World-first cancer trial using genomic profiling to personalise combination therapies

Medical oncologist and renowned expert in precision medicine, Dr. Razelle Kurzrock, visited Australia recently as a speaker for a series of educational meetings.

Health Industry Hub had the pleasure of meeting with Dr. Kurzrock to discuss precisionalised medicine and how cancer therapy is being transformed by using advanced technological tools to predict who will respond to a specific treatment, and how to match each patient with the best drugs for a particular tumour.

Dr. Kurzrock is the Director, Centre for Personalised Cancer Therapy, Senior Deputy Director for Clinical Science, Moores Cancer Centre and Chief, Division of Haematology-Oncology, Department of Medicine at the University of California San Diego, United States.

Health Industry Hub: What is precisionalised medicine and how is it different to precision medicine?

Dr. Kurzrock: ‘Precision medicine’ has been used interchangeably with ‘personalised medicine’. I am often asked, ‘Is it precision medicine or is it personalised medicine?’ It is in fact both because we know that tumours are individually very complicated and each tumour is unique. Therefore, in order to be precise, we have to personalise. We have to give an individualised or personalised therapy to each patient. Precisonalised medicine reflects the concept of being precise by personalising.

Health Industry Hub: How is precisionalised medicine transforming oncology care in terms of clinical trials, patient outcomes and cost to the economy?

Dr. Kurzrock: It is just beginning to change oncology care. In the past, before we had the ability to perform genomic sequencing, we provided drugs to patients in a clinical trial then in clinical practice and measured responses. In a way we were blindfolded. We really did not know which patients would respond and even when we saw responses, we would not be able to understand why certain patients responded to a drug and others did not. We did not have the tools to understand what was wrong with the tumour.

Sequencing and comprehensive genomic profiling have allowed us to dive deep into the cell and understand precisely what is wrong with that cancer cell, and therefore be able to match patients with the right drugs for their cancer, rather than guessing which drug is best by looking at the overall population. Historically, we would say, can we get 20% of the population to respond? Now we are saying, what is wrong with your particular tumour? That means matching patients with the right drugs for their tumour. It also means that we really have some remarkable new drugs that have high response rates that could never have been developed previously, because they target a very small fraction of the population. If we had used them 10 years ago, the response rates would be less than 1%. When we identify the right patients, that response rates may be 80% because we treat only those patients with the target.

I am not an economist so I am going to share my views regarding cost from the perspective of an oncologist. I spent the first 20 years of my life in oncology giving drugs that were fairly useless to patients that generally made them sick without shrinking the cancer. Sick patients cannot work. The entire family is affected by a person with cancer, whether it is the husband, the wife, even worse if it is the child. Having patients debilitated cannot be good economically. Now, many patients are doing better. We are not perfect at this yet because this is really rapidly evolving technology. Patients get these drugs and they feel well often for long periods of time. And yes, the drugs are expensive, but they are making people better and allowing them to be functional parts of society.

Health Industry Hub: Who is involved in the multidisciplinary team treating oncology patients? How has this evolved with the introduction of precisionalised medicine?

Dr. Kurzrock: The multidisciplinary teams have expanded. We continue to work very closely with our surgeons, pathologists, radiologists and radiation therapists. The idea is to integrate these types of care with the caveat that we want to give the right care to the right patient. We need additional people that were less important before but have become very important now, for example, the genetic counsellors, translational scientists and bioinformatics specialists. As we are performing genetic profiling, we find more patients that may have hereditary disposition to cancer. The bioinformatics specialists help us review our data and see relationships between certain abnormalities that we may not have expected and subsequently we can better understand why certain cancers respond and others do not. The additional members of the multidisciplinary care team are bringing critical expertise in science and genetics.

Health Industry Hub: Tell us about the I-PREDICT study and its potential impact in precisionalised medicine.

Dr. Kurzrock: The I-PREDICT study is a break-the-glass type of trial. It stands for Investigation of Profile Related Evidence Determining Individualised Cancer Therapy. I collaborate with Dr Jason Sicklick who is the lead and I am the senior investigator.

The I-PREDICT study allows us to provide customised combinations of therapy, not just single agents, to cancer patients. This includes two, three or even more agents that are tailored to the genomic profiling of the patient. The trial is using Foundation Medicine profiling, both the blood profiling and the tissue profiling. To my knowledge, this is the first trial, that customises a combination therapy based on genomic profiling for each patient.

Historically, the first generation of trials gave individual agents based on the genomic profiling, However, patients have complicated genomics. While individual agents sometimes work, many patients many need more than one drug, and each of those drugs needs to be customised to the patient.

We published the results of the first 149 patients in Nature Medicine in May 2019. Targeting of a larger fraction of identified molecular alterations, yielding a higher ‘matching score’, was correlated with significantly improved disease control rates, as well as longer progression-free and overall survival rates, compared to targeting of fewer somatic alterations. Stronger matches generally required combination treatments, not single drugs.  

We have completed accrual for the second part of the trial and now analysing the data. I think this is a second break-the-glass approach. We believe that for the most part, comprehensive genomic profiling has been used too late in the disease. In other words, the patients that are treated often have been through multiple treatments and are end stage. These are the most difficult patients to treat. We believe that if we can get to the patients earlier, where their disease is less evolved, we may see better responses. The second part of the trial includes patients that have newly diagnosed metastatic disease with no prior conventional therapy and 50% chance of dying in two years with conventional therapy. For these patients with very aggressive tumours we conduct comprehensive genomic profiling and match them to a customised drug combination.

