BRAF or KRAS, and clinical history of Lynch syndrome. Twelve-month PFS was 71% (95% CI, 61.4%-78.7%), and 12-month OS was 85% (95% CI, 77.0%-90.2%). These outcomes were also superior to those observed in the nivolumab monotherapy cohort. Grade 3/4 AEs were more common in the combination therapy cohort (32% vs 20%), but no new safety signals were raised.
After a longer follow-up of 21 months in the monotherapy cohort, nivolumab continued to demonstrate a durable clinical benefit in patients with dMMR/MSI-H metastatic colorectal cancer, based on blinded independent central review.7 The 74 patients in the monotherapy cohort had a median age of 52.5 years (range, 26-79 years), and 59% were male. All of the patients had an ECOG performance status of 0 or 1, 45% had stage IV disease, and 54% had received 3 or more prior lines of therapy.
The ORR was 34%, and 31% of patients had stable disease. A reduction in tumor burden from baseline occurred in 60% of patients. The median duration of response was not reached (range, 1.4+ to 31.6+ months), and 64% of patients had responses that lasted 12 months or longer. The complete response (CR) rate increased from 32% after 13 months of follow-up to 34% after 21 months of follow-up. The median PFS was 6.6 months (95% CI, 3.0 months to not reached), and the median OS was not reached (95% CI, 19.6 months to not reached; Figure 3). Fifty-three patients had received 3 or more prior chemotherapies, most commonly a fluoropyrimidine, oxaliplatin, irinotecan, and a vascular endothelial growth factor (VEGF) inhibitor. Among these patients, the median PFS was 4.2 months, and the median OS was not reached.
Treatment-related grade 3/4 AEs were reported in 20% of patients. No new safety signals were raised.
References
1. Koopman M, Kortman GA, Mekenkamp L, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer. 2009;100(2):266-273.
2. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.
3. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):
1182-1191.
4. Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(7):883-895.
5. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):
23-34.
6. André T, Lonardi S, Wong M, et al. Nivolumab + ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): first report of the full cohort from CheckMate-142 [ASCO GI abstract 553]. J Clin Oncol. 2018;36(suppl 4S).
7. Overman MJ, Kopetz S, McDermott RS, et al. Nivolumab in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): long-term survival according to prior treatment from CheckMate-142 [ASCO GI abstract 554]. J Clin Oncol. 2018;36(suppl 4S).
REVERCE: Randomized Phase II Study of Regorafenib Followed by Cetuximab Versus the Reverse Sequence for Metastatic Colorectal Cancer Patients Previously Treated With Fluoropyrimidine, Oxaliplatin, and Irinotecan
Regorafenib is approved by the US Food and Drug Administration for the treatment of patients with metastatic colorectal cancer who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF therapy; and, for patients with wild-type KRAS, a therapy that targets the epidermal growth factor receptor (EGFR).1 Treatment with an anti-EGFR agent is therefore followed by regorafenib, but the optimal sequencing of agents is unknown.2 The phase 2 REVERCE trial evaluated the efficacy and safety of regorafenib followed by cetuximab vs cetuximab followed by regorafenib in patients with metastatic colorectal cancer.3 Eligible patients had developed relapsed or refractory disease after treatment with fluoropyrimidines, oxaliplatin, and irinotecan, and had not received anti-EGFR therapy. Eligible patients also had wild-type KRAS exon 2. Patients with minor RAS mutations were excluded during the latter part of the trial. Treatment consisted of regorafenib at 160 mg for 3 weeks on and 1 week off, followed by cetuximab (with irinotecan), or the reverse treatment. Patients received treatment until disease progression or unacceptable toxicity. The trial’s primary endpoint was to demonstrate a similar OS in both arms (hazard ratio [HR], 0.8-1.25), with an expected median OS of 12 months.
The study randomly assigned 51 patients to treatment with regorafenib followed by cetuximab and 50 patients to cetuximab followed by regorafenib. The baseline characteristics were well-balanced between the 2 arms. Patients had a median age of approximately 67 years (range, 34-83 years), and 64% were male. The primary tumor was located on the left side in more than three-fourths of patients. Nearly all patients (97%) had received prior bevacizumab.
After a median follow-up of 29 months, the median OS was 17.4 months for the regorafenib-first arm vs 11.6 months for the cetuximab-first arm (HR, 0.61; 95% CI, 0.39-0.96; P=.029; Figure 4). At the end of treatment with the first therapy, the median PFS was 2.4 months with regorafenib vs 4.2 months with cetuximab (HR, 0.97; 95% CI, 0.62-1.54; P=.91). At the end of the complete regimens, the median PFS was 5.2 months for regorafenib followed by cetuximab vs 1.8 months for cetuximab followed by regorafenib (HR, 0.29; 95% CI, 0.17-0.50; P<.0001; Figure 5).
In subgroup analysis, a primary tumor on the left side was associated with an HR of 0.51 (95% CI, 0.30-0.86), whereas a primary tumor on the right side was associated with an HR of 0.88 (95% CI, 0.32-2.40). Among the 81 patients with a left-sided primary tumor, the median OS was 20.5 months in the regorafenib-first arm vs 11.9 months in the cetuximab-first arm (P=.011). Among the 86 patients with wild-type RAS and RAF, the median OS was 18.2 months with regorafenib first vs 12.7 months with cetuximab first (HR, 0.60; 95% CI, 0.37-0.98; P=.036).
