Jan 9, 2020
ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Lauren Davis, and joining me today is Dr. Jeanny Aragon-Ching, a medical oncologist who serves as the clinical program director of genitourinary cancers at Inova Schar Cancer Center in Fairfax, Virginia. She treats patients with genitourinary cancers. Dr. Aragon-Ching, welcome to the podcast.
Dr. Jeanny Aragon-Ching: Thank you very much, Lauren, glad to be here.
ASCO Daily News: We're glad you're here. Today we're talking about new treatment options for patients with prostate cancer and renal cell carcinoma. There are new therapies available, but I wonder how do you decide which combination of drugs to use for a particular patient?
Dr. Jeanny Aragon-Ching: Yes, Lauren, so there has been a lot of exciting challenges and changes actually in both prostate and advanced kidney cancer treatment, so let me first start off with advanced kidney cancers. There has been several recent approvals with a combination of immuno-oncology drugs-- so that's what they're called, I-O drugs-- and VEGF TKIs, which have paved the way for better treatment outcomes. But it is very crucial to pay attention to potential side effects, as we decide to choose between different treatment options.
So for first-line metastatic kidney cancer treatment, the options have always included TKIs alone. So for instance, we've always had sunitinib and pazopanib, although cabozantinib soon joined the first-line TKI therapy, since about late December 2017. So more recently, combination I-Os using nivolumab and ipilimumab, as well as I-O plus TKI combinations, such as pembrolizumab and axitinib, or avelumab and axitinib, have been approved and are currently available commercially.
So one way to distinguish these different regimens would be to evaluate what to call the IMDC criteria. So that stands for international Metastatic RCC Database Consortium criteria. So these are six different factors that the clinician can evaluate for each of their patients. So any time they have presence of anemia, leukocytosis, thrombocytosis, hypercalcemia, and a poor performance status, and if their time from diagnosis to systemic treatment is less than a year, they get a point for each.
So if a patient has none of these factors, they would be considered to have favorable risk disease. And if they have one to two factors, then they are considered to have intermediate risk disease. If they have three or more of these, they're considered poor risk. And that's important because we want to be able to distinguish between these different categories of patients.
So for instance, if we think about intermediate or a poor-risk disease patient, they benefit a lot from the combination of nivolumab and ipilimumab. And this is based on what you call the CheckMate 214 trial. And they reported the 30-month update at ASCO GU earlier this year. So the results showed 11.3% complete response rate compared to sunitinib, which only yielded 1.2% complete response rate. So if we look at the overall response rates for all the patients, 42% versus only 29% in the sunitinib arm.
Now, on the other hand, pembrolizumab and axitinib with the KEYNOTE-426 Trial, also showed remarkable objective responses at around 59% versus only 35% for the sunitinib arm. And the complete responses was also impressive, occurring in about 5.8% in the combination arm.
Now, if we look at the risk of death, it was 47% lower in the pembro/axitinib group compared to the sunitinib group. And the 18-month overall survival was 82% compared to 72% in the sunitinib arm. Now, there's another trial that looked at combination of avelumab and axitinib. This was called the JAVELIN Renal 101 Trial. And it also showed an impressive objective response rate of 55% in the PD-L1 positive population. And that's compared to sunitinib which only yielded like a 25% response rate.
However, the concern was a primary endpoint for the JAVELIN Trial was a dual PFS, so that's Progression Free Survival, and overall survival endpoints. But the overall survival data is not yet mature at this time. And so preliminary results may be really inadequate to draw definitive conclusions as to which one is really the best.
So regardless, the combination I-O and axitinib yielded a good response regardless of these IMVC risk groups. However, if we think about patients who have favorable risk, they really did not benefit as much from the combination pure I-O therapy, such as nivolumab and ipilimumab. And if we look further at the CheckMate 214 Trial that looked at Nivo/Ipi it showed that sunitinib actually had better responses than Nivo/Ipi in that population of favorable risk patients. So it was around 50% versus 39% in those who got Nivo/Ipi.
