Research Highlights from the European Society for Medical Oncology 2019 Congress, with Ricardo Cubedo, MD

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The European Society for Medical Oncology 2019 Congress was held in Barcelona, Spain, from September 27 to October 1. In this podcast, Dr. Ricardo Cubedo shares highlights from the meeting, including treatment advances in ovarian and lung cancer. He also discusses a new type of clinical trial known as “basket trials” and the ways they are changing the shape of cancer research.

Dr. Cubedo is the Head of Sarcomas and Hereditary Cancer with the Medical Oncology Service at MD Anderson Cancer Center Madrid. He is also a member of the Cancer.Net Editorial Board.

ASCO would like to thank Dr. Cubedo for discussing this research.

Dr. Ricardo Cubedo: Good day, everybody. My name is Dr. Ricardo Cubedo. I am a medical oncologist from Madrid, Spain, from MD Anderson Cancer Center Madrid, and I was among the 25,000 attendees coming from all around the world, attending the last European Society for Medical Oncology Meeting, which took place between 27 September and 1st of October in Barcelona, which is a very beautiful Spanish city by the Mediterranean sea. We had a record-breaking 3,900 scientific communications, so you can bet that there is a lot to choose from, but I have chosen for you 3 topics. Two of them are relevant on their own, and very important results, and the last 1 I think it goes beyond the results themselves, changing the way we figure out things in order to fight cancer.

The first item is the results of the PAOLA-1 trial, focused on advanced ovarian cancer patients. You know that ovarian cancer is the most lethal gynecological cancers, because we cannot cure it when it is diagnosed too late to remove it, usually because it is too widespread within the belly. Nowadays, those patients rely on chemotherapy in order to stop the disease, control their symptoms, and live longer. We usually use chemotherapeutics based on platinum as front-line treatment, which are just too toxic to use all the time. So the way we do it, we give the chemotherapy for some months, then stop, then used again when the disease starts progressing and the patient becomes symptomatic. Those months between one chemo period and the next one, are precious for ovarian cancer patients, because they can enjoy them free from both the burden of progressing disease and the side effects of platinum chemotherapy.

The new drug that was the center of the PAOLA-1 trial is called olaparib. It is a new non-chemotherapy drug that targets directly the DNA of the tumor cells. And what it does is to prevent the DNA in the tumor cell from repairing itself when it is damaged, and that ultimately leads to the death of the tumor cell. What PAOLA-1 researchers really wanted to know is if olaparib, the new drug, was useful to delay progression once the disease was already stabilized by chemotherapy, giving patients a longer period free from chemo between 1 treatment and the next 1. That seemed a good idea, because olaparib is given as pills and has few side effects. 800, more or less, ovarian cancer patients were recruited into the trial from several countries all across Europe and were divided into 2 groups. Group number 1 were treated in the standard fashion: that is, chemotherapy until the tumor stopped, and then, maintenance with a drug called bevacizumab, which already been proven to delay the need for further chemotherapy. That is the standard. In the group B, the second group, that was the experimental group, olaparib, the new drug, was used on top of the standard treatment. Once the disease was [ceased?] with chemotherapy, patients were put on olaparib, and the results were impressive. In the control group, the median time that the cancer took to reactivate was 16 months, one-six, but the group of women treated with Olaparib didn’t need further chemotherapy for a period just shy of 2 years. Researchers even spotted a group of patients with certain mutations in the tumor DNA that achieved an astounding 37-month progression-free survival. Being able to delay a new period of chemotherapy for over 3 years is a big, big improvement for women with advanced ovarian cancer, and a very welcome new tool in our weaponry against the disease.

That was the first item I wanted to discuss with you. The second one is also a clinical trial, a big clinical trial, called CheckMate 227. You know, we oncologists like to give trials those funny names. This is a trial for lung cancer patients. It is a very large study. It is still ongoing in over 300 hospitals all over the world, also in America. The non-small cell variety of lung cancer is the most common subtype of the disease and a really ruthless one. Lung cancer kills, every year, more Europeans or Americans than any other malignant tumor. So it’s no wonder that huge resources are devoted to research against this beast. Being such an aggressive disease, equally aggressive chemotherapy has been the cornerstone of its treatment, when the tumor has grown or spread beyond the reach of surgery. Again, the problem is that such overaggressive treatments like combination chemotherapy with 2 or 3 drugs at the same time, might put a temporary break on the disease but unfortunately at the expense of quality of life.

What the CheckMate 227 trial explores is the role of immunotherapy. Immunotherapy, I am sure you have heard about it, is a new field of anticancer drugs, non-chemotherapy drugs, that do not attack cancer cell themselves but, instead, use some kind of molecular trickery to shake our own immune system against the tumor. The combination of 2 of such immunotherapeutic drugs, which are called nivolumab and ipilimumab, was compared in this trial to standard chemotherapy. So 1 group received the usual chemotherapy, and the other group received no chemotherapy at all, but those 2 immunotherapeutic agents combined.