No new safety signals were observed in either arm. Quality of life was comparable between the arms, and decreased during treatment with regorafenib vs cetuximab.
References
1. Stivarga [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals; 2017.
2. Loree JM, Kopetz S. Recent developments in the treatment of metastatic colorectal cancer. Ther Adv Med Oncol. 2017;9(8):551-564.
3. Shitara K, Yamanaka T, Denda T, et al. REVERCE: randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for metastatic colorectal cancer patients previously treated with fluoropyrimidine, oxaliplatin, and irinotecan [ASCO GI abstract 557]. J Clin Oncol. 2018;36(suppl 4S).
A Phase Ib Study of Safety and Clinical Activity of Atezolizumab and Cobimetinib in Patients With Metastatic Colorectal Cancer
For patients with locally advan-ced, metastatic, or chemotherapy-refractory colorectal cancer, standard-of-care treatment is associated with a survival that is measured in months.1,2 Although PD-1 pathway inhibitors have shown activity in many tumor types, approximately 95% of patients with metastatic colorectal cancer have microsatellite-stable disease, which correlates with a poor response to inhibition of PD-1 or PD-L1.3 Combination therapy may be necessary to enable effective outcomes with immune checkpoint inhibitors in this setting. Atezolizumab binds to PD-L1, restoring tumor-specific immunity.4,5 Cobimetinib is a potent inhibitor of MEK1 and MEK2, and it promotes T-cell accumulation in tumors while limiting T-cell exhaustion.6 In a mouse tumor model, simultaneous inhibition of the MEK pathway and PD-L1 resulted in synergistic and durable tumor inhibition.6
The combination of atezolizumab plus cobimetinib was investigated in a phase 1b dose escalation and cohort expansion study of patients with metastatic colorectal cancer.7 Eligible patients were not screened for PD-L1 status. MSI status was locally reported and centrally confirmed. The atezolizumab dose was fixed at 800 mg every 2 weeks. In the dose-escalation stage, patients received cobimetinib at doses ranging from 20 mg/day to 60 mg/day, for 21 days of each 28-day cycle. The combination of atezolizumab administered at 800 mg every 2 weeks plus the highest dose of cobimetinib was chosen for dose expansion.
The 84 patients had a median age of 56.5 years (range, 23-81 years). Seventy-nine percent of patients had received 5 or more prior therapies, and 68% of patients had mutant KRAS. PD-L1 expression was less than 5% in 57% of patients, 5% or higher in 8% of patients, and unknown in the remainder. Fifty percent of patients had microsatellite-stable disease.
The 2-drug combination yielded an ORR of 8%. All of the responses were partial, and 23% of patients had stable disease (Figure 6). Among the 7 patients who experienced a partial response, 4 had microsatellite-stable disease. Similar ORRs were observed in the KRAS wild-type and KRAS mutant subpopulations. The median duration of response was 14.3 months (95% CI, 6.0 months to not estimable). The median PFS was 1.9 months (95% CI, 1.9-2.3 months) in the 84 metastatic colorectal cancer patients and 2.5 months (95% CI, 1.9-3.7 months) in the microsatellite-stable subgroup of 42 patients. The median OS was 9.8 months (95% CI, 6.2-14.1 months) in the 84 patients with metastatic colorectal cancer, and 13.0 months (95% CI, 6.0-25.8 months) in patients with microsatellite-stable disease. Median PFS and median OS were similar in patients with wild-type or mutant KRAS. The combination of atezolizumab plus cobimetinib vs regorafenib is being investigated in a phase 3 trial.8
Most AEs were manageable. Treatment-related AEs of any grade occurred in 96% of patients. The most common treatment-related grade 3/4 AEs were rash, diarrhea, fatigue, and increased blood creatine phosphokinase, each occurring in 5% of patients. AEs caused 13% of patients to discontinue atezolizumab and 24% to discontinue cobimetinib. Treatment-related serious AEs were reported in 12% of patients. No treatment-related deaths occurred.
References
1. Grothey A, Van Cutsem E, Sobrero A, et al; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312.
2. Mayer RJ, Van Cutsem E, Falcone A, et al; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-1919.
3. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.
4. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18(24):6580-6587.
5. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563-567.
6. Ebert PJR, Cheung J, Yang Y, et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity. 2016;44(3):609-621.
7. Bendell JC, Bang YJ, Chee CE. A phase Ib study of safety and clinical activity of atezolizumab (A) and cobimetinib (C) in patients (pts) with metastatic colorectal cancer (mCRC) [ASCO GI abstract 560]. J Clin Oncol. 2018;36(suppl 4S).
8. ClinicalTrials.gov. A study to investigate efficacy and safety of cobimetinib plus atezolizumab and atezolizumab monotherapy versus regorafenib in participants with metastatic colorectal adenocarcinoma (COTEZO IMblaze370). Identifier NCT02788279. https://clinicaltrials.gov/ct2/show/NCT02788279. Accessed February 7, 2018.
