Dostarlimab: is the battle against colorectal cancer being won?

Publication in scientific journal The New England Journal of Medicine of an article that confirmed the complete remission of all cases of colon cancer in a group of patients treated with a drug called dostarlimab has aroused great public interest. But how should we interpret these data?

First of all, it should be noted that it is not a new drug, as it has been authorized since April 2021 for the treatment, as monotherapy and under certain circumstances, of adult patients with endometrial cancer.

Dostarlimab is a drug that belongs to the group of so-called immune checkpoint inhibitors (ICIs). Technically, it consists of a mAb – humanized monoclonal antibody of the IgG4 isotype – capable of binding to immune T-cell receptors, called PD-1, and blocking the binding of their endogenous ligands (PD-L1/2). ), the natural substances that our body synthesizes to bind to these receptors.

In other words, it is about avoiding the binding of the ligand to the receptor, because it causes an inhibition of the activity of the T cells: it slows down their proliferation, the production of cytokines and their cytotoxic activity, that is, their ability to destroy other cells.

Thus, dostarlimab enhances T-cell responses and increases the antitumor immune response, as has been shown to decrease tumor growth in syngeneic (gene-identical) mice.

What are immune checkpoint inhibitors (ICIs)?

ICIs could be considered as a type of passive immunotherapy that facilitates and enhances the body’s existing immune response. Currently, there are two families of ICI, with different mechanisms and sites of action: anti-CTLA-4 and anti-PD/PD-L1/2. Dostarlimab belongs to the latter.

When T cells are stimulated by an antigen –a substance foreign to the body–, they express PD molecules (programmed death receptors) on their surface that prevent overactivation of the immune system. But when their ligands (PD-L1/2), usually expressed by dendritic cells or macrophages, bind to them, a deactivation signal is produced.

Precisely, this phenomenon occurs in multiple tumors that express large amounts of PD-L1/2 on their surface, which allows them to escape the control of the immune system and continue their proliferation. It can be said that the evasion of immune surveillance plays a fundamental role in carcinogenesis, the process by which normal cells become cancerous.

PD-1 and 2 inhibitors (nivolumab, pembrolizumab, and dostarlimab) or PD-L1/2 inhibitors (atezolizumab, avelumab, and durvalumab) act on T cells and block checkpoint proteins. This is how they stimulate the immune response, by allowing T cells to destroy cancer cells. This effect in different types of cancer has motivated the search, in recent years, for more potential immune checkpoints as a therapeutic target.

Targets of currently FDA/EMA approved immune checkpoint inhibitors. PDL1 and PDL2 ligands can bind to programmed cell death 1 (PD1) receptors, causing T cell anergy and/or apoptosis. ICI monoclonal antibodies that bind to these receptors or their ligands on cancer cells antagonize the inhibitory signaling and enable T cell activation and cytotoxic destruction of tumor cells. Dostarlimab is an FDA/EMA approved ICI that blocks PD1 (adapted from Ganesh et al., 2019).
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Manifestations of colorectal cancer

Colorectal cancer (CRC) is the third most prevalent type of tumor and the second in terms of mortality worldwide. In Spain, the estimated incidence is 43,398 cases: 28,706 colon tumors and 14,664 rectal tumors in 2022.

About 25% of patients have metastatic disease at diagnosis, and a third of people with limited disease initially will develop metastases later. This explains the high mortality rates reported for colorectal tumors.

CRC is a very heterogeneous disease. A well-described genetic subgroup is tumors with mismatch repair system deficiency or high microsatellite instability (dMMR or MSI-H, respectively). They account for 15% of all patients with CRC and 4% of patients with metastatic CRC.

There are two forms of MSI-H colorectal cancer. The first consists of the hereditary type, caused by the deficiency of the MMR system due to a mutation of the MMR genes. It predisposes to Lynch syndrome or hereditary non-polyposis colorectal cancer, the most common hereditary colon cancer.

The second is the sporadic form, which is related to an epigenetic inactivation of the same pathway. That is, genetic modifications develop randomly throughout life, and are not associated with hereditary factors.

