Study: Promising early results for people with DNA mismatch repair deficient rectal cancer
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STUDY AT A GLANCE
What is this study about?
This study tests the usefulness of an drug (the anti-PDL1 checkpoint inhibitor dostarlimab) to treat a type of 2-3 rectal cancer before using any other treatments or surgery ( treatment). The goal was to control cancer and reduce the need for surgery.
Why is this study important?
People with locally advanced rectal cancer ( 2 or 3) typically have chemotherapy and radiation treatment followed by surgery. These treatments can have serious side effects and rectal surgery can be life-altering. It often requires a colostomy, in which a person's colon is permanently connected to an artificial opening and empties bowel movements into a bag on the body. If a treatment was found that allowed people to avoid surgery, it would be a vast improvement in their quality of life.
One promising approach is treatment with a type of drug known as immune checkpoint inhibitors. These drugs have been shown to be effective for treating cancers that are ( mismatch repair-deficient) or (microsatellite instability-high). Less than 10 percent of rectal cancers are or , but MSI-High/dMMR cancers are common in people with .
Immune checkpoint inhibitors have been helpful for treating other types of cancers and several are approved for advanced cancers with this specific . We reviewed the approval of the immune checkpoint inhibitor dostarlimab (brand name Jemperli) for endometrial cancer in 2021 (link here).
In this study, researchers tested whether dostarlimab would benefit patients with rectal cancer that was before any other traditional therapy was offered.
This study enrolled 16 people who had known rectal cancer that was 2 or 3. Among participants, 94 percent had cancer that spread to their ( 3). Participants received an injection of dostarlimab every three weeks for six months (nine total injections). Because this is an early phase of research, no comparison group of people was included, and all participants received dostarlimab. This treatment was given prior to any other treatment. Patients were supposed to transition from dostarlimab to chemotherapy, radiation and surgery if they did not achieve a complete clinical response.
At the time of publication, four participants were still undergoing dostarlimab treatment and did not have complete results yet. The early study results focused on the first 12 participants who had completed treatment and were observed for another six months or more at the time of publication.
Researchers used multiple tests to look for cancer in each participant. Prior to treatment, each participant had:
- a digital rectal exam.
- imaging of the rectum by an endoscopic exam (insertion of a tube with a camera into the rectum). If cancer was present, a biopsy removed a small portion of the tumor for .
- imaging of the rectum by .
- imaging of the chest, pelvis and abdomen by FDG-PET and CT.
Six weeks after the start of treatment, participants had additional digital and endoscopic exams with biopsy only. All of the above tests were repeated at three months and six months from the start of treatment and every four months thereafter.
Rectal cancers disappeared with dostarlimab treatment.
- No patients (0 of 12, 0%) had evidence of cancer after treatment with dostarlimab according to the tests done.
- The shortest follow-up time was an additional 6 months
- The longest follow-up time was an additional 25 months.
- No cancer was detected in any patient during the study period (or so far in later reports).
- All participants avoided rectal surgery, chemotherapy or radiation treatments.
- No severe adverse events were reported.
- Some participants had less severe side effects, including skin irritation, nausea and fatigue.
- The results were clear: Participants' cancer disappeared in response to dostarlimab treatment during the study. This is a remarkably strong response to drug treatment, presumably by encouraging their own immune systems to attack and destroy the cancer. Typically cancers may somewhat shrink with chemotherapy and radiation and the remainder is then removed by surgery. Because cancer was not detected, participants did not need surgery or other treatment.
- The study was well-designed. Researchers evaluated patients with several different tests to ensure they did not miss any remaining cancers. They followed participants regularly after treatment to see if their cancer returned.
- While the cancers appeared to shrink to the point of disappearing, the true absence of the cancer can’t be confirmed without the patients either having surgery to look under the microscope to confirm cancer is gone or with longer follow-up to confirm the cancer doesn’t come back.
- Only a few patients have been treated with dostarlimab for locally advanced rectal cancer. While these early results are promising, many more people will need to be treated to understand the effectiveness of this treatment. It is possible that these results are a fluke and that another group of patients would have different outcomes. The consistency of response among the participants suggests that this is not the case. However, many studies have shown promising early results that were found to be less effective when larger and more varied groups of people were tested.