Regorafenib in Antiangiogenic-Naive, Chemotherapy-Refractory Advanced Colorectal Cancer: A Phase IIb Trial
Regorafenib was investigated in patients with chemotherapy-refractory, advanced colorectal cancer in an open-label, single-arm, phase 2b study performed at a single center.1 Patients were excluded from enrollment if they had received prior antiangiogenic treatment, such as bevacizumab. Patients received daily regorafenib at 160 mg for 21 days of each 28-day cycle. Treatment was administered until disease progression, unacceptable toxicity, withdrawal of patient consent, or investigator decision. The primary endpoint was PFS at week 8, tested against the null hypothesis that the true PFS at 8 weeks would be less than or equal to 30%, based on the inclusion of patients with potentially more advanced disease than those in the CORRECT study (Patients With Metastatic Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy).2 Tumor response was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.3 Tumor metabolic response was assessed by 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT), based on criteria from the European Organization for Research and Treatment of Cancer (EORTC).4
Fifty-nine patients received at least 1 dose of regorafenib. Patients had a median age of 58 years (range, 30-74 years), and 59% were male. The primary disease sites were the rectum (30.5%), proximal colon (27.1%), distal colon (23.7%), and colon and rectum (18.6%). A KRAS mutation was observed in 57.6% of patients. The time since first diagnosis until treatment assignment was 18 months or longer in three-fourths of patients. Prior to study enrollment, 28.8% of patients had undergone radiotherapy, and 47.5% of patients had received 4 or more prior lines of systemic therapy.
Among the 59 enrolled patients, the PFS rate at week 8 was 52.2% (Figure 7), and the OS rate at week 8 was 98.3%. The median PFS was 3.5 months (95% CI, 1.8-3.6 months), and the median OS was 7.4 months (95% CI, 5.3-8.9 months). Based on RECIST, the disease control rate was 50.8%. Tumor response according to FDG PET/CT assessment was greater using EORTC criteria compared with RECIST criteria (40.7% vs 1.7%). The median OS was 8.5 months in responders vs 6.0 months in nonresponders (based on EORTC criteria; P=.1079).
No new safety signals emerged. The most common treatment-emergent grade 3/4 AEs included hyperten-sion (36.6%), hand-foot skin reaction (25.4%), and hypophosphatemia (22.0%). Serious treatment-related AEs were reported in 8.5% of patients. No treatment-related deaths occurred. An AE, primarily hand-foot skin reaction, led to a dose reduction in 42.4% and a dose interruption in 64.4%.
References
1. Riechelmann R, Leite LAS, Glasberg J, et al. Regorafenib in antiangiogenic-naive, chemotherapy-refractory advanced colorectal cancer: a phase IIb trial [ASCO GI abstract 782]. J Clin Oncol. 2018;36
(suppl 4S).
2. Grothey A, Van Cutsem E, Sobrero A, et al; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312.
3. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
4. Young H, Baum R, Cremerius U, et al; European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. Eur J Cancer. 1999;35(13):1773-1782.
SCOT: Tumor Sidedness and the Influence of Chemotherapy Duration on Disease-Free Survival
For more than a decade, the standard adjuvant treatment for colorectal cancer has been 6 months of oxaliplatin-based therapy. However, oxaliplatin is associated with cumulative neurotoxicity that is dose-limiting and potentially irreversible. The international, noninferiority, phase 3 SCOT trial (Combination Chemotherapy After Surgery in Treating Patients With High-Risk Stage II or Stage III Colorectal Cancer) evaluated 3 months vs 6 months of oxaliplatin-based chemotherapy in patients with stage III or high-risk stage II colorectal cancer.1 Patients were treated with capecitabine plus oxaliplatin or folinic acid, fluorouracil, and oxaliplatin (FOLFOX), based on patient and physician choice. Patients were randomly assigned to receive 3 or 6 months of treatment. Noninferiority was defined as a reduction of 2.5% or less in 3-year disease-free survival after 3 months of treatment compared with 6 months of treatment. The study was designed to achieve 90% power at the 2.5% level of statistical significance based on recruitment of 9000 patients and 2750 disease-free survival events, including relapses, deaths, and the emergence of new colorectal cancer tumors. However, based on slow recruitment, the trial enrolled 6088 patients in 244 centers in 6 countries. FOLFOX was administered to 1981 patients, and capecitabine plus oxaliplatin to 4107 patients. The SCOT trial met its primary endpoint, demonstrating a reduction of 0.4% in 3-year disease-free survival for treatment of 3 months (76.7%) vs
6 months (77.1%; HR for noninferiority, 1.008; P=.014).
A recent study of 1869 patients with stage III colon cancer suggested that the anatomic location of the primary tumor may influence outcomes, such that patients with right-sided tumors have a worse survival after relapse.2 To further evaluate this possibility, data from the SCOT trial were analyzed for the impact of tumor sidedness on disease-free survival.3 Information on the primary tumor location was collated from pathologic reports and available for 3219 patients. Right-sided tumors included those in the cecum or ascending or transverse colon. Left-sided tumors included all those distal to and including the splenic flexure.
