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ROLE OF BIOLOGICS IN FIRST-LINE TREATMENT OF mCRC
Sonia Esparza, MDUniversity of North Carolina at Chapel Hill, NC
October 18 th, 2019
DISCLOSURE
Dr. Sonia Esparza does not have any relevant financialrelationship to disclose
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PATIENT CASE
• 67 year old male with a history of DM who presented with progressive fatigue and dyspnea on exertion over several months. ECOG 1
– Labs: Hg 4.7 and he received 5 units pRBCs
– EGD: Barretts esophagus and esophageal ulcers with possible gastric varices, no obstruction
– Colonoscopy: oozing, partially obstructing rectal mass
– Staging scans: multiple pulmonary nodules and an enlarged paraaortic node in addition to the primary rectal mass
• FoundationOne for KRAS, NRAS, BRAF, HER-2, and MSI
– WT in KRAS, NRAS, and BRAF. HER-2 negative
– MS-stable
• Treatment
– FOLFIRI Cycles 1-2, then FOLFIRI + panitumumab starting Cycle 3
• Follow Up
– Completed 24 cycles of FOLFIRI + panitumumab and recent CT C/A/P with stable disease
CT, computerized tomography; C/A/P, chest abdomen pelvis; DM, diabetes mellitus; ECOG, Eastern Co-operative Oncology Group; EGD, esophagogastroduodenoscopy; FOLFIRI, irinotecan, fluorouracil and folinic acid; HER-2, human epidermal growth factor receptor 2; Hg, mercury; MSI, microsatellite instability; MSS, microsatellite stable; pRBCs, packed red blood cells; WT, wild-type; CT C/A/P, computed tomographic chest abdomen pelvis
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TREATMENT SELECTION
• Patient characteristics
– comorbidities
– performance status
• Biomarker analysis
– BRAF, NRAS, KRAS, HER-2 status can help determine if patients qualify for EGFR or VEGF inhibitors
• Sidedness
– left sided vs right sided
• Side effects
– diarrhea, delayed wound healing, hypertension, thrombosis
EGFR, epidermal growth factor receptor; HER-2, human epidermal growth factor receptor 2; VEGF, vascular endothelial growth factor 4
EGFR INHIBITORS
• Epidermal growth factor receptor (EGFR) inhibitors
• Benefit in left-sided BRAF/RAS WT tumors
• Similar efficacy between cetuximaband panitumumab
• Who will not benefit from EGFR inhibitors:
– RAS mutations (55% of patients)
• KRAS and NRAS exons 2, 3, and 4
– BRAF V600E mutations (5-10%)
– HER-2 amplification (2%)
– Right side colonic tumors
EGFR, epidermal growth factor receptor; HER-2, human epidermal growth factor receptor 2; WT, wild-type;
Source: Leto, S.M. & Trusolino, L. J Mol Med (2014) 92: 709. https://doi.org/10.1007/s00109-014-1161-2 5
EGFR INHIBITORS
Cetuximab
• Chimeric mouse/human antibody
• 400 mg/m2 IV initial loading dose, then 250 mg/m2 weekly
• Alpha-gal reaction
• Side Effects:
– Monotherapy (incidence >25%): cutaneous adverse reactions (rash, pruritis, nail changes), headache, diarrhea, and infection
– With irinotecan: Grade 3-4 include diarrhea (22%) leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%)
• Monotherapy:
– One U.S. Phase II trial
– Showed single-agent response of ~10%1
• Combined:
– One Phase II Trial irinotecan + cetuximab vs cetuximab
– Rate of response on combined 22.9% vs 10.8% with monotherapy2
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EGFR, epidermal growth factor receptor; FOLFOX, folinic acid, fluorouracil and oxaliplatin; IV, intravenous; OS, overall survival; WT, wild-type