Lynch syndrome increases the risk of other types of cancer and has implications for relatives of those affected. Therefore, these patients need continuous surveillance, while their relatives must be preventively evaluated for the detection of dMMR.

ICI and colorectal cancer dMMR

ICIs have transformed the treatment of this cancer subtype, as well as other solid tumors with dMMR, producing durable responses that prolong patient survival.

The first such drug tested in dMMR CRC patients was the anti-PD-1 antibody pembrolizumab. It confirmed a significantly longer progression-free survival and with fewer adverse effects than chemotherapy as first-line treatment in metastatic RCC.

Dostarlimab and dMMR colorectal cancer

Dostarlimab is also being evaluated in phase II clinical trials in patients with dMMR CRC. The results of the NCT04165772 trial have been published, in which 500 mg was administered every 3 weeks for 6 months to people with stage II or III.

The primary endpoints were complete clinical response (no evidence of tumor on clinical, endoscopic, or imaging examination) within 12 months after completion of dostarlimab treatment or pathologic complete response (no tumor lesion on examination of low-lying tissue). microscope) after completion of such treatment, with or without chemoradiotherapy.

However, the sample of this study was very small: only 12 patients. In any case, remission was complete in all people and the tumor was undetectable by physical examination, endoscopy, and imaging techniques (PET and MRI).

The efficacy and safety of dostarlimab are being evaluated in the GARNET clinical trial (NCT02715284). It includes women with advanced dMMR solid tumors, and one of the subgroups is made up of patients with mostly gastrointestinal tumors.

For colorectal cancer patients (144), the confirmed objective response rate is 36.2% and treatment-related serious adverse events were reported in 8.3%. The most frequent was an increase in lipase, a pancreatic enzyme, although only two patients had to stop immunotherapy due to these reactions.

Other ongoing clinical trials, such as NCT02817633, NCT03250832 or NCT05239546, are also analyzing the benefit of dostarlimab in this context.

Safety of ICIs and dostarlimab

The adverse effects of ICIs are completely different from those seen with chemotherapy. The most common are related to impaired immunity, including autoimmune effects.

Of the two families of ICI agents, gastrointestinal symptoms appear to be more common with CTLA-4 inhibitors, whereas pulmonary or thyroid manifestations may occur more frequently with PD-1 inhibitors. Liver problems are less common and occur with almost similar frequencies in both types of drugs.

In general, the most common side effects for the two types of compounds are skin symptoms. Pruritus or vitiligo stand out, which must be addressed with an initial specific treatment and continue with oral steroids.

Regarding dostarlimab, in the 515 patients with advanced or recurrent solid tumors who participated in the GARNET study, including patients with colorectal cancers, the most frequent adverse reactions (with a prevalence greater than 10%) were anemia (25.6 %), nausea (25%), diarrhea (22.5%), vomiting (18.4%), arthralgia or joint pain (13.8%), pruritus (11.5%), rash (11, 1%), fever (10.5%), and hypothyroidism (10.1%).

Serious adverse reactions occurred in 8.7% of patients, most of them immune related. Dostarlimab treatment had to be permanently discontinued due to side effects in 17 patients (3.3% of the sample).

Conclusion: more clinical evidence is needed

The results published by The New England Journal of Medicine they may seem spectacular and it is clear that we find a new way of approaching the treatment of patients with CRC. However, the small size of the analyzed sample (12 people) is a very important limitation and its confirmation in a larger series of patients is required.

The really revolutionary thing would be that patients with this type of colorectal cancer can be treated only with immunotherapy before surgery. In cases in which the response was complete, it would simply have to be followed up and if, after two or three years, there are no recurrences (reappearance of the tumor after a more or less long period of absence of disease), we could consider that the disease would be cured, without the need for surgery, radiotherapy or chemotherapy.

But to confirm this hypothesis, it is necessary to study the efficacy of dostarlimab in a much larger sample of patients and to follow them up for longer. And, above all, compare the results with conventional treatments: radiotherapy, chemotherapy and surgery. Although the results of the study are truly positive, the necessary level of evidence has not yet been reached.

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