The results were eagerly awaited, probably the most expected results in the whole meeting, and were disclosed in Barcelona amidst much expectation at a fully packed hangar-sized conference room. The full size of the trial is suspected to be north of 2,000 individuals, but we already know what happened to the first 800 group of patients during a 2-year period, and the results are quite encouraging. Unfortunately, non-small cell lung cancer is still a deadly disease, because no matter which treatment patients received within the trial, less than half of them were still alive at the 2-year mark. But while only one-third of the patients treated with current state-of-the-art chemotherapy were alive 2 years after treatment, 40% reached the 2-year bar among those treated with immunotherapy. Moreover, and more importantly, there were hints of a small group within that 40%, approximately 2 out of every 10 patients, that stabilized for long periods of time. Something very similar, stabilization, was observed some years ago, when we started to use immunotherapy in melanoma patients. And we now know that many of those patients, stabilizing for many years, are now in fact cured, even with extensive metastasis widespread into many organs. So at first glance, CheckMate 227 results might not seem much, but they mean that, for the first time, we have proved we can treat advanced lung cancer patients without a single drop of chemotherapy, which means much better quality of life. And we have, also for the first time, a realistic prospect for a cure, more beyond mere wishful thinking.

So we have seen the results of a couple of trials which are what we call “practice changing,” which means that many ovarian or lung cancer patients worldwide, should be treated in a different way, with better results, as soon as their oncologists attending the meeting fly back to their working sites.

Lastly, the third piece of information I would like to share with you proves we are now right in the middle of a medical revolution. It’s not surprising if I tell you that the first thing an oncologist like me will try to figure out when faced with a new advanced cancer case is where it comes from, because we do not equally treat a breast cancer case, a stomach cancer, or lung cancer. Well, it has been so until recently. During the last decade we have learnt quite a bit about the nuts and bolts of cancer. Specific gene mutations and wrecked proteins are both the hallmarks of cancer cells and targets for new drugs. I will give you an example: several years ago researchers found a protein called HER2 on the surface of cancer cells in 2 or 3 out of every 10 breast cancer patients. What this protein does is to rev up the cell’s machinery keeping it in constant multiplication and leading to fast tumor growth, so those were patients with very bad prognosis, as the tumor that grows rapidly, also spreads rapidly. But a new drug called trastuzumab was tailored to disable HER2, the protein that was accelerating the tumor cell, and that made a huge leap in the treatment of HER2-positive breast cancer patients. But the white-coated guys at the research labs showed us that HER2 was not only present in breast cancer, but also in subsets of gastric, lung, ovary, womb, bladder, colon, and head and neck tumors, which was quite surprising, because those are completely unrelated malignancies. Nowadays, trastuzumab, the breast cancer drug, is also used to treat gastric tumors and is beginning to raise interest in the lung cancer arena too.

Well, inspired by those facts, some brave oncologists began to think out of the box and wondered if all we really need to know is the mutations and other molecular characteristics of the tumors in order to select treatments targeted against them, no matter where the cancer comes from. To treat in the same way, a colon cancer, a thyroid cancer, a breast cancer, or a brain cancer, provided they have the same molecular basis. Well such ideas were so revolutionary, they raised a few eyebrows and a lot of skepticism, but, well, this is science and we do not dismiss ideas without some previous research. Thus, the so-called “basket trials” were designed and carried out. Patients in such “basket trials” were hand-picked based on specific mutations and put to treatment, just like one chooses ripe berries and collects them into the basket.

The result of such ground-breaking trials proved that the concept was right. In this Barcelona meeting, Dr. Christian Dittrich from Vienna presented us with the combined results of 2 basket studies: the SCOUT and the NAVIGATE trials. Both explore the activity of a new drug called larotrectinib, in patients with any kind of cancer, provided their tumors had a mutant form of a protein called TRK. When healthy, TRK proteins are essential for a healthy brain and nervous system. But once mutated, TRK leads to cancer in several organs. And that was the basis of the trial. The new drug, larotrectinib, is carefully designed to disable the mutated TRK proteins while sparing the healthy ones you need. Both clinical trials combined included, more or less 160 patients, from children under 1 year to 84 year old adults. The results presented at the meeting in Barcelona were rewarded with the general applause from the audience, because they were astounding. 80% of the patients responded to the drug, more than thee-quarters of them still without signs of any health deterioration 1 year after they were given their first dose. Such results are really remarkable, as we are speaking of a group of patients diagnosed with no less than 18 different types of cancer, treated with a single drug, many of them having failed to several previous treatments or resistant to any known therapy.

Those results are not practice changing, because we have to resolve a lot of questions first, but are very exciting because they open a new drug for cancer treatment.

After a good medical meeting you go back home with some answers. But after a really good one you collect many more questions than answers. Are we going to treat patients based on their tumor genetics instead on classical tumor types? How are new treatments to be combined? Which ones should be given frontline, which ones after progression? What genes should be checked in tumor biopsies on a routine basis? Are there late side effects still to be seen from the new drugs? When to stop maintenance treatments? Are some long-lasting responders really cured of their cancer? How are we going to pay for the new ultra-expensive fancy drugs, some of which are to be maintained for years, even lifelong? Many, many questions to answer.

One thing I assure you: these are thrilling times to be an oncologist. I thank you all for your attention.

ASCO: Thank you, Dr. Cubedo.

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