1. Saltz, et al. JCO 2004; 2. Cunningham, et al. NEJM 2004; 3. Van Cutsem, et al. JCO 2007; 4. Douillard, et al. JCO 2010;5. Source: US PI Cetuxima (version 2019) and US PI Panitumumab (version 2017)
Panitumumab• Human antibody
• 6 mg/kg IV every 14 days
• Side Effects:
– Monotherapy (>20%): skin rash, paronychia, fatigue, nausea, and diarrhea
– With FOLFOX (>20%): diarrhea, stomatitis, asthenia, anorexia, and rash
• Monotherapy:
– Large international Phase III trial
– Showed single-agent response of ~10%similar to cetuximab3
• Combined:
– PRIME Phase III FOLFOX + panitumumabvs FOLFOX
– Median OS was improved in WT KRASFOLFOX+ panitumumab compared topanitumumab (23.9 v 19.7 months)
– In mutant KRAS, median OS was significantly reduced in panitumumab +FOLFOX v panitumumab (15.5 v 19.3 months)4
VEGF INHIBITOR- BEVACIZUMAB
• Bevacizumab
– A recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF)
– Dosing: 5 or 10mg/kg every two weeks
– Side effects:
• Hypertension, proteinuria, bleeding, gastrointestinal perforations (2.4%), impaired surgical wound healing, and arterial and possibly venous thrombotic events
– Combined:
• Large Phase III, 813 patients1
Irinotecan/fluorouracil/LV (IFL) vs IFL + Bevacizumab
Addition of Bev increased RR (44.8% v 34.8%), PFS (10.6 v 6.2 months), and median OS (20.3 v 15.6 months)
• FIRE-3, Phase III, 592 patients2
KRAS exon 2 WT to receive FOLFIRI + cetux vs FOLFIRI+ Bev
• Primary endpoint of response rate not reached, no difference in PFS
• Difference in median OS of 3.7 mo(p=0.017) in favor of +cetux
Bev, bevacizumab; cetux, cetuximab; FOLFIRI, folinic acid, fluorouracil and oxaliplatin; IFL, irinotecan, 5-fluorouracil and folinic acid.; LV, leucovorin; OS, overall survival; PFS, progression free survival; RR, response rate; VEGF, vascular endothelial growth factor1. Hurwitz, et al. NEJM 2004; 2. Heinemann, et al. Lancet Oncol 2014. Source: US PI Bevacizumab (version 2018) .- source figure: Bupathi et al. 2016
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KEY POINTS
• Consider adding biologics in patients with a good performance status
• EGFR (cetuximab/panitumumab) and VEGF (bevacizumab) inhibitors are equivalent choices in the first-line metastatic setting, thus consider mutation status and tumor sidedness when choosing between them
• Patients with a left-sided, wild-type RAS and BRAF, and HER-2 negative tumor, will benefit from EGFR inhibitors
– avoid cetuximab in patients who harbor IgE antibodies to alpha-gal that lead to hypersensitivity reactions
– avoid EGFR inhibitors if patient has underlying diarrhea or electrolyte abnormalities
• If unable to use EGFR inhibitors, opt for bevacizumab
– avoid in patients with concern for gastrointestinal perforation, need for urgent surgery, significant cardiac disease, or bleeding/thrombotic disorders
EGFR, epidermal growth factor receptor; HER-2, human epidermal growth factor receptor; IgE, immunoglobulin E; VEGF, vascular endothelial growth factor 8
ROLE OF BIOLOGICS IN FIRST-LINE TREATMENT OF mCRC
SYED MOHAMMAD ALI KAZMI, MDAssistant Professor
Division of Hematology and OncologyDepartment of Internal Medicine
University of Texas Southwestern Medical Center Simmons Comprehensive Cancer Center
Dallas, TX
October 18 th, 2019
DISCLOSURE
Dr. Syed Mohammad Ali Kazmi does not have any relevant financial relationship to disclose.
