The drug works by targeting KRAS, a cancer-driving gene mutation found in the vast majority of pancreatic tumours and one that researchers have spent decades trying to effectively shut down. The findings have generated excitement among oncologists because progress in treating pancreatic cancer has historically been slow.
“For years, the average (median) survival for patients with advanced pancreatic cancers has hovered around one year. It was six months in the late 1990s and just about 9-12 months three decades later. Improvements in survival have been minimally incremental despite active research over the last two decades,” says Professor Anant Ramaswamy, specialist in GI cancers and Geriatric Oncology, Tata Memorial Centre, Mumbai.
“In such a scenario, the impact of an oral pill improving or rather, doubling survival in pre-treated patients with pancreatic cancer is great news. Also, this is just the beginning for this new class of drugs. Patients and oncologists can expect more improvements in the times to come,” he told The Indian Express.
Why has pancreatic cancer remained so difficult to treat compared with some other cancers?
There are multiple reasons. First, a majority of patients (70-90%) are diagnosed at an advanced stage and that itself is a major limiting factor. Second, while a number of other cancers have had targeted agents and immunotherapy markedly improving survival, till date these have not shown significant effects in pancreatic cancer. Third, and a bit technically, in pancreatic cancer, it’s not just the tumour but also the surrounding tissue around the tumour (called the stroma) that have been very resistant to available treatment approaches.
What role does the KRAS gene play in pancreatic cancer? The drug is described as “locking onto” the mutated KRAS gene. In simple terms, how does it work?
RAS is a protein that is ubiquitously expressed in almost all cell types in the human body. It is encoded for by a gene called RAS gene. Mutations (damaging alterations in the gene which cause cancer) in the RAS gene family (of which KRAS is the most common) affect approximately 20% of all cancers. Approximately 80% of pancreatic cancers have alterations in the KRAS gene, which has made it a major area of research in pancreatic cancers.
Basically, when the KRAS gene is mutated, it becomes continually active or ‘ON’ mode by binding to some small molecules in the cells and then ensures that there is disruption of activity in normal cells. That’s how these cells become dysregulated and cancerous. Daraxonrasib inhibits this state from inside the cell and suppresses pathways that are involved in perpetuating cancer cell growth. It is the first drug of its class that has shown such successful results, though many drugs with similar activity are in the pipeline and should emerge in a few years.
What makes daraxonrasib different from existing treatments?
Daraxonrasib is the first drug of its category that has shown to successfully inhibit RAS activity, including the various subtypes of RAS as well, irrespective of whether RAS is mutated or not. This makes it a notable triumph in the era of precision oncology.
The drug appeared to cause fewer severe side-effects than chemotherapy. What kinds of side-effects did patients experience?
Even though it is an oral drug, daraxonrasib had a significant incidence of side-effects almost on a par with chemotherapy, to which the drug was compared. The common side effects included a skin rash, loose motions, oral ulcers, vomiting and vomiting like sensations, tiredness and fall in haemoglobin levels, among others. About one-third of patients required reduction in dose as well. Since it is a new drug, oncologists and physicians over the world will slowly learn to use this drug so that side effects can be ameliorated to some extent.
Which patients are most likely to be eligible for this treatment?
As of now, patients with pancreatic cancer, who have previously received chemotherapy and have worsening disease, are candidates for receiving daraxonrasib. However, clinical trials and studies are already exploring these drugs in patients who are treatment-naïve (meaning an individual has never received therapy or medication for a specific medical condition or disease) and I think that these will possibly be used earlier rather than later in pancreatic cancers as well as other cancers in the coming times.
Can this drug have applications beyond pancreatic cancer?
Daraxonrasib as well as other drugs similar to it, which inhibit activity of RAS, are being explored in a number of cancers since RAS mutations are noted in about 20% of all cancers. They are actively being evaluated in lung and colon cancers since these are relatively common and have a high incidence of RAS mutations.
What about accessibility and drugs?
The drug is not available in India but with the kind of scope it has, I think this class of drugs will soon make their way to India. Everyone is interested in these drugs because of their potential to treat a number of cancers. Informally, we have heard that there is a long waiting list even to get into clinical trials evaluating RAS inhibitors. So, we will have to wait and see with regard to accessibility of daraxonrasib and other such drugs to Indian patients.
What does this breakthrough tell us about the future of precision medicine in cancer treatment?
Precision medicine is an important component of cancer treatment and it is heartening to note that research has yielded an exciting molecule representative of precision medicine in a difficult to treat cancer like pancreatic cancer.
Precision medicine has already transformed the management of certain cancers like lung cancers. With more research, oncologists like me can hope for more personalised and precise treatments for our patients in the future. At the same time, we also need to remember that the basics of cancer therapy — surgery, chemotherapy, and radiotherapy — are very important and precision medicine has to work in tandem with these specialties to ensure that our patients receive the best possible treatment.
A new generation of personalised cancer vaccines is designed to teach the immune system to recognise the molecular fingerprints or identity of a patient’s tumour and destroy cancer cells before they can return or spread. (AP File Photo) 
Share
