The Eye Of Media

By Charlotte Webster-

A promising breakthrough for the treatment of rectal cancer has been made after a small drug trial conducted in the US found every patient treated in the experiment had their cancer successfully go into remission.

The womb cancer drug has shocked researchers with how effective it is against colorectal tumours, after it seemingly cured every patient in a clinical trial.

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The monoclonal antibody therapy Dostarlimab, already approved for women in the UK, defied expectations in a study at Memorial Sloan Kettering Cancer Center in New York.

All 18 colorectal cancer patients who participated in the trial were still in remission a year after it finished, with no signs of tumour reformation

The medication called dostarlimab and sold under the brand name Jemperli, is an immunotherapy drug used in the treatment of endometrial cancer, but this was the first clinical investigation of whether it was also effective against rectal cancer tumors.

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The research team say the successful cancer remission seen in every trial patient may be unprecedented for a cancer drug intervention.

Throughout the study, patients took Dostarlimab every three weeks for six months followed by a number of follow-up tests including physical exams, MRI scans and PET scans on the participants.

However, within a year of the trial, every one of the 18 patients who took part was in remission.

Not only that, but none of the patients involved experienced any serious complications during the trial either.

“I believe this is the first time this has happened in the history of cancer,” medical oncologist Luis Diaz Jr. from Memorial Sloan Kettering Cancer Center (MSK), the senior author of a new paper reporting the results, told The New York Times.

The positive results have only been seen in 12 patients so far (the trial is ongoing), all of whom had tumors with genetic mutations called mismatch repair deficiency (MMRd), seen in a subset of approximately 5–10 percent of rectal cancer patients.

Patients with such tumors tend to be less responsive to chemotherapy and radiation treatments, which increases the need for surgical removal of their tumors.

However, MMRd mutations can also make cancer cells more vulnerable to immune response, especially it’s bolstered by an immunotherapy agent – in this case, a checkpoint inhibitor, which unleashes restrictions on immune cells so they can more effectively kill cancer cells.

“When those mutations accumulate in the tumor, they stimulate the immune system, which attacks the mutation-ridden cancer cells,” Diaz says. “We thought, ‘Let’s try it before cancer metastasizes as a first line of treatment’.”

Patient’s rectal tumors might expect to undergo chemotherapy and radiation therapy prior to surgical removal of the cancer. Unfortunately, for many patients this gamut of treatments comes with long-lasting consequences that can last the rest of their life.

“The standard treatment for rectal cancer with surgery, radiation, and chemotherapy can be particularly hard on people because of the location of the tumor,” says MSK medical oncologist Andrea Cercek, the first author of the study.

“They can suffer life-altering bowel and bladder dysfunction, incontinence, infertility, sexual dysfunction, and more.”

The patients who enrolled in this trial have so far completely avoided both these procedures and their associated side effects.

In the phase 2 study, patients were given dostarlimab every three weeks for six months, with standard chemoradiotherapy and surgery set to follow if tumors returned. They didn’t.

After six months of follow-up, all 12 patients in the trial showed a “clinical complete response”, with no evidence of tumors to be seen via MRI scans, PET scans, endoscopy, and biopsy, among other tests.

“Dr. Cercek told me a team of doctors examined my tests,” explains Sascha Roth, the first patient enrolled in the trial. “And since they couldn’t find any signs of cancer, Dr. Cercek said there was no reason to make me endure radiation the

Dostarlimab, a monoclonal antibody, works by attaching to a protein called PD-1 on the surface of cancer cells. This helps the immune system effectively ‘unmask’ hiding cancer cells and destroy them. The drug, which is made by GlaxoSmithKline, is given intravenously in a 500mg dose

Dr Luis Diaz (second left) and Dr Andrea Cercek (fourth left) stand with some of their patients. The patients and doctors from a landmark trial: Sascha Roth, patient; Dr. Luis Diaz, Memorial Sloan Kettering; Imtiaz Hussain, patient; Dr. Andrea Cercek, Memorial Sloan Kettering; Avery Holmes, patient; and Nisha Varughese, patient

.All of the patients in the study had a rare genetic signature in their tumors, known as mismatch repair deficiency. This means that cells are not as able to repair errors in DNA, a process that can lead to cancer. Eight of the 12 patients described in the New England Journal paper, including Roth, had Lynch syndrome, a genetic condition that causes mismatch repair and carries a much higher risk of colon cancer; Roth believes the condition may be why her father developed brain cancer, which killed him.

