New Delhi: For nearly a decade, pembrolizumab—sold under the brand name Keytruda—has dominated the cancer immunotherapy landscape by increasing the lifespans of millions of cancer patients worldwide suffering from various types of malignancies including lung cancer, considered among the deadliest.
For this reason, this drug—manufactured by US-based pharma giant Merck—which costs Rs 2 lakh per vial in India, has been among top selling drugs by revenue globally for the past several years.
When the drug is used for a treatment cycle spanning 18 months, the cost may go up to Rs 50 lakh.
But another experimental monoclonal antibody—ivonescimab—has created ripples in the field of oncology research, by beating the blockbuster medicine pembrolizumab in the third phase of a head-to-head clinical trial (one in which two different interventions or treatments are compared to determine which is most effective) known as HARMONi-2, results of which were announced on 8 September.
Monoclonal antibodies are laboratory-made proteins that bind to specific targets in the body, such as immunity or cancer cells.
Ivonescimab has been developed by Chinese biotechnology firm Akeso, which has tied up with US-based Summit Therapeutics to develop and commercialise the medicine in Western countries and Japan.
The data presented by Akeso and Summit Therapeutics at the World Conference on Lung Cancer in San Diego, California, showed that ivonescimab significantly extended median progression-free survival (the length of time a patient lives with a disease, without it getting worse, during and after treatment) for patients with advanced lung cancer, compared to Keytruda, with both statistical and clinical significance.
According to the results from HARMONi-2, ivonescimab reduced the risk of tumour progression by 49 percent.
Also, at median, it was observed that in patients treated with ivonescimab, the tumour did not grow again until 11.1 months after the treatment, while in those treated with Keytruda, tumours began to grow again 5.8 months after the treatment.
“This is exciting news because as of now, pembrolizumab, along with chemotherapy, is the most effective treatment for advanced lung cancer—in terms of cancer free survival,” Dr Kamal Saini, a medical oncologist based in Cambridge, UK, and a clinical fellow at Cambridge University’s Addenbrooke’s Hospital, told ThePrint.
Pembrolizumab is used as part of a treatment called immunotherapy, which helps prime the body’s own natural immune system to help fight cancer cells. Ever since pembrolizumab was first approved by the US Food and Drug Administration (FDA) in 2014, it became the backbone for treating 18 different types of cancer, including lung cancer.
However, cancer researchers now say that ivonescimab, a new generation immunotherapy, has the potential to further advance cancer management for patients globally.
Cancer is now considered a leading cause of deaths worldwide, with a significant impact on health and economies. According to the World Health Organization WHO), there were an estimated 20 million new cancer cases globally in 2022.
Lung cancer was the most common cancer, accounting for almost 2.5 million new cases.
A total of 14,13,316 new cancer cases were detected in India in 2022 and of these, 91,68,827 succumbed to the disease. Cancers of breast, lip and oral cavity and lungs are the most common in the country.
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Promising results of ivonescimab
As part of the HARMONi-2 trial, about 400 patients of advanced non-small cell lung cancer, the most common type of lung cancer, were enrolled across 57 sites in China.
During the trial, patients were randomly assigned to receive either Keytruda or ivonescimab, and the results showed that those in the latter group had a much longer time before their cancer worsened (a trial endpoint that statisticians term progression-free survival).
According to Akeso, ivonescimab significantly improved progression-free survival compared to pembrolizumab, markedly reducing the risk of disease progression or death.
Further, subgroup analyses revealed that ivonescimab outperformed pembrolizumab across various factors, including age, sex, ECOG (Eastern Cooperative Oncology Group) performance status (scale used to assess functional status of cancer patients), and PD-L1 expression (tumours that express high amounts of PD-L1, a protein found in tumour cells and some normal cells which prevents the immune system from attacking cancer as well healthy cells), among others.
“This is a very promising development, especially since it was a head-to-head comparison between single-agent pembrolizumab versus ivonescimab,” pointed out Saini, who is also the European head of Fortrea, a clinical research organisation that works with pharmaceutical and biotech companies in running clinical trials.
Dr Salil Patkar, consultant in medical oncology at Fortis Hiranandani Hospital in Mumbai, told ThePrint that the early data from HARMONi-2 has clearly shown the benefits of ivonescimab over pembrolizumab which, he feels, is “great news”.
Advantage of ivonescimab over Keytruda
Keytruda’s mechanism of action involves blocking the PD-1 protein on T cells (a type of white blood cell that protects the body from infections and diseases), helping prevent interaction between T cells and PD-L1 on cancer cells.
PD-1 protein is a cell-surface receptor that regulates immunity-related functioning of T cells by stopping them from attacking the body’s own cells. This natural process, though good for preventing autoimmune disorders, hampers regulation of cancer cells.
Thus, Keytruda’s mechanism takes the brakes off of the immune system, allowing T cells to recognise and attack cancer cells more effectively.
Ivonescimab, on the other hand, belongs to a new generation of immunotherapy called “bispecific” antibodies, which means it can target two different cancer receptors.
In addition to PD-1, this drug also blocks Vascular endothelial growth factor (VEGF)—a protein that promotes blood vessel growth, which helps tumours grow and spread.
“To be clear, both are monoclonal antibodies but while pembrolizumab has a single target, ivonescimab has two. This makes it more complex and evolved with higher theoretical advantages over Keytruda,” Saini explained, adding that this new drug was akin to “killing two birds with one stone.”
But there’s a catch
Oncologists, meanwhile, also highlight that while the results of HARMONi-2 are exciting, it is important to bear in mind that this trial was conducted in one single country (China) and in a fairly limited number of patients—about two hundred in each arm of the trial.
“It is critical that these results be replicated in a larger global trial, as racial differences are known to influence anti-cancer therapies, and thus, this bispecific antibody must be tested in a more diverse population,” Saini said.
Patkar, too, stressed that more detailed data should be there before ivonescimab is dubbed a “breakthrough therapy”.
He explained that in progression-free survival, there is a benefit in terms of the time that one gets before the disease resurfaces or the disease progresses. “But progression-free survival is not as good as overall survival. Hence, we must always encourage new treatment modalities and their findings.”
However, the real goal for any drug used in a trial for cancer patients is overall survival, the oncologist stressed.
“Regarding this trial, we are happy with the results, but we have to wait for more data, especially related to overall survival, to come out before calling it a paradigm shift treatment or before seeing it as a major hope for lung cancer patients,” he said.
(Edited by Radifah Kabir)
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