The 1207 patients with right-sided tumors had a median age of 66 years. Fifty-three percent were male, 41% had T4 tumors, and 17% had stage II disease. The 2012 patients with left-sided tumors had a median age of 64 years. Sixty-six percent were male, 24% had T4 tumors, and 21% had stage II disease. Patient characteristics were well-balanced between the 2 groups (P<.001).
Three-year disease-free survival was significantly worse in patients with tumors on the right vs the left (73% vs 80%; HR, 1.401; 95% CI, 1.216-1.615; P<.0001). Adjusting for tumor, node, and metastasis staging reduced the HR to 1.215 (95% CI, 1.051-1.404; P=.009). The analysis did not suggest that sidedness affected the impact of chemotherapy duration on 3-year disease-free survival (right-sided HR, 1.049; 95% CI, 0.849-1.296; left-sided HR, 0.910; 95% CI, 0.753-1.099; test for heterogeneity, P=.327).
References
1. Iveson T, Kerr R, Saunders M, et al. Updated results of the SCOT study: an international phase III randomised (1:1) non-inferiority trial comparing 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy for colorectal cancer [ESMO abstract LBA22]. Ann Oncol. 2017;28(suppl 5).
2. Taieb J, Kourie HR, Emile JF, et al. Association of prognostic value of primary tumor location in stage III colon cancer with RAS and BRAF mutational status [ASCO abstract 3515]. J Clin Oncol. 2017;35(15 suppl).
3. Saunders MP, Paul J, Crosby J, et al. SCOT: tumor sidedness and the influence of chemotherapy duration on DFS [ASCO GI abstract 558]. J Clin Oncol. 2018;36(suppl 4S).
Phase II Dose Titration Study of Regorafenib for Patients With Unresectable Metastatic Colorectal Cancer That Progressed After Standard Chemotherapy
The CORRECT study showed a significant improvement in OS with regorafenib compared with placebo in patients with metastatic colorectal cancer that had progressed after standard therapy.1 The OS improvement was also observed in a subgroup of Japanese patients.2 The standard starting dose of regorafenib is 160 mg/day, irrespective of the patient’s body weight or other parameters. In the CORRECT study, dose reduction owing to an AE was common among both Japanese and non-Japanese patients (84.6% vs 51.3%, respectively). Rates of discontinuation owing to AEs were relatively low, but these rates were higher in Japanese patients than in non-Japanese patients (13.8% vs 7.4%).
A single-arm, multicenter, phase 2 dose-titration study investigated a reduced starting dose of regorafenib in Japanese patients with unresectable, metastatic colorectal cancer.3 The study design included an option of increasing to the standard dose. Eligible patients were at least 20 years old and had histopathologically diagnosed colorectal cancer that had progressed during standard chemotherapy or within 3 months of the last chemotherapy cycle. Prior treatment with trifluridine/tipiracil was not permitted. All patients had an ECOG performance status of 0 or 1.
Patients initially received regorafenib at 120 mg every day for 3 weeks, followed by 1 week off. In subsequent cycles, dose escalation to
160 mg was permitted in patients who did not experience an AE of grade 2 or higher. An exception was made for patients with any grade of liver toxicity, including transaminase elevation or increased bilirubin, in whom the dose was not increased. Radiographic evaluation was performed every 8 weeks. The primary endpoint was the disease control rate after 6 weeks. A disease control rate of 40% was defined as evidence of activity, and the confidence interval lower limit was set at 27%.
The 60 enrolled patients had a median age of 68.5 years (range, 47-80 years), and half were male. Most primary tumors were located in the sigmoid colon (45%), followed by the rectum (30%) and the ascending colon (15%). Sixty percent of patients had moderately differentiated adenocarcinoma, 36.7% had well-differentiated adenocarcinoma, and 3.3% had mucinous adenocarcinoma. Metastases were observed primarily in the liver (67.3%), the lung (53.8%), and the peritoneum (28.8%). Patients received up to 9 cycles of treatment.
The regorafenib dose was escalated from 120 mg to 160 mg in 2 patients (3.3%): 1 during cycle 2 and 1 during cycle 4. In 24 patients (40%), the regorafenib dose was decreased to 80 mg owing to an AE that occurred in at least 1 of the treatment cycles. The trial met its primary endpoint, with a disease control rate of 38.3%, exceeding the prespecified threshold of 27%. The disease control rate represented 23 patients (38.3%) with stable disease. There were no CRs or partial responses. The median PFS was 2.45 months (95% CI, 1.9-3.7 months; Figure 8), and the median OS was 6.93 months (95% CI, 5.7-9.1 months).
AEs were consistent with the known safety profile of regorafenib. Fifty-two percent of patients experienced a grade 3/4 AE. The most common grade 3/4 AEs were grade 3 hand-foot skin reaction and hypertension, each occurring in 20% of patients. Grade 4 AEs included increased aspartate transaminase (3%), increased alanine transaminase (2%), and hyperglycemia (2%).
