Precision Approaches in the Management of Colorectal Cancer: Current Evidence and Latest Advancements towards Individualizing the Treatment
Abstract
:Simple Summary
Abstract
1. Introduction
2. Signaling Pathways and Therapeutic Targets
2.1. RAS and EGFR
2.2. Microsatellite Instability (MSI), Mismatch Repair (MMR), and Immune Checkpoint Inhibitors
2.3. BRAF
2.4. VEGF
2.5. HER2
2.6. PI3KCA
3. Novel Therapeutic Modalities
3.1. Oncolytic Viruses
3.2. CAR T-Cell
4. Platforms for Personalized Approach
5. Conclusions and Future Directions
Funding
Conflicts of Interest
References
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Signaling Pathway | Approved Targeted Therapy | Mechanism of Action | Indication |
---|---|---|---|
EGFR RAS/RAF/ERK | Cetuximab Panitumumab | anti-EGFR MoAb | RAS/BRAF wt mCRC (preferred 1st line for left-sided tumors) |
MMR | Pembrolizumab Nivolumab | ICI-Anti PD-1 MoAb Anti PD-1 MoAb | dMMR/MSI-H mCRC |
RAS/RAF/ERK | Encorafenib | BRAF kinase inhibitor | mCRC with BRAF V600E mutation |
VEGF | Bevacizumab Regorafenib Ramucirumab Aflibercept | anti-VEGF MoAb anti-VEGF-R anti-IgG1 MoAb Recombinant fusion (VEGFR-1/2 & IgG1) | (Bev.) first-line regimen for unresectable metachronous mCRC; mCRC which has progressed with standard treatment |
EGFR 2 (HER2) | Trastuzumab Lapatinib | Anti-HER2 MoAb TKI (anti-EGFR1/HER2) | HER2-overexpressed CRC after failing 1st line |
Study | NCT02060188 (Checkmate-142) * | NCT01876511 * | NCT02460198 (KEYNOTE-164) * |
---|---|---|---|
Phase | II | II | II |
Population | 74 recurrent or metastatic CRC patients with confirmed dMMR or MSI-H | 41 patients with progressive mCRC regardless of MMR/MSI status or patients with other metastatic carcinoma known to have dMMR or MSI-H | 124 mCRC patients with confirmed dMMR or MSI-H, cohort A was treated with ≥2 prior therapies, cohort B treated with ≥1 prior therapy |
Treatment arms, prescribed regimen(s) | Nivolumab 3 mg/kg every 2 weeks | Pembrolizumab 10 mg/kg every 2 weeks | Pembrolizumab 200 mg every 3 weeks for up to 2 years |
Primary endpoint(s) | Objective response rate (ORR) | ORR and PFS | ORR |
Response rate, progression free survival and overall survival | ORR 68.9%, PFS 50% at 12 months, OS 73.4% at 12 months | ORR 40%, median PFS and median OS not reached at 12 months in dMMR/MSI-H mCRC patients | ORR 33% for both cohorts, median PFS was 2.3 months (cohort A) and 4.1 months (cohort B), median OS was 31.4 months (cohort A) and not reached at 27 months in cohort B |
Grade 3 and 4 adverse events | Elevated lipase (8.1%), elevated amylase (2.7%) | Rash/pruritus (24%), hypothyroidism or other thyroid concerns (10%), pancreatitis (15%) | Grade 3–4 adverse events (16% cohort A, 13% cohort B) including colitis, hepatitis, pancreatitis, pneumonitis, skin reactions, arthralgias, asthenia and fatigue |
Other significant findings | Patients with at least partial response had 12.8% greater decline in CEA level compared to patients with stable disease | There was a mean of 1782 somatic mutations per tumor in patients with dMMR or MSI-H | 18% (cohort A) and 11% (cohort B) of participants had RAS/BRAF wt tumors |
Study | NCT03202758 * | NCT04262687 * | NCT03832621 * |
---|---|---|---|
Phase | I/II | II | II |
Condition/Disease/Population | Will include mCRC 48 patients with microsatellite stable (MSS), RAS mutant tumors. Actively recruiting and data not yet available | microsatellite stable mCRC patients with high immune infiltrate | Microsatellite stable, MGMT silenced mCRC |
