Second-Generation Combination Treatment Shows Long-Term Efficacy Against Advanced Kidney Cancer

Thomas Hutson, DO, PharmD, SCRI at Texas Oncology, part of The US Oncology Network, joins Pharmacy Times to discuss positive 4-year follow-up data from the pivotal phase 3 CLEAR study, which compared lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in patients with advanced renal cell carcinoma (aRCC). Hutson presented the prespecified overall survival (OS) analysis at the 2023 Annual Meeting of the American Society of Clinical Oncology. Hutson’s unique background also comes into play as we discuss end-of-life care and the oncologist’s ability to help someone pass with dignity.

PT Staff: What is the mechanism of action of L+P for aRCC compared to S?

Thomas Hutson, DO, PharmD: So L + P is a combination therapy and it really represents what I would call our second generation of treatments for aRCC. Our first generation started backing and with our first approvals in 2005, of what we call oral targeted tyrosine kinase inhibitors (TKI), oral TKI therapy, which targeted the vascular endothelial growth factor (VEGF) pathway and some other components that were shown to be involved in the pathogenesis of the cancer really things that were related to Von Hippel-Lindau (VHL) mutation and expression of VEGF, which is an angiogenic factor.

For our second generation therapies, what we what we have are oral targeted therapies that not only target the VEGF pathway, which we know is very important in the pathogenesis of the disease, but also start targeting some other things that are involved in angiogenic escape resistance pathways and so we see the second generation pills, what we call multitargeted tyrosine kinases (like L) which hit the market, and they (within the case of L) target VEGF, CD117 (c-KIT), platelet-derived growth factor (PDGF), and most importantly fibroblast growth factors (FGFs). And so L is a powerful kind of second generation TKI. That is a first approval was in the refractory setting, where it was able to show patients who add progression on things like S could go on to receive this agent that also targets VEGF, but targets other things and could overcome the resistance and we saw significant benefit. in the case of L, it was combined with everolimus.

And P is also what I call a second generation— at least for kidney cancer therapy. And it targets a completely different process. And that's the checkpoint process where we know that certain cancers of which kidney cancers are prototype would evade immune detection by exploiting this checkpoint pathway that you and I normally have to control immune response and so that cancer cells would have this programmed cell death protein 1 (PD-1) on its surface, and it would interact with the immune cells in through the programmed death ligand 1 (PD-L1). And they would essentially (when they touched each other) they would join and they would turn off the immune cell. And the checkpoint inhibitors were designed as antibodies that go in and prevent that negative immune interaction, allowing the immune cells that were normally in the environment of the cancer cell, to be able to recognize it as foreign and fight it.

And so naturally, in oncology, we have a lot of combination regimens. And so we try to take therapies that have individual activity in the cancer, in which case Keytruda, and then fat nib have individual activity in the cancer, and combine them together in hopes that we get at least additive.

But that's not the only story here. So we have known that these that these oral TKIs, some of them have the properties to modulate the immune system themselves. And L also had the ability to cause immune cells to infiltrate the tumor, they could affect T-cell trafficking, and modulate the immune response there. So not only do we think of an additive effect of combining the 2, but possibly a synergistic effect because the L was able to help bring in the immune cells. And then the checkpoint inhibitors help is able there to make sure that they stay on, if you will. So it's really a 1 + 1 = 3 would be the hope of it. But at the minimum of 1 + 1 = 2.

PT Staff: How is S currently used in combination with other treatments for aRCC?

Thomas Hutson, DO, PharmD: So in the trial, the CLEAR study, as well as really all of the pivotal trials that that have been done over the past 5 to 6 years, the control arm of these trials, we're submitting them. S was a first-generation oral therapy. It was the second one approved back in 2006. And it was the best therapy we had produced the greatest efficacy of any of the therapies we had. And it stayed that way up until about 2014/15. When these newer generation the second-generation drugs were coming out and showing that there was superiority to S. So S is now move back in the lines of therapy to something, fourth, fifth, or six.