- Participants were observed for only 6-25 months after treatment (an average of 12 months). Participants need to be followed for a longer period to understand when they relapse (their cancer returns) or whether they are cured.
- As a phase 2 study, there was no comparison group of participants who received standard-of-care treatment.
- This study was small, and the number of people of different racial or ethnic ancestry was especially small. Only 1 Black participant, 3 Asians and 1 Hispanic person were included among the 16 enrolled participants. The only Black participant was among the 4 who had not yet completed treatment, so their results are unknown. A larger trial including many more participants is needed to understand whether people of different racial or ethnic groups have any differences in their response to this treatment.
Only a minority of rectal cancers are or . Testing for these biomarkers are commonly available at the time of diagnosis of rectal cancer through tests on the biopsy obtained. Understanding whether your rectal cancer is or may help you and your doctor decide the best treatment for your situation.
If you have newly diagnosed, 2 or 3 rectal cancer that is or , you may want to ask your doctor if you are eligible to receive dostarlimab or a similar treatment, potentially through a clinical trial since these drugs are not yet approved for early rectal cancer. Because many people with dMMR/MSI-high cancers have , genetic counseling and testing are also warranted.
Cerek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient locally advanced rectal cancer. New England Journal of Medicine 2022; 268: 2363-76. DOI:10:1056/NEJMoa2201445.
Loe M, Chamberlin M, and Lewis B. Rectal cancer patients in remission after promising study, but that doesn’t mean there’s a ‘cure for cancer’. VERIFY 2022, Published online September 2, 2022.
Disclosure: FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.
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This article is relevant for:
People with rectal cancer with high mutational burden or mismatch repair problems including people with Lynch syndrome.
This article is also relevant for:
People with metastatic or advanced cancer
People with a genetic mutation linked to cancer risk
People with a family history of cancer
People newly diagnosed with cancer
People with colorectal cancer
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IN-DEPTH REVIEW OF RESEARCH
Most commonly, patients with locally advanced rectal cancer ( 2 or 3) have chemotherapy and radiation treatment followed by surgery. Rectal surgery is often life-altering particularly when it requires a colostomy. A colostomy is created after some types of rectal cancer surgery where a patient's colon permanently empties bowel movements into a colostomy bag. If a treatment was found that allowed patients to avoid surgery, it would be a vast improvement in a patient's quality of life.
Some patients who are treated with drugs for rectal cancer prior to surgery ( treatment) have no evidence of cancer (a complete pathological response). Because there is no cancer remaining they do not need surgery. Up to 25 percent of patients treated with fluoropyrimidine and oxaliplatin had a complete response. However, this treatment was also linked to a high rate of complications and severe side effects. Researchers were looking for alternative treatments with better outcomes.
One promising treatment may be drugs that affect cancers that are mismatch repair-deficient (MMR-deficient). Drugs called PD-1 inhibitors, a type of checkpoint inhibitor, have been a useful treatment for MMR-deficient cancer in other organs.
Five to ten percent of rectal cancers are mismatch repair-deficient (MMR-deficient), and even fewer have early (non-spread) rectal cancer. Rectal cancers that are MMR-deficient can occur sporadically but others are associated with inherited mutations including those in the genes (, , and ). A 2022 report showed that up to 90 percent of rectal cancer patients with MMR cancers have a mutation in a gene.
In this study, the researchers were looking at the PD-1 inhibitor dostarlimab (brand name Jemperli). Because dostarlimab has been beneficial in treating MMR-deficient advanced colorectal cancers, researchers thought that it may also be useful as an early rectal cancer treatment. They wanted to know whether dostarlimab would slow or stop the progression of MMR-deficient, locally advanced rectal cancer. In this study, they tested whether dostarlimab improved outcomes for people when given as a drug, prior to any other treatments, including chemotherapy, radiation and surgery.
Researchers of this study wanted to know
Researchers wanted to know whether dostarlimab given prior to any other treatments would improve outcomes for people with 2 or 3 MMR-deficient rectal cancer.