Immunotherapy

Dostarlimab (also known as TSR-042) is a type of immunotherapy called a monoclonal antibody.

It works by attaching to a protein called PD-1 on the surface of cancer cells.

This helps the immune system to recognise and attack the cancer.

A 500mg dose of he drug is administered into the blood stream through a drip into a vein over a 30-minute period.

The treatment can trigger mild side-effects, including a rash, dry and itchy skin, fatigue and nausea.

It is already used to treat around 100 women with advanced endometrial cancer in the UK. For these patients, the drug is given every three weeks for 12 weeks.

In the trial involving 18 colorectal cancer patients in the US, it was administered every three weeks for six months.

Dostarlimab costs about $11,000 per 500mg dose in the US. In the UK, it is sold for £5,887 per dose.

However, the NHS has agreed a discount with the manufacturer GlaxoSmithKline.

All 18 patients in the trial had cancers that shared a gene mutation that prevented cells from repairing damage to DNA.

But Dr Diaz, who is also a member of the White House’s National Cancer Advisory Board, told the New York Times the discovery was ‘the tip of the iceberg.’

‘We are investigating if this same method may help other cancers where the treatments are often life-altering and tumours can be MMRd,’ he said.

‘We are currently enrolling patients with gastric (stomach), prostate, and pancreatic cancers.’

Around 43,000 Britons and 150,000 Americans are diagnosed with colorectal cancer every year.

Dostarlimab is made by designing antibodies in a lab to attach to proteins called PD-1 on the surface of cancer cells.

This helps the immune system effectively ‘unmask’ hiding cancer cells and destroy them.

The body makes antibodies on its own but the natural response is often not enough to tackle aggressive tumours.

Dostarlimab can be used in patients who have tumours with a specific genetic makeup known as mismatch repair-deficient (MMRd) or microsatellite instability (MSI).

Just five to 10 percent of all bowel cancer patients are thought to have MMRd tumours, including all the patients in the clinical trial.

The 18 trial patients had all gone through previous treatments for colorectal cancer before the trial, including chemotherapy and surgeries.

They received Dostarlimab every three weeks for six months.

Researchers followed up with the patients 12 months later, and the cancer had seemingly vanished from their bodies, with the medical staff unable to find signs of tumours with any of the available screening methods.

Dostarlimab costs about $11,000 per 500mg dose in the US. In the UK, it is sold for £5,887 per dose.

However, the NHS has agreed a discount with manufacturer GSK, which sponsored the US trial, to treat advanced endometrial cancer.

Dostarlimab is given to around 100 advanced endometrial, or womb, cancer patients every year. The life-extending drug aims to improve their quality of life and avoid chemotherapy, which has more side effects and a limited benefit.

Dr Diaz said: ‘Our message is: Get tested if you have rectal cancer to see if the tumour is MMRd.

‘No matter what stage the cancer is, we have a trial at Memorial Sloan Kettering that may help you. And MSK has special expertise that really matters.’

‘At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up,’ researchers wrote in the study published in the New England Journal of Medicine.

‘There were a lot of happy tears,’ said Dr Andrea Cercek, an oncologist at Memorial Sloan Kettering Cancer Center and a co-author of the paper, which was presented Sunday at the annual meeting of the American Society of Clinical Oncolo

‘It’s incredibly rewarding to get these happy tears and happy emails from the patients in this study who finish treatment and realize, “Oh my God, I get to keep all my normal body functions that I feared I might lose to radiation or surgery”, Dr Cercek said.

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Sascha Roth was the first person to join the Memorial Sloan Kettering clinical trial for rectal cancer

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While the results of the study are ground breaking, researchers note that the sample size was relatively small and it will take more research to determine whether they have actually stumbled on a cancer cure (file photo)

Colorectal cancer: cases and survival rates

Signs and symptoms may include blood in the stool, a change in bowel movements, weight loss, and fatigue.

Every year, in the US:

106,180 new cases of colon cancer

44,850 new cases of rectal cancer

Every year, in the UK:

43,000 new cases of bowel cancer

Five year survival rate, if not spread:

US = 90 percent

UK = 65 percent

Screening:

US = for all aged 45 or over, or younger if family history or aggravating factors

UK = from the age of 60, or younger if medically necessary

As a result, all of the participating patients were able to avoid going through more dangerous, taxing, treatments.

‘[The results] enabled us to omit both chemoradiotherapy and surgery and to proceed with observation alone,’ researchers wrote.

