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Varshit Dusad
A cancer diagnosis is generally perceived to be a death sentence. With millions of people dying of cancer every year, this does not seem to be at all outrageous. However, researchers all over the world, in academia and industry alike, have been relentlessly pursuing novel therapies and drugs to find that ever-elusive cure to cancer.
One therapy which has made strong ripples across the cancer community is cancer immunotherapy. Cancer immunotherapy has been received very favorably and was awarded the Nobel Prize in 2018. We have talked about cancer immunotherapy, in general, a lot at Oncobites. Today, I would like to focus on one particular drug, an astounding example of cancer immunotherapy, which has recently developed from an active line of research into a full-fledged clinical therapy.
This drug is pembrolizumab and with the success it has shown, it could very well be called a miracle drug.
Pembrolizumab was first developed by Gregory Carven, Hans van Eenennaam and John Dulos who began to work on it at Organon. After two successive rounds of acquisition, the company and its underlying technology ended up in the portfolio of global pharmaceutical giant Merck. While Merck had little interest and expertise in developing cancer immunotherapy drugs, the positive results presented by its competitors prompted Merck to gear up in this race. Despite being 5 years behind its competition, Merck allocated significant resources and attention to the development of their cancer immunotherapy drug. This culminated in the drug which is currently known as pembrolizumab and is sold under the market name Keytruda®.
Pembrolizumab is a monoclonal antibody which binds to a particular receptor target (PD-1) in T-cells. T-cells are the body’s police force and they detect and eliminate any foreign pathogens that they discover. However, immune cells normally rely on PDL-1 expression by the body’s own cells to ensure that they are not accidentally targeted. Cancer cells take advantage of this loophole and overexpress PDL-1 to escape immune scrutiny. However, pembrolizumab selectively binds with PD-1 receptors, obstructing cancer’s safety mechanism. This allows immune cells to find and attack cancer cells. Thus, pembrolizumab does not directly attack cancer cells (unlike traditional chemotherapy-based drugs) but instead enables the body to better attack cancer on its own.
“What we are really trying to do with this drug is teach your immune system to do what it failed to do: recognize and kill the melanoma,” – Eric Whitman (MD), Director of the Atlantic Melanoma Center
Pembrolizumab is considered miraculous because it has been extremely successful in multiple clinical trials (and it has gone through more than 1,000). For example, a 5-year follow-up study on patients enrolled in the Phase 1 trial of pembrolizumab revealed an astonishing overall survival rate of 41% in all patients suffering from advanced skin cancer which was significantly higher than the other market alternatives. It has also shown remarkable promise in clinical practice as well since its launch in the market in 2015 with numerous doctors and patients registering their public testimonies (1,2,3,4) towards the spectacular success of this drug.
Merck has also won the FDA’s “Breakthrough therapy award” for pembrolizumab. This award is given to drugs that treat serious life-threatening conditions and display promising preliminary clinical evidence in improving patients’ outcomes. Subsequently, it was approved for the FDA Fast Track Development program which allowed Merck to get priority in the drug approval process. By 2016, pembrolizumab was also approved for marketing in Europe and Japan.
Though originally meant for advanced drug-resistant melanoma, it was extended for use in recurrent metastatic head and neck squamous cell carcinoma and lung cancer. Currently, it is also considered the first line of treatment for non-small cell lung cancer which contains PDL-1 overexpression. It is the first anti-tumor drug so far to be approved on purely genetic signatures.
Despite a stunning track record, pembrolizumab is not without its side-effects. There are two possible groups of side effects that can present the greatest danger to patients taking pembrolizumab. Pembrolizumab, by its mechanism of action, aggravates auto-immune responses by reducing the natural inhibitory signals that prevent your immune cells from attacking the rest of your body. Thus, people suffering from auto-immune conditions could suffer a serious exacerbation following treatment with pembrolizumab. Also, animal trials have suggested that pregnant women should not be treated with pembrolizumab because it reduces fetal tolerance by the immune system. Apart from these two, the majority of side-effects are less severe, such as rash, fatigue, itchiness, nausea and joint pain.
Nonetheless, based on survival statistics and testimonies of patients mentioned above, pembrolizumab has raised hopes for millions of patients and their families that, perhaps, cancer is not a definite death sentence after all. Maybe one day we will be able to combine this treatment with other new therapies to significantly improve survival rates for patients with cancer, just like how we have drastically improved our ability to treat measles and other formerly-unsolved diseases in the past 100 years.
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