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dostlimumabA monoclonal antibody that blocks the receptor for programmed cell death protein 1 (PD-1) replaces it Anti-PD-1 Treatmenthas been shown to be able to achieve a Complete clinical response in locally advanced rectal cancer With the lack of mismatch repair. And the most recent thing is that the answer has been received special drug administrationwithout radiation or surgery, as noted Andrea CercekA medical oncologist at Memorial Sloan Kettering Cancer Center in New York, United States, whose team has presented the results of their work at the American Society of Clinical Oncology (ASCO22) meeting to be held in Chicago, United States. latest issue of The New Journal of Medicine of England (NEJM),
Neoadjuvant chemotherapy And this radiation afterwards surgical resection Rectal cancer is often the standard, multimodal treatment for locally advanced rectal cancer. Within this, a subset a . Due to this Failure to repair misalignmentCertain genes carry information that tells the cells of the body how to function and helps repair of a specific type of damage in DNA through a process called mismatch repair.
It is estimated that between 5 and 10% rectal adenocarcinoma is lacking error correction pairing and it has been shown that these tumors respond poorly to chemotherapy regimens Standard, including neoadjuvant chemotherapy in locally advanced rectal cancer. But, it is also seen that self-imposed blockade of defense checkpoints It is highly effective as a first-line treatment for patients with metastatic colorectal cancer For patients with poor mismatch repair as well Refractory disease to treatObjective response rates ranging from 33% to 55%, with clinically significant duration of response and prolonged overall survival, are discussed in the article.
“Based on the observed benefits in the setting of metastatic disease, we hypothesized that blockade of programmed death 1 (PD-1) with only one agent can be beneficial in locally advanced rectal cancer and poor at mismatch repair,” Cercek says.
To do this, the researchers began a prospective phase 2 study in which the anti-PD-1 monoclonal antibody dostarlimab was administered as a single agent. every 3 weeks for 6 months in patients with rectal adenocarcinoma Phase II or III With a reduction in the repair of coupling errors.
This treatment was to be followed by standard chemoradiation therapy and surgery, but patients who had a complete clinical response After completion of dostarlimab therapy Continue without chemoradiotherapy or surgery.
“The primary endpoints are clinical response full continuous 12 months after completion of dostarlimab therapy or complete disease response after completion of dostarlimab therapy with or without chemotherapy and overall answer for neoadjuvant therapy with or without chemoradiotherapy, with or without dostarlimab”, indicated the authors of the research.
Based on the data presented, 12 patients completed treatment with dostarlimab and had at least 6 months of follow-up. 12 patients had a complete clinical responseNo evidence of tumor on follow-up examinations: magnetic resonance imaging, F-fluorodeoxyglucose-positron emission tomography (PET), endoscopic evaluation, digital rectal examination, or biopsy.
“At the time of this report, the researchers indicated, no patients had been found chemotherapy or radiation therapyAnd no cases of progression or recurrence during follow-up—with a range of 6 to 25 months—were reported, nor were Grade 3 or higher adverse events reported.
Key observations of the New York team’s work conclude that mismatch repair of locally advanced rectal cancer was deficient. Highly sensitive to single-agent PD-1 blockade, However, it is also underlined that “a long follow-up To assess the duration of the response.
Included patients had stage II or stage III rectal cancer with mismatch repair deficiency Diagnosed with standard diagnostic criteria,
Mismatch repair condition a . was determined using Chromogenic Immunohistochemical Assay To detect loss of expression of MLH1, MSH1, MSH6 and PMS2 genes.
An important question raised by the authors after what was observed in the work is why these rectal tumors are lacking in the repair of localized anomalies. respond more strongly that colorectal tumor metastasis,
Another study involved patients with metastatic disease who had not previously received any treatment, complete response rate was based on images of colorectal tumors with poor error repair 11,1% “Despite the presence of molecular features at baseline which were tumor-like evaluated in our study,” Cercek says.
Possible explanation related to tumors of the gastrointestinal tract the impact of the gut microbiomeAs a growing literature supports the immunomodulatory role of certain bacterial species In the enhancement of the antitumor immune response potentiated by the blockade of checkpoints.
Thus, a neoadjuvant checkpoint blockade study in NSCLC showed that a large number of Ruminococcus Intestines and species Akkermansia if you join a major disease response, It has also been found that Fusobacterium a. is associated with Immunoreactive tumor microenvironment in deficient tumors In repairing pairing errors.
It is therefore hypothesized that, in addition to the tumor cell intrinsic factor driving the response to PD-1 blockade—that is, the extremely high tumor mutational burden associated with mismatch repair deficiency—there is a factor external tumor cells, such as microbiomewho might be driving it exceptionally good response,
For the researchers, “intrinsic characteristics of tumor cells, such as clonality, aneuploidy and mutation class, beyond the mutational burden of the tumor, which have been shown to Effect response to immunotherapymay influence the difference in response between localized and metastatic disease.”
Cercek indicates that although the results of our study are promise ofespecially since 12 consecutive patients had a complete clinical response, The study is small and represents the experience of a single institution, need this conclusion can be reproduced in a large potential group which balances academic and community practices and ensures the participation of patients from diverse racial and ethnic backgrounds.
“Once available, data on duration of complete response, the study’s other primary endpoint, will address the question of whether this approach, over the long term, Avoid surgery in all or most patients.
optimism and ignorance
one in editorial who appears last The New England Journal of Medicine, Hannah K. sanofifrom the Department of Oncology at the Cancer Center, University Chapel Hill, North Carolina, USA, discusses the results of “a small but compelling study”. clinical progress In patients with stage 2 or 3 rectal cancer with mismatch repair.
In his opinion, the results are “cause for great optimism” but such an approach Still cannot replace current curative treatment, The stated goal, complete clinical response, is “an incomplete surrogate for long-term cancer control.”
Patients who have a complete clinical response after chemotherapy and radiation therapy have a better prognosis than those who do not have a complete clinical response, but ” Recurrence occurs in 20 to 30% of patients treated for cancer without surgery,
In their opinion, these recurrence dynamics may or may not differ between immunotherapy and chemotherapy and radiotherapy. early and late stage of the disease, “Indeed, little is known about the time required to know whether full clinical response to dostarlimumab equates to cure.”
At this time, Sanoff believes it is unknown whether the results of this small study conducted at Memorial Sloan Kettering Cancer Center can be replicated. generalization to a large population of patients with rectal cancer.
“Further trials should be performed to provide more information on which patients may benefit from immunotherapy.” pointing to disparity in age, coexistence status and tumor characteristics. Enrollment of patients from diverse communities can also address Changes in the composition of the gut microbiome which are known and which may affect the response to immunotherapy”.
The authors of this editorial do not forget that diversity of clinical practice It’s also important to make sure it’s a secure way to deploy at scale. “Safe non-surgical management includes access to specialized care Not all centers have procedures available to perform direct intraluminal visualization, as well as to interpret rectal magnetic resonance data. without them, the patient May miss opportunity for remedial resection If new tumors develop.
However, despite these uncertainties, the editorial acknowledges the work of Cercek’s team, “with a promising but unknown future with immunotherapy that has provided what could be Early glimpse of a revolutionary treatment change which, however, cannot be forgotten adverse events with PD-1 inhibitors that are generally higher than the inhibitors seen in this study.
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