Health Industry Hub: With regards to the drug combinations, are there any issues from a funding perspective to access these medications?

Dr. Kurzrock: There is not a funding issue for our clinical trial due to the way it was set up to take advantage of the multiple ways there are to obtain drugs for patients in the United States, and that includes off label drugs as well as navigating patients to one of our many clinical trials based on their genomic profile. The way we have conducted this trial and specifically the way we access the off-label drugs is not scalable for the country. In saying that, the purpose of the trial is not to scale for the country. The purpose of our trial is to prove that our strategy works. The key stakeholders then need to work with the regulatory agencies to determine how to change the current regulatory framework so that patients can access combination therapies through precisionalised medicine.

Health Industry Hub: Form an adverse event profile perspective, do the benefits outweigh the risks when combining multiple oncology treatments?

Dr. Kurzrock: This is a critical question. It is one of the reasons that people have not previously given customised combinations. In oncology, there has been a culture that you do not combine cancer drugs together, unless there has been a phase I trial of the two drugs. A phase I trial takes progressive groups of patients and gives them higher doses to figure out the optimal dosing of the drug. In a similar way, when no previous phase I trial has been conducted, we dose escalate within the patient. We start at a lower dose and we escalate the dose of each drug until we reach the maximum dose that patient is able to tolerate. We have an independent Data Safety Monitoring Board that monitors our trial and the toxicities in the patients that were treated in this way versus patients that were treated with conventional therapy. The toxicity for our patients was lower than those treated with traditional anticancer medications, perhaps due to how carefully we titrate the doses and monitor the patients.

Interestingly the average patient that comes into the cancer clinic is on eight different drugs for health conditions other than cancer. This is because the average patient is an older patient with multiple co-morbidities. As physicians, we give drugs together all the time. It turns out that oncology is the exception to the rule in the concern about combining drugs. But the tradition of not combining oncology drugs is a legacy of the chemotherapy era. Chemotherapies are very harsh and difficult to combine safely. Newer drugs, while not free from side effects, are less harsh than chemotherapy and easier to combine.

What we are doing now in our oncology program, with these drugs that are much safer and easier to combine, is simply what we have always done in medicine outside of oncology, and that is to individualise drugs. By titrating the doses up slowly, we have demonstrated that we are able to combine multiple oncology treatments safely.

Health Industry Hub: What do you see as the potential barriers with precisionalised medicine?

Dr. Kurzrock: Comprehensive genomic profiling leads to precisionalised medicine. The profiling is a technology that has emerged at breathtaking speed. One of the barriers is that physicians are unfamiliar with it. Unfortunately, even the physicians that are graduating through medical school and starting their fellowships are not being adequately trained in genomics. We need to have physicians that go through medical school, residency and fellowship be native speakers in genomics.

The genomic revolution is going to impact all of medicine, not just oncology. Physician training needs to reflect this. For physicians in practice, there may be opportunities to familiarise themselves with this very powerful new technology through continued graduate education programs and symposiums.

Another barrier is that we still require to publish more data to firmly establish precision medicine approaches that work best.

The third barrier is access to the drugs, because that is a very big barrier for physicians. The regulatory structure in most countries was not set up to accommodate this powerful technology. There are a number of critical changes required for precisionalised medicine to take hold in the next 5-10 years.

Health Industry Hub: What opportunities are there for collaborative US/AUS research in precisionalised medicine?

Dr. Kurzrock: Currently we are not conducting any trials in collaboration with Australian centres. I was invited last year to present at the Garvan Institute of Medical Research about precision medicine so I see that there is a real appetite for understanding genomics and Australia is leading major efforts in sequencing rare tumours. I would be open to collaborative trials and to helping academic centres and researchers establish similar trials. In fact, I want to see researchers replicating these trials. I am convinced that what we are doing is the right thing for patients and we can learn from each other for the benefit of our patients.

Health Industry Hub: What is your vision for the future in oncology treatment and precisionalised medicine?

Dr. Kurzrock: My vision is that in the next 5-10 years the patient will immediately have their cancer tissue profiled genetically upon diagnosis. We also would take a blood specimen because we are able to conduct comprehensive genomic profiling on a vial of blood. The matched therapies would be chosen for that patient early in the course of the disease before we do the guesswork therapies. Right from the beginning, we would choose the therapies that match their tumour so that each patient receives a precisionalised cancer treatment regimen. The bottom line is that we would match oncology patients with the right drugs early in their disease course to enhance patient outcomes.

About Dr. Razelle Kurzrock

University of California San Diego (UC San Diego), United States

• Director, Centre for Personalised Cancer Therapy
• Senior Deputy Director for Clinical Science, Moores Cancer Centre
• Chief, Division of Haematology-Oncology, Department of Medicine

Before joining University of California San Diego in 2012, Dr. Kurzrock developed one of the largest Phase I clinical trials programs in the world while at the University of Texas MD Anderson Cancer Centre. A central theme of that program was the personalised medicine strategy, which matched patients with targeted cancer treatments that optimised chances for response.

Dr Kurzrock received her medical degree from the University of Toronto. She has more than 750 peer-reviewed publications and a uniquely strong record of competitive grant funding within the setting of Phase I clinical trials program building. She has previously been the principal investigator of the National Cancer Institute Phase I Studies of Targeted Anti-Cancer Agents. She is also a frequent speaker at national and international meetings.