Populations looked at in this study
A total of 16 participants with 2 or 3 rectal cancer were enrolled. This study reports some information for all 16 individuals but focuses on 12 who had completed treatment and were observed for another six months or more.
Participants’ cancer was verified by imaging tumors with and CT and by digital rectal exam and endoscopy. Tumors were confirmed to be MMR-deficient based on testing of the biopsy obtained that confirmed the initial diagnosis. Participants were excluded if they had prior , chemotherapy or radiation for rectal cancer, currently had an infectious or autoimmune disease or were on an immunosuppressant within the prior week.
The average age of participants was 54 years; 62 percent were women. No participants have withdrawn from the study. The 16 participants self-reported their race and ethnicity: 11 were white (69 percent), three were Asian (19 percent) and two were Black (12 percent); one participant was Hispanic (6 percent). Fifteen participants had 3 cancer, while one individual had 2 cancer; 94 percent had node-positive cancer. The most common symptoms of patients at enrollment were rectal bleeding (88 percent), constipation (31 percent) and abdominal pain (25 percent). Analysis of tumor biopsies prior to treatment verified that all participants' cancers were MMR-deficient. Although no participant had a known family history of , eight of 14 participants (57 percent) had inherited mutations in a gene (one in , four in , two in and one in ). Two participants had not yet had genetic testing at the time of this report. All six participants without an inherited mutation were missing one or more proteins in their tumors.
This study was published on June 23, 2022, in The New England Journal of Medicine. It reported results from 12 participants with locally advanced 2 or 3 rectal cancer who had already completed six months of treatment with dostarlimab and had 6 months or more of follow-up observation.
This was a single arm, phase 2 study that followed the cancer outcomes of participants with 2 or 3 MMR-deficient rectal cancer. Participants received 500 milligrams of dostarlimab every three weeks for six months (nine total injections). Because this is an early phase 2 study, no comparison group (people who did not get the drug) was included.
After treatment with dostarlimab (six months of treatment), any participant with remaining cancer detected by the tests listed below, received standard chemotherapy and radiation treatment followed by surgery. Any participants who had no evidence of cancer (a clinically complete response) did not have chemotherapy, radiation treatment or surgery and was just monitored.
To determine a clinically complete response, researchers used multiple tests to look for cancer in each participant. Prior to treatment, each participant had:
- a digital rectal exam.
- an endoscopic exam (insertion of a tube with a camera to look at the rectum) and a biopsy to remove a small portion of the tumor for pathology .
- an imaging of the rectum.
- FDG-PET and CT imaging of the chest, pelvis and abdomen.
Each test was repeated at three months and six months from the start of treatment and every four months thereafter. Six weeks after the start of treatment, participants had digital and endoscopic exams with biopsy only.
The goals of this study were to determine:
1. how many participants had either:
- a pathological complete response (pCR—no cancer found in the tissue upon surgery) after drug treatment among patients who did have surgery (with or without follow-up chemotherapy and radiation), OR
- a clinical complete response (no signs of cancer by non-surgical tests) 1 year after the start of their dostarlimab treatment (6 months of treatment plus 6 months of follow-up) among patients who did not have surgery
2. the overall response (OR) after dostarlimab treatment (with or without chemotherapy and radiation).
This study reports on 12 patients who completed treatment with dostarlimab and at least six months of follow-up. The median follow-up time was 12 months. The shortest follow-up time was six months and the longest was 25 months.
All participants (12 of 12, 100%) had a clinical complete response (no evidence of cancer).
- Without exception, every one of the 12 participants (100%) had:
- no evidence of cancer with imaging.
- no evidence of cancer with imaging.
- no evidence of cancer with endoscopic imaging (direct imaging with a camera in the rectum).
No participant’s cancer progressed or recurred after dostarlimab treatment at the time of this study report.
All participants avoided rectal surgery or other chemotherapy or radiation treatments.
No severe adverse events were reported.
- No serious side effects (grade 3 or higher) were reported.
- Less severe side effects occurred. Of these, the most common were rash (31%), itchy skin (25%), fatigue (25%) and nausea (19%).