References
1. Grothey A, Van Cutsem E, Sobrero A, et al; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312.
2. Yoshino T, Komatsu Y, Yamada Y, et al. Randomized phase III trial of regorafenib in metastatic colorectal cancer: analysis of the CORRECT Japanese and non-Japanese subpopulations. Invest New Drugs. 2015;33(3):740-750.
3. Kudo T, Kato T, Kagasa Y, et al. Phase II dose titration study of regorafenib for patients with unresectable metastatic colorectal cancer that progressed after standard chemotherapy [ASCO GI abstract 821]. J Clin Oncol. 2018;36(suppl 4S).
SAPPHIRE: A Randomized Phase II Study of mFOLFOX6 + Panitumumab Versus 5-FU/LV + Panitumumab After 6 Cycles of Frontline mFOLFOX6 + Panitumumab in Patients With Colorectal Cancer
FOLFOX therapy is a common first-line option for patients with unresectable, advanced, or recurrent colorectal cancer. However, long-term exposure to oxaliplatin is associated with dose-limiting peripheral neuropathy.1 Oxaliplatin can be discontinued after 6 cycles of first-line therapy. In patients who do not develop peripheral neuropathy, inclusion of oxaliplatin in later treatment cycles could be beneficial. Panitumumab is a fully human monoclonal antibody that binds to EGFR. In 2010, panitumumab was approved in Japan as monotherapy and in combination with chemotherapy for the treatment of KRAS wild-type metastatic colorectal cancer.
SAPPHIRE (Safety and Efficacy Study of mFOLFOX6 + Panitumumab Combination Therapy and 5-FU/LV + Panitumumab Combination Therapy in Patients With Chemotherapy-Naïve Unresectable Advanced Recurrent Colorectal Carcinoma) was an open-label, randomized phase 2 study that investigated panitumumab plus either modified FOLFOX6 or 5-fluorouracil (FU)/leucovorin (LV) after first-line treatment with 6 cycles of panitumumab plus modified FOLFOX6 administered in 2-week cycles.2,3 The modified FOLFOX6 regimen consisted of 6 cycles of oxaliplatin (85 mg/m2) and LV (200 mg/m2), administered on the first day of the treatment cycle. A 400-mg bolus of 5-FU was administered on day 1, followed by a 2400-mg infusion on days 1 to 3. Panitumumab at 6 mg/kg was also administered on day 1. Patients had wild-type KRAS and NRAS, and they had measurable lesions based on RECIST 1.1. Patients had not received prior chemotherapy, including adjuvant oxaliplatin. They had an ECOG performance status of 0 or 1.
The study randomly assigned patients with no signs of progressive disease to treatment after the sixth cycle of induction therapy. The primary endpoint was the PFS rate at 9 months after randomization. The threshold PFS rate was defined as 30%. The expected PFS rate was set at 50%, with a 90% power and a 1-sided alpha value of 0.10.
The trial randomly assigned 56 patients to modified FOLFOX6 and 57 patients to 5-FU/LV. Patients had a mean age of approximately 67 years, and one-fourth were ages 70 years and older. Most tumors were located in the colon, and approximately three-fourths were left-sided. Approximately 53% of patients had 2 or more metastatic sites.
The trial met its primary endpoint in both arms. The 9-month PFS was 46.4% (80% CI, 38.1%-54.9%; P=.0037) in the modified FOLFOX6 arm vs 47.4% (95% CI, 39.1%-55.8%) in the 5-FU/LV arm (P=.0021). The median PFS was 9.1 months (95% CI, 8.6-11.2 months) in the mFOLFOX6 arm and 9.3 months (95% CI, 6.0-13.0 months) in the 5-FU/LV arm (Figure 9). The ORR was 80.4% (95% CI, 68.0%-88.8%) vs 87.7% (95% CI, 76.4%-94.2%), respectively.
No grade 3/4 peripheral neuropathy was observed in either arm. Peripheral sensory neuropathy of any grade occurred in 5.4% of the mFOLFOX6 arm vs 5.6% of the 5-FU/LV arm. Peripheral motor neuropathy of any grade was observed in 0% vs 1.9% of patients, respectively. Peripheral neuropathy of any grade occurred in 14.3% vs 11.1% of patients, and grade 2 peripheral neuropathy was observed in 10.7% vs 1.9%.
References
1. Starobova H, Vetter I. Pathophysiology of chemotherapy-induced peripheral neuropathy. Front Mol Neurosci. 2017;10:174.
2. Nagata N, Mishima H, Kurosawa S, Oba K, Sakamoto J. mFOLFOX6 plus panitumumab versus 5-FU/LV plus panitumumab after six cycles of frontline mFOLFOX6 plus panitumumab: a randomized phase II study of patients with unresectable or advanced/recurrent, RAS wild-type colorectal carcinoma (SAPPHIRE)-study design and rationale. Clin Colorectal Cancer. 2017;16(2):154-157.e1.
3. Nakamura M, Munemoto Y, Takahashi M, et al. SAPPHIRE: a randomized phase II study of mFOLFOX6 + panitumumab versus 5-FU/LV + panitumumab after 6 cycles of frontline mFOLFOX6 + panitumumab in patients with colorectal cancer [ASCO GI abstract 729]. J Clin Oncol. 2018;36(suppl 4S).