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BIOLOGICS IN FIRST-LINE TREATMENT FOR mCRC• Current paradigm of first-line treatment:
Chemotherapy (FOLFOX or FOLFIRI) + biologic targeting VEGF or EGFR
• Recent data suggest that primary tumor location may have different outcomes with the choice of biologic agent in first-line mCRC treatment1
EGFR, epidermal growth factor receptor; FOLFOX, folinic acid, fluorouracil and oxaliplatin; FOLFIRI, irinotecan, fluorouracil and folinic acid; mCRC, metastatic colorectal cancer; VEGF, vascular endothelial growth factor1Lee GH, et al. Eur J Surg Oncol 2015; 41:300-308
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Left-sided CRC Right-sided CRC
Location of CRC
Distal to the spleen flexure Proximal to the splenic flexure
Characteristics • Males• Have predominant alteration in
chromosomal instability pathway-related mutations, such as KRAS, APC, PIK3CA, p53 mutations
• Have polypoid-like morphology
• Females• Elderly• Have microsatellite instability• RAS and BRAF mutations• CpG island methylator
phenotype• Mucinous histology
ANTI- EGFR AND ANTI- VEGF MAB IN FIRST-LINE TREATMENT FOR mCRC
• EGFR inhibitors (cetuximab and panitumumab) and VEGF pathway inhibitors (bevacizumab) have demonstrated benefit in the first-line in combination with cytotoxic chemotherapy in several studies1–3
• The phase III multicenter prospective CALGB/SWOG 80405 clinical trial examined first-line chemotherapy in combination with either bevacizumab or cetuximab4
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CALGB, Cancer and Leukemia Group B; CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; mAb, monoclonal antibody; mCRC, metastatic colorectal cancer; OS, overall survival; SWOG, Southwest Oncology Group; VEGF, vascular endothelial growth factor1Saltz LB, et al. J Clin Oncol. 2008;26(12):2013-2019; 2 Douillard J Y, et al. Annals of Oncology. 2014; 25(7): 1346-1355; 3Heinemann V, et al. Lancet Oncol. 2014;15(10):1065-1075; 4Venook AP, et al.. JAMA. 2017;317(23):2392-2401.
Chemotherapy + cetuximab
Chemotherapy + bevacizumab
Overall survival 30.0 months 29.0 monthsStratified HR, 0.88; 95% CI, 0.77-1.01; p=0.08
OVERALL SURVIVAL AMONG PATIENTS RANDOMIZED TO FIRST-LINE CHEMOTHERAPY+ CETUXIMAB OR FIRST-LINE CHEMOTHERAPY+ BEVACIZUMAB
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CI, confidence interval; HR, Hazard ratio; mo, months; OS, overall survival1Venook AP, et al. JAMA. 2017;317(23):2392-2401.
This study failed to show a significant difference between OS when comparing bevacizumab to cetuximab1
PRIMARY TUMOR LOCATION: PROGNOSTIC IN FIRST-LINE mCRC• An analysis of CALGB/SWOG80405 stratified clinical outcomes by primary
tumor location – Overall survival for all patients
• Left-sided primary vs. right sided primary: 34.2 months vs. 19.4 months (P
PRIMARY TUMOR LOCATION: PREDICTIVE OF RESPONSE TO BIOLOGICS IN FIRST-LINE mCRC TREATMENT
• Subsequent analysis of CALGB/SWOG80405 stratified clinical outcomes by
biologics and primary tumor location in KRAS wt (n=1025)1
– Overall survival
• Left sided primary: Cetuximab 36.0 months vs. Bevacizumab
31.4 months (p=0.018)
• Right sided primary: Cetuximab 16.7 months vs. Bevacizumab
24.2 months (p=0.065)
• Retrospective analysis of CRYSTAL and FIRE-33 trials also showed similar
findings2
151Venook AP, et al. American Society of Clinical Oncology. 2016 (abstract 3504); 2Tejpar S, et al. JAMA Oncol. 2017;3(2):194-201; 3Heinemann, V., et al. Lancet Oncol, 15(10), 1065-1075
Overall survival
CRYSTAL FIRE-3
FOLFIRI+cetuximab
FOLFIRI FOLFIRI+cetuximab
FOLFIRI+bevacizumab
Left-sided tumors 28.7 months 21.7 months 38.3 months 28.0 months
Right-sided tumors 18.5 months 15.0 months 18.3 months 23.0 months
16EGFR, epidermal growth factor receptor; mAb, monoclonal antibody; mCRC, metastatic colorectal cancer; VEGF, vascular endothelial growth factor
• Primary tumor location is prognostic in first-line treatment in mCRC
• During first-line treatment combination of biologics with chemotherapy in first-line treatment should be the standard.
• The decision about the choice of biologics should be stratified according to primary tumor location and after discussing efficacy and side effects of biologics.
• Combination of biologics with chemotherapy such as anti EGFR mAb(cetuximab or panitumumab) should be a preferred option of RAS wild-type left-sided mCRC
• For right-sided or RAS mutated mCRC, anti-VEGF mAB (bevacizumab) is favored biologic agent
CONCLUSIONS
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