However, for patients who have intermediate or poor-risk disease, I think it's very important to have shared decision-making between the provider and the patient so that they can both determine if the dual immunotherapy, I-O, I-O therapy, versus let's say, an I-O plus TKI would be the best treatment option.
Now, it's very important to also note that beyond the discussion of efficacy, which is defined by what I mentioned earlier about CR aids and objective response rates, toxicity is very important to think about with regard to choice of treatments. So for instance, the I-O combination, the Nivo/Ipi in the in the CheckMate 214 Trial resulted in 35% of patients who required high dose prednisone. So for us, we defined this as using prednisone of 40 milligram doses or more. So that's certainly a high number, 35%.
However, there seems to be less in the combination I-O plus TKI, only, let's say, 11% in the JAVELIN Trial. So I would say if a patient has strict contraindications and can't safely receive high dose steroids, these different regimens would have to be weighed carefully by the clinician.
Now, on the other hand, there are certain toxicities that are far more frequent in the combination I-O/TKI, for instance, the grade 3 or 4 elevations in liver enzyme levels. So in the pembro/axitinib group, it was certainly higher than previously observed when each agent was used alone as monotherapy. So for instance, in the pembro/axi arm, it was 27% versus only 16% in the sunitinib arm.
I would like to switch gears now for prostate cancer. So treatment for metastatic hormone-sensitive prostate cancer has undergone dramatic changes, also this far. So ADT has been what we've been using for men with metastatic disease. So ADT is short for Androgen Deprivation Therapy, that is until data on CHAARTED and STAMPEDE and LATITUDE showed that adding early docetaxel chemo or abiraterone, respectively, are better in improving overall survival outcomes.
So recent FDA approvals of apalutamide, which is a novel anti-androgen drug, based on the TITAN Trial in the metastatic hormone-sensitive space, is really the newest addition. And it shows improved outcomes. So similarly, another trial that adds enzalutamide to ADT plus docetaxel was presented at ASCO during the plenary session, and this is called the ENZAMET trial, and it showed improvement in outcomes, with 80% of the men surviving in three years, compared to only 72% in those who got ADT plus other non-steroidal anti-androgens, like old generation drugs, like bicalutamide or nilutamide.
However, in the pre-specified subgroup analysis of this trial, it was shown that the effects of enzalutamide was actually smaller among patients who are pre-specified to have planned early docetaxel or in those who have high-volume disease. In addition, we also are aware that while more drugs may mean better efficacy, it actually may also mean more toxicity.
So, for instance, in the enzalutamide arm, where patients also received early docetaxel, there were more grade 2 neuropathy, like 9%, compared to 3% in the other arm. Fatigue was also far higher, at 20% versus only 14.5%, as well as other toxicities, like nail discoloration. Most importantly, 16% of patients in the enzalutamide arm, in addition to the chemo arm, had to stop because of an adverse event, compared to 4% in the non-steroidal arm.
So this tells us that we have to really think about what to give patients with high-volume disease who are otherwise fit for chemotherapy. Since docetaxel appears to be still the most important optimal treatment option, I think adding enzalutamide to ADT and docetaxel may not confer additional benefits, and we would still better serve patients by offering ADT plus docetaxel alone for those who are otherwise fit for chemotherapy.
In contrast, there is no direct evidence of benefit for early docetaxel in patients with low-volume disease and those who are already deemed to have good prognosis. As such, for patients with high-volume disease and not fit for chemotherapy, as well as patients with low-volume disease, we now have direct evidence that overall survival benefit is seen from using abiraterone, apalutamide, and enzalutamide when it is added to ADT.
Now, another phase of prostate cancer that has undergone revolutionary change is what we call the non0metastatic CRPC, Castrate-Resistant Prostate Cancer space. So in this area, we now have three novel anti-antrogens that have been approved in the past year alone that can be added with ADT. So that includes apalutamide, enzalutamide, as well as darolutamide, all of which were approved just in the last year and a half alone.
Now, they do have different side effect profiles, including CNS effects, patients can have more risk of falls, hypertension, fatigue, cardiovascular disorders. Therefore, the ultimate choice for an individual patient really depends on the physician detailing the risks and benefits of each approach and considering the patient's other health care issues. So if they have hypertension, diabetes, certainly assessing access to the care, as well as costs, and most importantly, patient preference.