Highlights in Metastatic Colorectal Cancer From the 2018 American Society of Clinical Oncology Gastrointestinal Cancers Symposium: Commentary
Axel Grothey, MD
Professor of Oncology
Mayo Clinic
Rochester, Minnesota
Studies at the 2018 American Society of Clinical Oncology Gastrointestinal Cancers (ASCO GI) symposium provided new insights into the management of colorectal cancer. Interesting new analyses were presented on nivolu-mab; atezolizumab plus cobimetinib; regorafenib; binimetinib, encorafenib, and cetuximab; oxaliplatin; and other treatments.
Nivolumab With or Without Ipilimumab
The CheckMate 142 study evaluated nivolumab with or without ipilimumab in patients with metastatic colorectal cancer and mismatch repair–deficient microsatellite instability (MSI) in a later-line setting.1,2 This nonrandomized study had 2 cohorts: in one, 119 patients received a combination of nivolumab and ipilimumab,2 and in the other, 74 patients received nivolumab as a single agent.1 Earlier data from this study, published in 2017, showed an overall response rate of 32% at 12.0 months of follow-up among patients treated with single-agent nivolumab, given at 3 mg/kg
every 2 weeks.3 A question was raised about the durability of these responses.
At the ASCO GI meeting, Dr Michael Overman provided an update for the monotherapy cohort, with a longer median follow-up of 21 months.1 There was a minimal increase in the response rate, to 34%. The rate of complete responses, however, increased from 3% to 9%. Longer follow-up with single-agent PD-1 antibodies suggested that the quality of the response may improve. The responses were durable. An intriguing observation is an apparent plateau in the rate of progression-free survival, starting at approximately 9 months, which reaches approximately 40% to 45%. The analysis showed that the better the overall responses, such as complete response or stable disease, the longer the overall survival. However, this finding is not unusual.
Dr Thierry André provided updated results for combination therapy.2 Nivolumab at 3 mg was given every 3 weeks with ipilimumab at 1 mg for the first 4 doses.2 Nivolumab at 3 mg was continued every 2 weeks. It is important to mention that ipilimumab was discontinued after the first 4 doses. In this analysis, the median follow-up was 13 months. The overall response rate with the combination was 55% (vs 31% with the single agent). This response rate is remarkable. The plateau for progression-free survival was at approximately 70%, which was 20% to 25% higher than that for nivolumab alone. As mentioned, the combination regimen used a short course of ipilimumab at a lower dose than that seen in other trials. The side effects, particularly grade 3/4 events, were manageable. Ipilimumab is a CTLA-4 antibody, and more toxic than the programmed death 1 (PD-1) antibody nivolumab. There were more autoimmune events with ipilimumab than nivolumab. However, at the schedule used in this trial, ipilimumab was well-tolerated.
With longer follow-up, the combination of nivolumab and ipilimumab may emerge as one of the best treatments for patients with colorectal cancer that has high MSI and is mismatch repair–deficient. It will be interesting to see how this combination works in earlier lines of treatment, particularly as compared with pembrolizumab. Nivolumab, as well as pembrolizumab, is approved for patients with mismatch repair deficient colorectal cancer. The combination of nivolumab plus ipilimumab is not yet approved.
Atezolizumab Plus Cobimetinib
Dr Johanna Bendell presented a study of atezolizumab and cobimetinib in metastatic colorectal cancer.4 Approximately 4% to 5% of patients with advanced disease are mismatch repair–deficient, and these patients are highly responsive to immunotherapy. The remaining 95% of patients with mismatch repair–proficient or microsatellite-stable tumors do not respond to immunotherapy. A goal in colorectal cancer would be to make these initially nonimmunogenic tumors immunogenic, so that these patients could benefit from immunotherapy.
In 2016, a study combining a MEK inhibitor, cobimetinib, with atezolizumab, a programmed death ligand 1 (PD-L1) antibody, showed interesting responses in a phase 1/1b cohort of 20 patients.5 The idea of combining a MEK inhibitor with a PD-L1 antibody is intriguing from a preclinical perspective. There is a higher influx of T cells in the context of MEK inhibition, where there is higher expression of MLH1 and MHC antigens. There is more immunogenicity in these cancers and in preclinical models. Among the 20 patients in the phase 1/1b cohort, 4 responded to cobimetinib and atezolizumab. The sample size was small, but the data were still intriguing because some of the responses were seen in patients with documented MSI cancers. For a few patients, the MSI status was unknown. These positive results led to an extension of this cohort, which now includes 84 patients.
At the ASCO GI meeting, Dr Bendell presented updated data for these patients.4 Unfortunately, the response rate attenuated. With the addition of 64 patients, only 3 more responses were seen. Therefore, enthusiasm for the combination of cobimetinib and atezolizumab was dampened. The phase 1/1b results also led to the phase 3 COTEZO IMblaze370 trial (A Study to Investigate Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy Versus Regorafenib in Participants With Metastatic Colorectal Adenocarcinoma), which randomly assigned patients to cobimetinib plus atezolizumab, single-agent atezolizumab, or regorafenib in the later-line setting.6 Results are expected in mid-2018. This registration study is targeting survival as the primary endpoint. It will be interesting to see whether results from the phase 1/1b study are maintained in the phase 3 study, possibly establishing a new standard of care.
