Dostarlimab: Wonder Drug Explained Simply

Introduction

The results of the recent dostarlimab clinical trial have grabbed headlines everywhere in the world. The drug resulted in a 100 per cent remission rate in all the 18 rectal cancer patients that had participated in the trial. Here’s a detailed explainer on the wonder drug being hailed as the ‘cure’ to cancer.

1. What is dostarlimab?

Dostarlimab (pronounced — dos-TAR-lih-mab) is a monoclonal antibody.

Monoclonal antibodies are immune system proteins that work like natural antibodies, except they’re made in labs. Just like antibodies in your system point out threatening bacteria and viruses for the immune system to kill off, monoclonal antibodies can also recognize certain targets for the immune system.

Other monoclonal antibodies used to fight cancer are nivolumab, pembrolizumab, cemiplimab, avelumab, atezolizumab, etc.

Certain monoclonal antibodies, like dostarlimab, work as ‘immune checkpoint inhibitors’. This means that they block ‘immune checkpoints’. Immune checkpoints keep a check on the immune response, making sure it doesn’t get too strong, which might affect the healthy cells in a normal body.

By blocking these checkpoints, the immune system is basically prevented from shutting off before the cancer is destroyed, which means a stronger immune response can be directed towards cancer cells.

Dostarlimab specifically works by blocking the programmed death receptors-1 (PD-1) on the T-cells and preventing them from interacting with its ligands PD L-1 and PD L-2, which keeps the immune response going, helping the T-cells identify and eradicate cancer cells.

Immune checkpoint inhibitors fall under a group of treatments called ‘immunotherapy’. Immunotherapy treatments use the immune system to fight cancer. Other examples of immunotherapy are T-cell transfer therapy, treatment vaccines and immune system modulators.

2. How is dostarlimab made?

Dostarlimab is produced using a Chinese hamster ovary (CHO) cell line by ‘recombinant DNA technology’ — technology by which genetic material is altered by various lab-techniques outside the organism to get the needed DNA segments.

CHO cells are often used in the pharmaceutical industry to manufacture therapeutic proteins.

According to this GlaxoSmithKline press release, dostarlimab was first discovered by AnaptysBio and was licensed to an oncology-centred company called TESARO Inc. in March 2014. TESARO was acquired by GlaxoSmithKline in January 2019.

In 2021, the United States Food and Drug Administration (FDA) approved dostarlimab for commercial treatment. Before the trial with rectal cancer patients, the drug was being used to treat endometrial cancer.

3. How was the dostarlimab trial conducted?

Objective of the trial

The objective of the trial was to see whether blocking immune checkpoints would work against mismatch-repair deficient, locally advanced rectal cancer, since mismatch-repair deficient colorectal cancer in metastasis responds to such blockading.

Candidates

18 rectal cancer patients participated in the trial.

To be eligible for the trial, the patients had to be 18 years or older with stage II or III mismatch-repair deficient rectal cancer that had not metastasized (spread to other parts of the body), and shouldn’t have had any chemotherapy, radiotherapy or surgery. Also, they had to be free from any active autoimmune disease, active infectious disease, and shouldn’t have received any recent immunosuppressive therapy.

Procedure

All the patients were given a standard 500 mg dose of dostarlimab intravenously every 3 weeks for six months, which came to a total of nine cycles. This was followed by standard radiotherapy, and then total mesorectal excision, which is the removal of the cancerous tumor from the rectal area.

Patients who had a clinical complete response — that is, they had no remains of the disease when examined digitally and through endoscopy and MRI — after they’d complete the cycles or get done with the chemoradiotherapy, were then subjected to a non-operative follow-up.

4. Results

The ‘clinical complete response’ was observed to be 100 per cent in all the patients. This means that all the patients in the trial went into remission.

Administering dostarlimab alone was enough for a clinical complete response. The tumors vanished in all the patients, as was confirmed by MRIs, endoscopy and digital examinations. The patients did not need to undergo chemotherapy, radiation or surgery and were set up for observation immediately.

5. Why are the results significant?

No accompanying cancer treatment needed

Surgery and radiation can have life-altering effects in patients, affecting their sexual health, fertility and bowel and bladder functions. Tumors vanishing on the strength of dostarlimab alone mean that patients wouldn’t have to go through these agonizing procedures and their devastating effects.

No accompanying cancer treatments would mean that the patients would be able to have a higher quality of life post-treatment. This is especially encouraging since cases of rectal cancer are rising in youths of childbearing age.

Minimal side-effects

Only mild side-effects, or ‘adverse-effects’, as they’re called in a clinical trial, were observed in patients. Adverse effects are measured on a scale of Grades 1 to 5, where Grade 1 is mild and Grades 3 and above are dangerous, with Grade 5 being fatal.

In the dostarlimab trial, no adverse effects of Grade 3 or higher were observed. Side-effects observed were rash/dermatitis, fatigue, pruritus (itchy skin) and nausea. One patient reported thyroid-related abnormalities.

6. Is dostarlimab really the wonder drug it’s being made out to be?

A 100 per cent remission rate in a cancer clinical trial hasn’t happened before, and this is truly path-breaking. That said, there are caveats to this wonder drug.

Firstly, we don’t know whether dostarlimab will work as effectively everywhere in the body. When talking of tumors of the gut alone, it is being believed that certain gut microbes enhance the immune response triggered by blocking immune checkpoints. This factor means that dostarlimab might not have such success everywhere in the body due to lack of such microbes.

Secondly, this trial was a small study, and only reflected the experience of a single institution. The trial needs to be reproduced on a wider scale and should include candidates from diverse ethnic backgrounds to truly test the response of this drug.

The dostarlimab trial is truly an event that comes once in decades and is a great breakthrough in cancer treatment. However, only a larger, more inclusive trial will truly reveal its effectiveness.