ASCO Daily News: That sounds very exciting. It sounds like you're really helping to move the field forward. So one of the goals is to improve the patient experience when they're undergoing treatment. What are some ways to reduce toxicity while maintaining efficacy? I know you touched on this a little bit earlier.
Dr. Jeanny Aragon-Ching: I really think the answer to that question is patient selection. Different regimens, we know, result in varying efficacy but also different side effects. So for kidney cancer, for instance, that combination I-O therapy with nivolumab and ipilimumab has the highest potential complete response rates in the order of 11% based on that 30-month follow up that I mentioned of the CheckMate 214 Trial compared to about 5.6% in the KEYNOTE pembro and axitinib study.
However, there was also a higher incidence of patients requiring high dose steroids, that's 35%. On the other hand, when we look at the combination I-O and TKI with pembrolizumab and axitinib or avelumab and axitinib, they have good objective response rates but less CR rates, though I would certainly caution against cross-comparison between trials.
Now, I think it's also important to know that toxicities that pertain to both I-O drug and TKI may not also be easily discernible when they're used together. So, for instance, in liver toxicities, whenever a patient manifests with liver enzyme elevation, the clinician has to determine is this autoimmune in nature versus just transaminitis from a VEGF toxicity so that treatment discontinuation for both would actually have to be undertaken.
On the other hand, treatment side effects that led to discontinuation of any treatment was seen in about 25%. So that's a quarter of patients who received the combination pembro and axitinib. It was about 22% in those who got Nivo/Ipi, and only 4% of those who got avelumab and axitinib. So very different.
So other things to consider, I think, would be the peculiar side effects that occur for each agent, such as perhaps, let's say, higher infusion reactions with avelumab is about 12%. And there's a need to premedicate patients. And the infusion frequency also for avelumab is every two weeks compared to, say, every three weeks for those who got pembro and every four weeks for those who are on maintenance phase of nivolumab. So it's very different in terms of convenience as well for patients.
However, more importantly, patients and physicians alike look at overall survival as well, with both nivolumab and ipilimumab, as well as pembro and axitinib achieving overall survival hazard ratios of 0.71, and 0.53, let's say, for the pembro/axi trial, while the avelumab/axitinib had a hazard ratio of 0.78 that was not statistically significant.
Now, if we look at prostate cancer, we look at similar issues. In order to minimize toxicity, patient selection, I think, is still key as well. So for the non-metastatic CRPC, where we can now add three potential anti-androgens, either apalutamide, enzalutamide, or darolutamide to ADT, we have to be very mindful of the possible additive side effects with hypertension, cardiovascular effects, fractures, seizures, or CNS effects.
So one way of mitigating these side effects is just being attuned to the possible increased risk. And we have to engage our partners, the internists, cardiologists, in monitoring for metabolic syndrome side effects, for instance. So it's very important to be vigilant in watching out for any neurologic effects and frailty for our patients who may be at risk.
ASCO Daily News: That's good to know. What about patients who have co-morbidities? How does that affect prescribing certain therapies?
Dr. Jeanny Aragon-Ching: Lauren, I think this is a very relevant question. There are certain prostate cancer patients, for instance, who are at high risk of developing toxicities, especially because of their cardiovascular, hypertension, diabetes, or even stroke. So if they already have pre-existing morbidity risks, like let's say, poorly controlled blood pressure, hyperlipidemia, they have very high blood sugar, we know that any ADT, as well as all these newer, even newer anti-androgens, have potential added risk.
And there is, unfortunately, no additional guidelines that we can really follow, for the clinicians to follow. So awareness, I think, is very important so that we can mitigate these side effects, and we can partner with their primary care doctors so that we can immediately address emerging issues as they come.
And this encompasses not just seizures, which really make up a very small number of the risks, but rather the mental impairment, memory loss, and a lot of these patients, remember, are elderly and also the patients we see. So they are at particularly higher risk. So it's important to take all of these into consideration.
