Study: Promising early results for people with DNA mismatch repair deficient rectal cancer

IN-DEPTH REVIEW OF RESEARCH
Study background

Most commonly, patients with locally advanced rectal cancer (stage 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 (neoadjuvant 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 neoadjuvant 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 stage (non-spread) rectal cancer. Rectal cancers that are MMR-deficient can occur sporadically but others are associated with inherited mutations including those in the Lynch syndrome genes (MLH1, MSH2, MSH6 and PMS2).  A 2022 report showed that up to 90 percent of rectal cancer patients with MMR cancers have a mutation in a Lynch syndrome 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 neoadjuvant 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 stage 2 or 3 MMR-deficient rectal cancer.

Populations looked at in this study

A total of 16 participants with stage 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 stage was verified by imaging tumors with MRI 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 immunotherapy, 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 stage 3 cancer, while one individual had stage 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 Lynch syndrome, eight of 14 participants (57 percent) had inherited mutations in a Lynch syndrome gene (one in MLH1, four in MSH2, two in MSH6 and one in PMS2). Two participants had not yet had genetic testing at the time of this report. All six participants without an inherited Lynch syndrome mutation were missing one or more Lynch syndrome 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 stage 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.

Study design

This was a single arm, phase 2 study that followed the cancer outcomes of participants with stage 2 or stage 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 staging.
• an MRI 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).

Study findings

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 MRI imaging.
  • no evidence of cancer with PET scan 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

Strengths

• 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.

Limitations

• 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 Lynch syndrome mutations or their tumor was missing one or more Lynch syndrome proteins. It remains to be seen how well dostarlimab works for each Lynch syndrome gene when evaluated separately.
• All participants in this study all had stage 2 or 3 rectal cancer. It is not known whether this treatment would be as effective for other stages of cancer.

Context

Neoadjuvant treatment is used for other solid tumors. However, the response to neoadjuvant 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 neoadjuvant 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 neoadjuvant treatment. The differences that allowed 100 percent of the rectal cancers in this study to respond are unknown.

Conclusions

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.

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posted 11/14/22