Regorafenib
Several studies shed new light on the use of regorafenib. This therapy was approved for metastatic colorectal cancer in 2012, based on results from the CORRECT trial (Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy).7 There have been some concerns regarding the toxicity of regorafenib when it is used at the standard starting dose of 160 mg (4 tablets). The side effects of regorafenib, in particular hand-foot skin reaction and fatigue, arise early in the treatment course. It was postulated that starting with a lower dose that is gradually raised could mitigate some of the early side effects. This question was evaluated in the phase 3 ReDOS trial (Regorafenib Dose Optimization Study), which was presented by Dr Tanios Bekaii-Saab at the ASCO GI symposium.8 The study randomly assigned 123 patients who were candidates for regorafenib to the package insert dose of 160 mg/day or an escalated dose that started at 80 mg/day for the first week and then increased to 120 mg/day and 160 mg/day in a weekly escalation schema. The primary endpoint was those patients who completed 2 cycles, which led them to the response evaluation by imaging, and then initiated the third cycle, which captured a composite endpoint of efficacy and toxicity. Patients would go beyond the scan only if they had been able to tolerate the treatment and could continue it, and also showed some efficacy (stable disease or better).
The primary endpoint was reached. In the standard-dosing arm of 160 mg/day, only 24% of patients started cycle 3 vs 43% of patients in the escalated dose arm (P=.0281). This highly significant difference allowed patients in the escalated-dose arm to receive a longer duration of therapy. Interestingly, the secondary endpoint of overall survival showed a strong trend toward improvement, at 5.9 months with the standard dose vs 9.0 months with the escalated dose. The overall survival of 5.9 months is comparable with that in previous studies that established regorafenib as a standard-of-care later-line therapy. It is intriguing that modification of the dosing schedule to make regorafenib more tolerable and allow longer treatment might also contribute to better outcomes. It will interesting to see how this strategy will be adopted into clinical practice, and whether it will be included in guidelines.
The REVERCE trial was an interesting study from Japan that evaluated sequencing of regorafenib and an epidermal growth factor receptor (EGFR) antibody in patients with KRAS wild-type tumors.9 During the development of regorafenib, the CONCUR study (Patients With Metastatic Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy) compared regorafenib vs placebo in a fairly heavily pretreated patient population in Asia.10 Many of the patients had received treatment with biologic agents. Among patients in the CONCUR study who were less heavily pretreated, regorafenib had better efficacy than that seen in the Western CORRECT trial.7
The REVERCE study compared regorafenib followed by cetuximab vs cetuximab followed by regorafenib in approximately 100 patients.9 Overall survival favored the regorafenib-first approach, at a median of 17.4 months, compared with 11.6 months with cetuximab first (hazard ratio, 0.61; P=.029). This improvement was surprising. Breaking it down, progression-free survival was similar after the first phase of treatment with regorafenib or cetuximab. In the second phase of treatment, after patients switched therapy, cetuximab was more active than regorafenib. This finding supported previous observations that EGFR antibodies maintain their efficacy after several lines of therapy. In the United States, many physicians reserve EGFR antibodies for a later time point, and do not use them early enough, particularly with regard to the skin toxicities that can occur with these agents (and which are seen more frequently than with the vascular endothelial growth factor inhibitors, such as bevacizumab).
Binimetinib, Encorafenib, and Cetuximab
The ongoing phase 3 BEACON study (Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-Mutant Metastatic Colorectal Cancer) is evaluating whether the addition of binimetinib, a MEK inhibitor, improves outcome when added to the BRAF inhibitor encorafenib and the EGFR inhibitor cetuximab in the second-line or third-line setting.11 This study was underappreciated at the ASCO GI symposium. The study population consists of patients with BRAFV600 mutant colorectal cancer. The control arm consists of irinotecan-based therapies, such as 5-fluorouracil, LV, and irinotecan (FOLFIRI) or irinotecan plus cetuximab.
Hopefully, the results of this trial will lead to a new standard of care. Among patients with the BRAFV600 mutation, the standard of care regimen of irinotecan and cetuximab does not work well.12 The BEACON study will accrue approximately 200 patients in each arm, and it is being used as a registration study for the US Food and Drug Administration. To confirm the safety of the triplet combination of binimetinib, encorafenib, and cetuximab, the study conducted a safety lead-in phase including 30 patients, 29 of whom had tumors with the BRAFV600 mutation. (Enrollment of a patient who did not have the BRAFV600 mutation was an oversight by the investigators.) Safety and efficacy data for these 29 patients were presented at the ASCO GI symposium. Patients with BRAFV600 immune tumors have a poor prognosis, with a median survival of approximately 5 to 6 months. Few responses to treatment are seen. In the safety lead-in phase of the BEACON trial, none of the patients treated with the triplet therapy developed progressive disease. The response rate was more than 45%, and the median progression-free survival was 8 months. These data are very intriguing. Several of the patients continue to receive therapy more than a year after initiation of treatment, which is impressive in this setting. I am hopeful that this regimen will emerge as a standard of care.