Intervention | Phase I: Durvalumab 750 mg every 2 weeks plus Tremelimumab 75 mg every 4 weeks plus FOLFOX during the 2 first cycles of treatment (1 month) Phase II: Durvalumab 750 mg every 2 weeks plus Tremelimumab 75 mg every 4 weeks plus FOLFOX | Drug: Capecitabine 2000 mg/m2/day, from day 1 to 14 of each cycle, Drug: Oxaliplatin 130 mg/m2 by IV infusion over 2 h, on day 1 of each cycle, Drug: Bevacizumab 7.5 mg/kg by IV infusion over 60 min, on day 1 of each cycle, Drug: Pembrolizumab 200 mg by IV infusion over 30 min, on day 1 of each cycle | Drug: Temozolomide 150 mg/sqm daily on days 1–5 every 4 weeks, Drug: Nivolumab 480 mg IV every 4 weeks, Drug: Ipilimumab (low-dose) 1 mg/Kg IV every 8 weeks |
Endpoints | Safety (after Phase I) and Efficacy (after Phase II) | Assessing efficacy of pembrolizumab in combination with xelox and bevacizumab as first-line treatment for microsatellite stable (non MSI-H) mCRC | 8-month PFS after treatment with combination of temozolomide, nivolumab and ipilimumab |
Enrollment (total, open: yes/no) | 48, Yes | 55, Not yet | 100, Yes |
Study | NCT04301011 * | NCT01394939 | NCT01274624 * | NCT03206073 * | NCT03225989 * |
---|---|---|---|---|---|
Phase | I/II | I/II | I | I/II | I/II |
Condition/Disease | Solid tumor, triple negative breast cancer, microsatellite stable colorectal cancer | Metastatic, refractory colorectal carcinoma | KRAS Mutant Metastatic Colorectal Cancer | Colorectal Cancer | Pancreatic adenocarcinoma; Ovarian cancer; Biliary carcinoma; Colorectal cancer |
Intervention | Biological: TBio-6517, Pembrolizumab | Biological: JX-594, Irinotecan | Biological: REOLYSIN, Drug: Irinotecan, Drug: Leucovorin, Drug: Fluorouracil (5-FU), Drug: Bevacizumab | Biological: Pexa-Vec, Drug: Durvalumab, Drug: Tremelimumab | Drug: Load703 (oncolytic adenovirus serotype 5/35 encoding immunostimulatory transgenes: TMZ-CD40L and 41BBL) |
Enrollment (total, open: yes/no) | 84, not yet | 52, Completed | 36, Completed | 35, Open | 50, Open |
Study | NCT03542799 * | NCT03692429 * | NCT03152435 * | NCT04348643 * | NCT03638206 * |
---|---|---|---|---|---|
Phase | I/II | I | I/II | I/II | I/II |
Condition Disease | Metastatic colorectal cancer (mCRC) | Colorectal Cancer | EGFR-positive Colorectal Cancer | Solid tumor, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer | Hematologic malignancies; HCC; Gastric Cancer; Pancreatic Cancer; Mesothelioma; Colorectal Cancer; Esophagus Cancer; Lung Cancer; Glioma; Melanoma; Synovial Sarcoma; Ovarian Cancer; Renal Carcinoma |
Intervention | EGFR IL 12 CAR T-cells | Allogeneic CAR T-cells, CYAD-101 | Biological: EGFR CAR T-cells | Biological: CEA CAR-T cells | Biological: CAR-T cell immunotherapy |
Enrollment (total, open: yes/no) | 20, not yet | 36, yes | 20, unknown | 40, not yet | 73, open |
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Shuford, R.A.; Cairns, A.L.; Moaven, O. Precision Approaches in the Management of Colorectal Cancer: Current Evidence and Latest Advancements towards Individualizing the Treatment. Cancers 2020, 12, 3481. https://doi.org/10.3390/cancers12113481
Shuford RA, Cairns AL, Moaven O. Precision Approaches in the Management of Colorectal Cancer: Current Evidence and Latest Advancements towards Individualizing the Treatment. Cancers. 2020; 12(11):3481. https://doi.org/10.3390/cancers12113481
Chicago/Turabian StyleShuford, Rebecca A., Ashley L. Cairns, and Omeed Moaven. 2020. "Precision Approaches in the Management of Colorectal Cancer: Current Evidence and Latest Advancements towards Individualizing the Treatment" Cancers 12, no. 11: 3481. https://doi.org/10.3390/cancers12113481