It's not a common frontline therapy at all anymore. So it'd be extremely rare for someone to get S as a first line agent really anywhere in the world. Right now there are unique situations however, when we will still consider using an agent like S or pazopanib as a frontline agent, but those are few and far between the SoC right now as reflected in all of the guidelines are to use a checkpoint inhibitor as a backbone therapy, of which P (Keytruda; Merck) is one and combine it with one of a few a handful of different oral therapies, of which L is one, the alternative and that we call that regimen and immune-oncology (IO)-TKI regimen. Or alternatively, one could use 2 IO drugs together and that is the only version of that that's approved is it ipilimumab and nivolumab. And so both of those strategies employ IO.

And so the most important thing for a clinician and for healthcare providers that that work together with the physician are to understand that the SoC really should be a checkpoint inhibitor, if at all possible.

PT Staff: Can you discuss outcomes (OS, PFS, ORR, and DOR) of L+P vs. S from the phase 3 CLEAR trial?

Thomas Hutson, DO, PharmD: So thiswas a trial for roughly 1,200 patients that had 3 arms, L + P, S, and L + everolimus. The topic moving forward was L + P, the most active arm. to go on to this trial you needed at least a component of clear cell; you could have been favorable intermediate report and your prognostic groupings throughout.

The patients were stratified based upon the geographic region the part of the world they were enrolled to, and they continued on therapy until unacceptable toxicity or progression of note P was given for a total of 2 years, which has become standard for all of the various trials it's used in and we did tumor assessments with computerized tomography (CT) scans every 2 months. And the primary endpoint of the trial was progression-free survival (PFS) by blinded review, and we saw significant PFS more than 23 months versus S, which was down around 9 months. So we saw a profound benefit in PFS that was highly statistically significant. And the hazard ratio was very low around 0.4. And this trial was positive.

Then the secondary endpoints of OS and objective tumor response rates (ORR) were also robust in the way of OS on its initial report, the median had not been reached. But the hazard ratios were sitting at about 0.7, which was very attractive. And the curves were certainly separated. When it comes to response rates, we saw the greatest amount of tumor shrinkage that we've seen reported to date with any of the therapies. And that is a 71% response rate, which means greater than 30% tumor shrinkage, and a 17% complete response (CR) rate. And then if you added up the clinical benefit rate, which includes stable disease that was more than 90%, that means that over 90% of people that get this therapy are at least going to have stable disease when they receive it.

So, it works in virtually all patients. And that was exciting enough to receive regulatory approval in the United States and many countries around the world and it became incorporated as a main frontline option for our patients. This was circa 2 to 3 years ago, what we reported at ASCO. This week was the final prespecified 4-year OS analysis and we've got 23 months of additional follow up. And we're we were happy to report that the PFS stays as robust at 23.6 (or 23.7) months. And so that was maintained with a hazard ratio I believe, roughly 0.48. And then when it comes to OS, we were able to report an OS hazard ratio of 0.79.

So, what we can conclude there is on further follow up that the robustness of the efficacy, PFS OS and response rates are maintained. So there should be no reason for a clinician or a patient to be worried or fear that that this this therapy will won't have the power to get them through if you will. And now we could report with 23 more months of additional follow up that there were no new safety signals and that the side effects were as reported and could be handled with the dose interruption dose reduction strategy as outlined.

PT Staff: I understand this combination is now standard of care for aRCC- how do you see it being used in the next decade for this disease or other similar disease types?

Thomas Hutson, DO, PharmD: So, L has been incorporated into our guidelines and is now a recommended standard frontline option. it also has been evaluated in other cancers and will continue to do so. And it has an approval, I believe in endometrial cancer and possibly even ovarian cancer, but it's being evaluated and other tumor types. And, and so each cancer brings its own uniqueness to it. But it's very encouraging as far as kidney cancer goes, and the landscape is that combination therapy is here to stay. We're really looking as a field to the next generation.

I kind of broke it down into these generations, and we're looking for the third generation, and hopefully in the next few years [we will] have small molecules or newer mechanisms of action, that will be even more combinable with what we currently have and push higher cure rates.