- These results indicate that dostarlimab was well tolerated by participants. This matches reports of dostarlimab for the treatment of other cancers.
Strengths and limitations
- None of the 12 participants who received a full treatment of dostarlimab had detectable cancer. This striking result is unusual. Even among successful treatments, often some patients do not respond.
- The follow-up tests to look for cancer were thorough and support the conclusion that no detectable cancer was present after dostarlimab treatment.
- This is a preliminary study reporting information on only 12 participants. More patients need to be treated to determine if these findings hold up. While promising, it is too early to fully understand how well this may work.
- Longer follow-up is needed to assess the duration of the response and confirm patients are cured in the long-run. The longest follow-up time was 25 months.
- Among the 12 participants, there were 7 white (58%), 1 Black (8%), 3 Asian (25%) and 1 Hispanic (8%) participants. While this group includes people of diverse ancestry, the numbers are too small to determine whether there may be any differences in effectiveness.
- All of the participants had MMR-deficient rectal cancers. This treatment cannot be generalizable to people with different cancers or non-MMR deficient rectal cancer.
- Many participants also had inherited mutations or their tumor was missing one or more proteins. It remains to be seen how well dostarlimab works for each gene when evaluated separately.
- All participants in this study all had 2 or 3 rectal cancer. It is not known whether this treatment would be as effective for other stages of cancer.
treatment is used for other . However, the response to treatment for rectal cancer reported in this study is much better than has been seen previously. These researchers pointed out that they treated for six months—longer than many other treatments. Most of the participants in this study experienced some shrinkage of their cancer after three months of dostarlimab treatment.
A prior study reported a 55 percent response of mismatch repair-deficient colorectal cancers to toripalimab, a different PD-1 inhibitor that was given alone or with the drug celecoxib. Of note, these participants had other prior treatments. It is not clear if the lower response in that study was due to differences in the drugs, location of the cancer in the GI tract or a prior treatment or some combination of them. In general, only 11 percent of mismatch repair colorectal cancers respond completely to treatment. The differences that allowed 100 percent of the rectal cancers in this study to respond are unknown.
The checkpoint inhibitor dostarlimab is a promising treatment for locally advanced, mismatch repair-deficient rectal cancer. This treatment may allow patients with this type of cancer to avoid life-altering rectal surgery while improving outcomes and quality of life. More research and follow-up is needed to determine if this very small study holds up for more patients, but it appears very promising.
Share your thoughts on this XRAY review by taking our brief survey.
- I have rectal cancer; what are the risks and benefits of different treatment options?
- Do I have a mismatch repair-deficient cancer?
- What treatments, if any, would target my type of cancer?
- Would a checkpoint inhibitor be helpful for my treatment?
- I have been newly diagnosed with rectal cancer; am I be eligible for the dostarlimab trial?
- What clinical trials, if any, are appropriate for me to consider?
- I have a mismatch repair-deficient cancer; should I consider genetic testing for or other inherited mutations?
- I have Lynch syndrome; how do I contact a genetic counselor to learn about my risk of other cancers?
- I have but do not have cancer; what risk-reducing or surveillance approaches for colorectal cancer should I consider?
The following organizations offer peer support services for people with or at high risk for colorectal cancer:
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- Visit our message boards.
- Once you register, you can post on the Diagnosed With Cancer board to connect with other people who have been diagnosed.
- Sign up for our Peer Navigation Program.
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Who covered this study?
New York Times
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Dostarlimab shows efficacy as curative-intent treatment in rectal cancer subset This article rates 4.5 out of 5 stars
100% Complete response rate in 14 patients with rectal cancer treated with neoadjuvant dostarlimab-gxly This article rates 4.0 out of 5 stars
Small Rectal Cancer Study Has Remission in Every Patient This article rates 4.0 out of 5 stars
Findings from a prospective phase II study with dostarlimab for advanced local rectal cancer This article rates 3.5 out of 5 stars
All cancer patients in drug trial appear to be cured for ‘first time in history’ This article rates 2.5 out of 5 stars
Palm Beach Post
Unheard of: Immunotherapy drug that in trial cured this cancer every time This article rates 2.0 out of 5 stars