Thomas Hutson, DO, PharmD, FACP, at Baylor Scott & White Charles A. Sammons Cancer Center talks about a treating kidney cancer with the CLEAR study.
Interview conducted by Ivanhoe Broadcast News in 2023.
Hutson: At the 2023 American Society of Clinical Oncology meeting, I presented the final prespecified overall survival results from the phase 3 CLEAR study. The phase 3 CLEAR trial was an international study involving roughly 1,200 patients with metastatic advanced clear cell renal cell carcinoma. These patients were randomized to receive Pembrolizumab, Lenvatinib, Everolimus, or Snibnib. The results had previously been published and are positive in regards to statistically significant prolongations in progression free survival improvements in response rate, as well as a safety profile that made it amenable for use in patients. These results have been published in the New England Journal Medicine and resulted in regulatory approval of the regimen around the world. At this meeting, we presented the 23 additional month follow up on overall survival, which was pre-specified, and we were able to show that the hazard ratio for overall survival of 0.79 was maintained now at four years. Additionally, the progression free survival and response rates were as robust as previously reported and maintained. In specifics, the objective response rate was 71% with a complete response rate of 18%. The toxicity profiles were also updated, and I am pleased to report that there were no additional new safety signals, so the regimen was as tolerated as initially reported. These results confirm the robustness of Lenvatinib, Pembrolizumab as a major frontline treatment for this cancer. They should also give great comfort to prescribing physicians around the world and patients that the therapy that they are receiving has stood the test of time with continued benefit.
That’s really good, really good. Move on.
Hutson: Phase 3 CLEAR study enrolled patients from around the world. The geographical distribution of that was broken down between U.S. and European as well as Asian and Asia Pacific regions. The average age of patients enrolled in this trial was balanced between treatment arms and was roughly 65 years of age, which correlates to the average age of diagnosis of this cancer. The cancer is more common in men, so that was represented in the clinical trial. All arms were balanced in regards to normal demographics and a site of origin, location of enrollment on the trial. That’s it for that.
That’s good. Anything else that we need to know about the study composite make up, something that maybe surprised you? I know this was a phase 3 and probably is no surprise, but is there anything that just really stood out to you from a researcher?
Hutson: The phase 3 CLEAR study was notable, not only because it was one of the largest reported phase 3 trials to date in kidney cancer, but because of the efficacy endpoints being some of the greatest we’ve seen to date. The overall survival being maintained at four years with a hazard ratio of 0.79 makes it one of our most active regimens. The ability of the regimen to produce tumor shrinkage in 71% of patients and a complete response rate in 18% of patients, makes it our most active regimen recorded so far.
The CLEAR study was looking at what type of cancer?
Hutson: The CLEAR study was evaluating patients with advanced and metastatic renal cell carcinoma.
What is that? Is that kidney cancer?
Hutson: Renal cell carcinoma is the most common cancer of the kidney. In fact, people will use the terms interchangeably. When patients say they have kidney cancer, usually they indeed mean they have renal cell carcinoma. The cancer can be cured, usually with surgery, but once it has spread beyond the confines of the kidney to other sites of the body, or has returned after initial attempts of curing it, then the cancer is generally not felt to be curable. This cancer has had many changes in its management over the years. Prior to 2000, this cancer was felt not to be treatable when it came back or spread. But through advances in science in the late 1990s has resulted in a couple waves, if you will, of therapies being developed. Our first wave generation of therapy was predominantly oral therapies that were identified that could target blood vessel development. This was followed by the current wave of therapies which was hallmarked by the discovery of immunotherapies. Immunotherapies, many people have recognized from various commercials on TV are antibody treatments that go in and turn on the body’s immune system and help it identify cancer cells. It turns out that kidney cancer is one of these cancers which has been able to learn how to survive in our bodies because of its ability to camouflage itself from the immune system. And so our next generation of therapies have incorporated this understanding with involving immune therapies, and we’re combining them now with newer generation oral therapies that target angiogenesis, as well as other things that we believe to be important in the pathogenesis and development of the cancer. So essentially, our initial therapies for this cancer are now what we call combination therapies using both immune therapy combined with most of the time with oral therapy. This combination of therapy has improved the outcomes in patients, and for the first time ever, there’s a small group of patients that can actually witness their cancer disappear on X-rays. Whether or not these patients have long term cures is unclear at this point, but it is nonetheless a big advance for us and more patients than ever are responding to this therapy. So for patients out there, they should approach this cancer with a lot of hope and optimism. For the first time ever, we have therapies that the majority of patients will achieve benefit and have a prolongation in their life, a meaningful prolongation in our life with controllable side effects, allowing them to do those next important things that they would like to do.
That was phenomenal. What was the drug that was being evaluated as part of this new breakthrough?
Hutson: So, the CLEAR study evaluated the approach of an immunotherapy, in this particular case, Pembrolizumab, which is an antibody that targets PD1, which is a special protein that is manipulated by the cancer to evade immune detection, and Lenvatinib, which is an oral multi targeted kinase inhibitor that targets VEGF, which is an anti-blood vessel protein, as well as other proteins such as FGF, which is a growth protein that the cancer utilizes to grow and spread.
So you’ve been able to witness the evolution of this particular therapy. What has been, from your perspective, responses from patients seen that now, yes, you mentioned that they have a sense of hope?
Hutson: The sense of hope comes that when we administer a regimen such as Lenvatinib and Pembrolizumab, first off, the vast majority, 90, 95% of patients can expect to have some benefit from the therapy with at least stable disease, no further growth on repeated imaging. And for 70% or more of them, they have a significant reduction in the size of tumor. And this is a durable benefit where they can stay on this therapy and have maintained control. And we’re turning the cancer into a chronic illness where with treatment, patients can have disease control, allowing them to continue on and live their lives and experience the joy of that, and to do things that they otherwise could not have done before this therapy came to market. In general, I think it’s fair to say with the various therapies that we utilize and we use them in sequence. So patients, if they lose benefit from one type of therapy, then we move on to a different line of therapy. And by doing that in sequence, patients can live 3-5 times longer than what they would have just a decade earlier.
So survivability has really increased as a result of this study and what you have found in the research, right?
Hutson: For sure, more patients with the advances we have in 2023 in the hope of AI and all these further advances in the next few years, patients can really approach their cancer therapy with great optimism that they are going to have the ability to live with their cancer. In fact, more patients are living with their cancer longer than ever before in history, and our goal is to cure more patients, and I think that’s a realistic expectation over time.
This is a great breakthrough and there’s always evolving trying to beat cancer and injury in any form. What’s the next step?
Hutson: The next step is to take where we are today and push the field even further. And that can be with the discovery of new types of therapies. These new types of therapies may replace what we’re currently using or they may be added to what we’re currently using to even get greater benefit. I think it’s important for patients to realize that these new therapies exist and to make sure when they’re seeing their physician, that their physicians are aware of the therapy, and to seek out expert medical care to make sure that they get the best, most up to date treatments.
END OF INTERVIEW
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