Disclaimer I do not have any financial conflicts to disclose. I will not be promoting any service or product. This presentation is not meant to offer medical advice and is not intended to establish a standard of care.
Objectives Briefly summarize the current state of colorectal cancer Briefly summarize the current standard of care for the management of colorectal cancer Highlight some of the most promising clinical trials in the areas of screening, preventing and treating colorectal cancer that may soon enter the clinical practice and even become the new standard of care
This day in history March 3, 1847
This day in history Alexandar Graham Bell Invented the telephone founding the American Telephone and Telegraph Company (AT&T) in 1885 Invented the metal detector March 3, 1847
Colorectal cancer facts
Colorectal cancer facts In 2017, There were an estimated 95,520 new cases of colon cancer and 39,910 cases of rectal cancer diagnosed in the US. The number of colon cancer is fairly equal in men and women but a large number of men (23,720) than women (16,190) was diagnosed with rectal cancer. About 4.6% of men (1 in 22) and 4.2% of women (1 in 24) will be diagnosed with colorectal cancer in their lifetime.
Colorectal cancer facts As of January 1, 2016, there were 724,690 men and 727,350 women alive in the US with a history of colorectal cancer. Some of these people were cancer free while others with active disease and undergoing therapy. Median age for colon cancer is 68 years of age in men and 72 in women Median age for rectal cancer is 63 years of age in both men and women
Colon cancer treatment
Colon cancer treatment
Rectal cancer treatment
Rectal cancer treatment
Rectal cancer treatment
Clinical trials in colorectal cancer Currently there is over 340 active clinical trials in the U.S. For nearly 40 years, the main drug used was the fluoropyrimidine, 5- fluorouracil (5-FU). Since the turn of the century 3 new chemotherapies have been approved by the FDA: Irinotecan, oxaliplatin, and capecitabine (oral fluoropyrimidine ). Since 2004, 6 biologic agents have been approved by the FDA: Anti vascular endothelial growth factor (VEGF) bevacizumab, ramucirumab & Aflibercept Anti epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab, A multikinase small molecule inhibitor regorafenib
Innovative way for colorectal cancer screening
Circulating tumor cells for colorectal cancer screening Presented in the 2018 ASCO gastrointestinal cancers symposium. A single center prospective blinded clinical study in 620 subjects including 438 with adenoma, polyps or stage I-IV CRC + 182 healthy controls 2 ml of peripheral blood collected and tested by CellMax biomimetic platform. Disease status was evaluated by standard clinical protocol which included colonoscopy and biopsy results.
Circulating tumor cells for colorectal cancer screening Subject (size) Subgroup (Size, %) Sensitivity (95% CI) Specificity (95% CI) AUC All (620) Healthy (182, 29%) Diseased ( 438, 71%) 84.0 (80.3-87.2) 97.3 (93.7-98.8) 0.87 Diseased (438) Precancerous lesions (111, 25%) Cancer (327, 75%) 76.6 (67.9-83.5) 86.9 (82.8-90.1) 97.3 (93.7-98.8) 97.3 (93.7-98.8) 0.84 0.88 The CellMax test overall accuracy was 88% for all stages of colorectal illness, including precancerous lesions
Chemoprevention of colorectal cancer
Eflornithine is an ODC enzyme inhibitor. ODC is an important enzyme in the polyamine synthesis pathway. Polyamine synthesis pathway is a cause of colon carcinogenesis. Sulindac is an NSAID (non selective cyclooxygenase inhibitor). Pilot phase IIa and IIb trials have showed that eflornithine reduces polyamine content in colorectal tissue. A considerable amount of experimental literature supports the notion that NSAIDs can prevent the development of colon adenomas and cancer.
Phase III double blind trial in 375 patients with resected adenomas. Randomly assigned to 36 months of difluoromethylornithine + Sulindac vs placebo Colonoscopy at 3 yrs from randomization Placebo group Prevention group Recurrence of adenoma 41.1% 12.3% Advanced adenoma 8.5% 0.7%
Treatment of colorectal cancer
Checkpoint inhibitors
DNA mismatch repair deficiency (dmmr) Two primary pathways of colon ca have been described and include tumors with chromosomal instability or deficient DNA mismatch repair resulting in microsatellite instability Microsatellite instability (MSI) is the condition of genetic hypermutability (predisposition to mutation) that results from impaired DNA mismatch repair. Sporadic in origin in 2/3 of cases and hereditary in 1/3 due to Lynch Syndrome 10-15% of stage III colon ca are MSI-H 5% of stage IV colon ca are MSI-H
Microsatellite instability (MSI) MSI-H colon cancers hypermutation results in production of mutant proteins and expression of abundant neoantigens. MSI-H colon cancers are typically right-sided, poorly differentiated and contain abundant tumor infiltrating lymphocytes (TILs). They have also shown overexpression of immune checkpoint proteins. With abundant lymphocytes, overexpression of immune checkpoint proteins and abundant mutant proteins and neoantigens they can elicit an enhanced immune response.