Now, for kidney cancers, as I alluded to earlier, given the possible autoimmune side effects from the use of I/O drugs, patients who have a pre-existing autoimmune disorders were typically excluded from a lot of those trials. However, it's also important to note that given the high potential risk to require steroids, especially for patients getting the combination nivolumab and ipilimumab, the I-O/I-O combination, it's really an important discussion to have with patients who may have a strong contraindication to receive high dose corticosteroids. So, for instance, those with uncontrolled diabetes or hypertension.
ASCO Daily News: That's great to know. So what's in the pipeline for new FDA approvals?
Dr. Jeanny Aragon-Ching: So yes, I think, I mean, the recent FDA approvals, for instance, in prostate cancer, the FDA has granted a breakthrough therapy designation to a PARP inhibitor called niraparib. So this is now indicated for patients with BRCA1 and 2 mutant metastatic CRPC. But they have to have failed prior toxin-based these chemo and AR, Androgen Receptor inhibitor.
Now, for bladder cancer, I would say treatment beyond immunotherapy or immune checkpoint inhibitors have really left a big void because this is an area of increased unmet need. So recent accelerated approval was granted to a drug called erdafitinib for those patients who have progressed on or at least one prior chemotherapy and had certain FGFR3 gene mutations or FGFR2 or three gene fusions after an FDA approved test.
Another drug that's very promising, not get approved, but was submitted to the FDA for a biologic license application is a drug called enfortumab. And this is for patients who have locally advanced or metastatic urothelial cancer who have previously received an immune checkpoint inhibitor and has received a palladium containing chemotherapy and has failed in the metastatic setting. So I think those are the recent FDA approvals that are really relevant for GU cancers.
ASCO Daily News: That's great. So my last question, I'm just curious about are there recent clinical trials with practice-changing results that you've seen?
Dr. Jeanny Aragon-Ching: Yeah, so I think that the two most influential trials would be in prostate cancer, and I've actually alluded to both of them earlier in our discussion. So one of them is the TITAN Trial which looked at apalutamide in the metastatic hormone-sensitive prostate cancer. So recall that apalutamide was initially approved actually by the FDA in February of 2018 initially for treatment of non-metastatic castrate-resistant prostate cancer.
But more recently, in September 2019, apalutamide was approved for the hormone-sensitive metastatic prostate cancer. So this was the TITAN Trial, which was also updated and presented at ASCO GU and published at the New England Journal of Medicine at the same time. It was combined with ADT and was found to be significantly important to extend overall survival in those patients who received it. It was a 33% reduction in the risk of death. So it also improved radiographic progression free survival compared to placebo plus ADT and resulted in a 52% lower risk of radiographic progression or death.
Another trial that I think is relevant and is practice-changing is the ENZAMET Trial. So this trial enrolled 1,125 men with metastatic hormone-sensitive prostate cancer, and they were combined with ADT and enzalutamide. And again, compared to older generation drugs, non-steroidal drugs, like bicalutamide or nilutamide or flutamide, and those patients also were allowed to receive docetaxel.
So this was a positive trial, as I mentioned earlier. 80% of the men treated with the enzalutamide with or without docetaxel were alive compared to 72% of the men who had received just standard non-steroidal anti-androgens. So this translated to a reduction in the rate of death by 33%.
And again, as I alluded to earlier, the subgroup analysis showed that the men who had a high-disease burden, 71% of the enzalutamide my group versus 64% of the comparator group were alive at three years. On the other hand, of the 537 men with low-disease burden, 90% in the enza group, versus 82%, were alive at three years.
So therefore, the interpretation of this trial is really survival is only improved more markedly with enzalutamide in men who did not receive early docetaxel. Therefore, men with high-volume disease who are fit for chemotherapy are probably the most appropriate patients to receive ADT with docetaxel because additional enzalutamide also brings about seemingly more toxicity.
ASCO Daily News: Wow, there's so much exciting research going on in GU cancers. Well, it's been a pleasure speaking with you. Thanks so much for being on our podcast today.
Dr. Jeanny Aragon-Ching: The pleasure was all mine. Thank you, Lauren.
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