These results are reminiscent of those from the randomized SWOG 1406 study, which Dr Scott Kopetz presented at the 2017 ASCO GI symposium.12 This study combined a BRAF inhibitor, vemurafenib, with the standard chemotherapies cetuximab and irinotecan. The use of an EGFR inhibitor in this setting, where BRAF is also inhibited, is mainly to block a feedback loop in which the MAP kinase pathway is inhibited by the BRAF inhibitor. The cancer cells try to reactivate the MAP kinase pathway by increasing agents of the signaling. This is where EGFR antibodies have a role. The efficacy data of the SWOG 1406 trial do not match the efficacy seen in the safety lead-in phase of the BEACON study.
Oxaliplatin
The randomized phase 2 SAPPHIRE study (Safety and Efficacy Study of mFOLFOX6 + Panitumumab Com-bination Therapy and 5-FU/LV + Panitumumab Combination Therapy in Patients With Chemotherapy-Naïve Unresectable Advanced Rec-urrent Colorectal Carcinoma) examined the duration of oxaliplatin-based therapy in patients with KRAS wild-type cancers who are first treated with FOLFOX plus panitumumab.13 The study randomly assigned 114 patients to modified FOLFOX plus panitumumab, with oxaliplatin discontinued after 6 cycles (meaning after 12 weeks of therapy), or to continuation of the modified FOLFOX plus panitumumab combination regimen for another 6 cycles. The idea behind the study was to evaluate whether the combination of panitumumab plus fluorouracil/leucovorin without oxaliplatin is as effective in maintaining the response achieved in the early phase of the induction treatment with the combination therapy.
Interestingly, when oxaliplatin was omitted from therapy after 6 cycles, there was no decrease in progression-free survival. In a Kaplan-Meier analysis, the progression-free survival curves almost completely overlapped. Therefore, it is safe to eliminate oxaliplatin from treatment. It is possible to maintain response with a combination of fluorouracil, leucovorin, and panitumumab in patients with RAS wild-type tumors. This finding is important because it allows us to potentially use oxaliplatin later and not treat patients to neurotoxicity, which is very much in line with the induction-maintenance approach,14 which we have been using for patients treated with FOLFOX/CAPOX plus bevacizumab.
Disclosure
The Mayo Clinic Foundation has received honoraria for consulting activities by Dr Grothey from Bayer, Genentech, ARRAY, Taiho, Boston Biomedical, and Eisai.
References
1. Overman MJ, Kopetz S, McDermott RS, et al. Nivolumab in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): long-term survival according to prior treatment from CheckMate-142 [ASCO GI abstract 554]. J Clin Oncol. 2018;36(suppl 4S).
2. André T, Lonardi S, Wong M, et al. Nivolumab + ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): first report of the full cohort from CheckMate-142 [ASCO GI abstract 553]. J Clin Oncol. 2018;36(suppl 4S).
3. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):
1182-1191.
4. Bendell JC, Bang YJ, Chee CE. A phase Ib study of safety and clinical activity of atezolizumab (A) and cobimetinib (C) in patients (pts) with metastatic colorectal cancer (mCRC) [ASCO GI abstract 560]. J Clin Oncol. 2018;36(suppl 4S).
5. Bendell JC, Kim TW, Goh BC, et al. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC) [ASCO abstract 3502]. J Clin Oncol. 2017;34(suppl).
6. ClinicalTrials.gov. A study to investigate efficacy and safety of cobimetinib plus atezolizumab and atezolizumab monotherapy versus regorafenib in participants with metastatic colorectal adenocarcinoma. https://clinicaltrials.gov/ct2/show/NCT02788279. Identifier: NCT02788279. Accessed February 20, 2018.
7. Grothey A, Van Cutsem E, Sobrero A, et al; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312.
8. Bekaii-Saab T, Ou FS, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)—an ACCRU Network study [ASCO GI abstract 611]. J Clin Oncol. 2018;36(suppl 4S).
9. Shitara K, Yamanaka T, Denda T, et al. REVERCE: randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for metastatic colorectal cancer patients previously treated with fluoropyrimidine, oxaliplatin, and irinotecan [ASCO GI abstract 557]. J Clin Oncol. 2018;36(suppl 4S).
10. Li J, Qin S, Xu R, et al; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16(6):619-629.
11. Cutsem E, Cuyle P-J, Huijberts S, et al. CRC study safety lead-in in patients with BRAFV600E metastatic colorectal cancer: efficacy and tumor markers [ASCO GI abstract 627]. J Clin Oncol. 2018;36(suppl 4S).
12. 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) [ASCO GI abstract 520]. J Clin Oncol. 2018;36(suppl 4S).
13. Nakamura M, Munemoto Y, Takahashi M, et al. SAPPHIRE: a randomized phase II study of mFOLFOX6 + panitumumab versus 5-FU/LV + panitumumab after 6 cycles of frontline mFOLFOX6 + panitumumab in patients with colorectal cancer [ASCO GI abstract 729]. J Clin Oncol. 2018;36
(suppl 4S).
14. 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(9980):1843-1852.