A phase II study of single agent anti-pd-1 antibody, pembrolizumab, in 41 patients with dmmr CRCs, pmmr CRCs, and dmmr cancers that were not CRCs. Median PFS for pmmr CRCs 2 months and median OS 5 months. dmmr CRCs PFS at 24 months was 61% and OS at 24 months was 66%. Pembrolizumab has been approved for patients with MSI-H or dmmr mcrc that has progressed on multiple lines of chemotherapy
CheckMate 142 Largest single study of immunotherapy combination in dmmr/msi-h mcrc
This is a phase III trial that is trying to change the current standard of care. 35-40% of colon ca patients have stage III disease at diagnosis. ~30-50% will develop cancer recurrence despite curative-intent surgery & adjuvant chemotherapy. 10-15% of stage III colon ca are dmmr/msi-h. Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 on immune cells and/or tumor cells and prevents interaction with either PD-1 receptor or B7.1 (CD80), both of which function as inhibitory receptors expressed on T cells.
Several preclinical studies indicate that certain chemotherapeutic agents can have an immunostimulatory effect. Oxaliplatin can alter tumor immune status to transiently increase inflammation. This so called immune priming may extend the inflammatory state to achieve enhanced and more durable responses to immunotherapies. Primary Objective Improvement in disease free survival Secondary Objectives Improvement in overall survival Assess the adverse events profile and safety of combination therapy
Vascular endothelial growth factor (VEGF), specifically VEGF-A, produced in the tumor microenvironment enhances expression of PD-1 and other inhibitory checkpoints proteins. The combination of anti-pd-l1 antibodies with VEGF-A blockade induced a strong and synergistic antitumor effect in tumors producing high levels of VEGF-A in murine models
Primary Objective PFS of combination & single agent therapies vs standard therapy. Secondary Objectives Overall survival Objective response rates The safety profiles of the combination therapy To compare the surgical conversion rate To compare disease control rate (CR + PR + SD) at 12 months. To determine the duration of response and stable disease
This day in history! March 3, 1845? becomes the 27th U.S. state.
HER-2 is amplified/overexpressed in 3-4% of of mcrc. HER-2 amplification is more seen in KRAS wild type (~4-5%) as compared to KRAS mutated group (1%). HER-2 amplification was shown to be an important mechanism of cetuximab resistance in mcrc patients Her2 amplified Her2 non amplified Retrospective study of 170 mcrc patients treated with anti EGFR + chemo, 4% with Her2 amplified Median PFS 2.5 months 6.7 months Median OS 4.2 months 13 months A cohort of 233 mcrc patients treated with anti EGFR + chemo, 5.5% with Her2 amplified Median PFS 2.9 months 5 months
A Phase II study of trastuzumab in combination with irinotecan in HER-2 overexpressed mcrc refractory to first-line therapy showed partial responses in 70% cases. Putting this data together, It seems that HER-2 amplification can be a negative predictor of response to EGFR inhibition and a positive predictor of response to HER-2-targeting agents. This trial hypothesize that dual anti-her-2 inhibition using monoclonal antibodies, trastuzumab and pertuzumab, will result in enhanced tumor suppression resulting in improved outcomes compared to therapy with cetuximab and irinotecan
Primary objective: Progression free survival Secondary objectives: Overall response rate Overall survival Toxicity of TP vs CETIRI
End points in clinical trials has been historically PFS or OS. These endpoints require long term follow-up, resulting in a slow pace of scientific progress in clinical research. Finding a short-term endpoints to serve as surrogates for PFS and OS would enable more rapid determination of success or failure of an experimental intervention. This will facilitate more scientific discovery and progress leading to clinical practice improvements
Velaparib is a PARP inhibitor In preclinical studies, it has been observed that PARP pathway inhibition leads to extreme sensitivity to high doses of gamma-radiation. This observation suggests that PARP inhibitors would sensitize cells to radiation.
Preclinical data showed that adding Velaparib to 5FU or Capecitabine during radiation has synergestic effect when compared to 5FU or capecitabine alone Phase I study of veliparib with capecitabine and RT in locally advanced rectal cancer 73% of patients had histologic downstaging at the time of surgery, including 28% pcr 28% of patients experienced grade 3 of 4 AE with diarrhea (9%) being the most common. There were no surgical complications attributed to the treatment.
Neoadjuvant chemotherapy in locally advanced rectal cancer
Why rock the boat!!
Other reasons Combined modality therapy is associated with considerable toxicity, which is seen in up to 50% of patients Autonomic nerve injury causing increased fecal incontinence, and frequency, and higher rates of bladder and sexual dysfunction Bone marrow suppression affecting the ability to withstand subsequent myelosuppressive therapy These toxicities lead to approximately 50% of patients unable to receive the planned postoperative chemotherapy doses
Primary objective: Time to Local Recurrence Disease-free Survival Secondary objectives: Overall survival pathologic complete response Adverse events & surgery complications between two groups
Summary CTCs detected by CellMax platform is a promising screening tool with high accuracy for CRC and high risk adenoma. Sulindac + Eflornithine is a promising combination for chemoprevention of CRC and high risk adenomas with acceptable toxicity profile. Checkpoint inhibitors have significant activity and durable responses in dmmr/msi-h CRC and are promising options to be incorporated in the adjuvant and first line setting. Her2 amplification in CRC may predict resistance to anti-egfr antibodies and may predict favorable response to Anti-Her2 antibodies.
Summary NAR score is a promising short term endpoint that serve as a surrogates for PFS and OS and seems more practical/predictable than pcr. PARP inhibitors are a promising radiosensitizer agents in rectal cancer Neoadjvuant systemic chemotherapy in locally advanced rectal cancer may save a subset of patients from the toxicities of concurrent chemoradiation while providing similar local control rates.
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