And so some of these small molecules are actually entering phase 1 trials. And so it's very exciting for me, being a phase 1 doctor and leading a phase 1 program for Sarah Cannon Research Institute, to be able to sit there and get access to some of these molecules and combine them. So not only molecules that would work, for instance, in patients who already had a drug like L and P and may have had progression. So drugs that may or may work similarly on the immune system, but can overcome resistance that you could bring and could continue to benefit patients.

And then also molecules that you could combine with the L and P and get even a higher degree of efficacy. So what I can tell the community is that in aRCC patients, these drugs do exist, and we are studying them, and studying them aggressively. And we there's great hope that will bring a third generation in in the next few years.

Now, the other area is in selecting of patients. And so this is a whole other area of field. This is where we look at biomarkers or ways that we can separate patients out genetically and try to predict who is going to benefit from one type of therapy or the other. So in kidney cancer, we do have a little bit of an embarrassment of riches where we have several agents to choose from. So how do we individualize to a particular patient in front of us, which of these agents may be best for them. And so, this is where we want to be able to look at people's tumors be able to in real time, sequence them, and understand which tumor would benefit from which therapy approach. And so this idea of selecting and biomarkers is going on not just in kidney cancer, but in many cancers. In fact, there were talks at ASCO about next-generation sequencing (NGS) as being the front tier for cancer. And that's where we are too. So, it's really a 2-prong approach moving forward; it's new therapies, new mechanisms of action, and then finding ways to select patients better.

PT Staff: I understand that you were the medical director for a Hospice center in Dallas. Seeing that aRCC remains a serious, deadly condition, what is your approach to helping patients that need end of life care?

Thomas Hutson, DO, PharmD: Yeah, and so part of the oncologist’s job is partnering with patients and their families and trying to take that step back. It's very difficult to not get emotionally involved because we are humans and we share these struggles and we celebrate the victories with them, too. But also they look for the oncologist and the medical professional to be able to take a step back and in and be honest with them.

So every patient I've met in their cancer journey has always wanted me to be honest with them. And that's why they choose to stay with me because they feel I am honest, and they feel like they're getting the truth. And so I think at the beginning of the cancer journey, it's important to, to sit down with the patient in the family and come up with goals and expectations and align them with what the reality is of what we can expect to achieve; we can always hope and we can always ask for divine intervention, which is always great, but we have to be realistic too and help patients set a set of a priority and a list of goals.

And then when we get to the point where it just seems that that modern medicine can't provide any more additional benefits are that the cost of the patient and their quality of life (QoL) is not worth what benefit they would get from it, then we must take a shift and talk about palliation and QoL as the primary focus—comfort. Really, it’s give the patient back the control to dictate how things go to the end. And this is something that patients are scared of and it's something they don't have control of a lot.

So, the irony of this is that patients come in to see their doctor with their diagnosis very much in control of their lives. Part of the journey with cancer is losing giving up control, where you must then realize “I'm not in control of what's going to happen to me. I can't control much; I'm taking medications, I don't know the responses. All I can do is listen and do what I'm told.”

And then at the end, it's giving back control to the patient and saying, “Hey, this is your time. We're here now to support you. You tell us what you want. done.” So, it's really again, it's that whole conversation with the patients, partnering with them, and making sure we give them dignity at the end of life. It's sad for me because I’m seeing a switch over [from] a patient that may have been seen me weekly [to] I never see them again. And so, it's a sad goodbye but at the same point it gives me great [joy], it makes me feel good that I was there to walk with them on their journey and at least get them to the point where they can take over controlling and pass with dignity.

PT Staff: Are there any remaining points that you would like to touch on?

Thomas Hutson, DO, PharmD: I think we're amazing to live in a time where it's exponential scientific progress. We didn't really get modern chemotherapy until the 1960s (70s) and just look where we are in a short 50 or 60 years; just how much we've learned. And it's just exponential growth in our understanding and in our ability to impact and treat cancers that, once, never would be treatable; that's certainly the case in kidney cancer. Kidney cancer reached the point where it could become a treatable cancer back in 2003. And it's just been amazing to see how that's impacted the life expectancy of patients with this cancer so it's a time for us all to be very, very happy to pat ourselves on the back but also to look forward to the continual challenges we face to push the field forward.