Surgery and radiation can have permanent effects on fertility, sexual health, and bowel and bladder function.

‘The implications for quality of life are substantial, especially among patients in whom standard treatment would affect childbearing potential.’

The treatment triggered mild side-effects, including a rash, dry and itchy skin, fatigue and nausea.

Around 20 percent of participants felt an adverse effect, but they were easily managed.

While this study is ground breaking, and looks like doctors may have stumbled onto a cancer cure, they know it is too early to declare this a miracle drug.

The researchers noted that the results are ‘promising’ but need to be repeated in larger studies.

Dr Hanna Sanoff of the University of North Carolina’s Lineberger Comprehensive Cancer Center, said the results were ‘small but compelling.’

Dr Sanoff, who was not involved in the study, said it is not clear if the patients are cured.

‘Very little is known about the duration of time needed to find out whether a clinical complete response to dostarlimab equates to cure,’ she said in an editorial.

The first patient of the 18 was Sascha Roth, then 38, who noted some rectal bleeding in 2019 but felt fine.

She had a sigmoidoscopy — a test to look inside the lower part of the bowel — and her gastroenterologist said: ‘Oh no. I was not expecting this.’

Ms Roth’s doctor called the next day, and told her: ‘It’s definitely cancer.’

Ms Roth told the New York Times: ‘I completely melted down.’

She was due to begin chemotherapy at Georgetown University, but a friend recommend she first see Dr Philip Paty at Memorial Sloan Kettering, who then told her that her cancer included the mutation that made it unlikely to respond well to chemotherapy.

She was, however, eligible to begin the trial with dostarlimab.

Ms Roth did not expect the trial to work, and had planned to move to New York for radiation, chemotherapy and possibly surgery after the trial ended – even having her ovaries removed and put back under her ribs to preserve them.

After the trial, Dr Cercek told her the good news.

‘We looked at your scans,’ she said. ‘There is absolutely no cancer.’

Roth added: ‘I told my family. They didn’t believe me.’

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Doctors left shocked after clinical trial for cancer drug cures the disease in every participant

Dr Luis Diaz (second left) and Dr Andrea Cercek (fourth left) stand with some of their patients. From left: Sascha Roth, Imtiaz Hussain, Avery Holmes and Nisha Varughese

Funded by numerous organizations, including the pharmaceutical company GlaxoSmithKline, which manufactures Jemperli – the research is still ongoing, and these are only preliminary results being reported so far.

About three-quarters of patients so far have experienced mild or moderate side effects, including rash, itching, fatigue, and nausea – but none have so far seen a regrowth in cancer, with the median follow-up being at one year, and some patients, like Roth, being cancer-free for two years.

Ultimately, the trial is expected to include about 30 patients. When we have data on the whole group, we’ll have a fuller picture of how safe and effective dostarlimab is in patients with rectal cancer, although much more study is yet needed in broader groups of patients.

Until such time, we need to treat the current results with both optimism and caution, says oncologist Hanna K. Sanoff from the University of North Carolina at Chapel Hill, who has written a commentary on the findings.

According to Sanoff, a clinical complete response to the treatment is not a surrogate for long-term cancer control, as even though checkpoint inhibitors like dostarlimab can have effects lasting years, cancer regrowth is generally expected to still occur in a minority of patients where tumors are managed non-operatively, let alone with an experimental treatment like this.

“Very little is known about the duration of time needed to find out whether a clinical complete response to dostarlimab equates to cure,” Sanoff explains, noting that we also need larger-scale replication of the results to be sure of the drug’s benefits, which so far have only been seen in a minority of patients with MMRd tumors.

“Whether the results of this small study conducted at Memorial Sloan Kettering Cancer Center will be generalizable to a broader population of patients with rectal cancer is also not known.”

Bearing these caveats in mind, there’s a lot to be hopeful for here; the researchers are already investigating whether their singular immunotherapy approach could also help patients with other tumors that have MMRd, such as some types of stomach, prostate, and pancreatic cancer.

It’s early days, and there’s still a lot we don’t know, but if further research can replicate the bright promise hinted at here, we might be witnessing the development of a new kind of cancer therapy, Sanoff says.

“Despite these uncertainties, Cercek and colleagues and their patients who agreed to forgo standard treatment for a promising but unknown future with immunotherapy have provided what may be an early glimpse of a revolutionary treatment shift,” Sanoff writes.

“If immunotherapy can be a curative treatment for rectal cancer, eligible patients may no longer have to accept functional compromise in order to be cured.”

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