The FD Approval of a Drug Combination for Advanced Non-Clear Cell RCC

Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss the CLEAR study in renal cell carcinoma, a new exploratory analysis combining the TheraP and VISION trials in metastatic urothelial cancer, and compelling advances in prostate cancer and across GU oncology in advance of the 2023 ASCO Annual Meeting.

TRANSCRIPT

Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host for the ASCO Daily News Podcast today. I'm the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to welcome Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical director of the Genitourinary Cancers Program at the Inova Schar Cancer Institute in Virginia.

Today, we'll be discussing some key abstracts in GU oncology that will be featured at the 2023 ASCO Annual Meeting.

Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcript at asco.org\DNpod.

Jeanny, it's great to have you on the podcast today.

Dr. Jeanny Aragon-Ching: Thank you so much, Dr. Agarwal, for having me.

Dr. Neeraj Agarwal: Jeanny, let's begin with Abstract 4502 regarding long-term updated results on the CLEAR study. The abstract reports the final, prespecified overall survival analysis of the CLEAR trial, a four-year follow-up of lenvatinib plus pembrolizumab versus sunitinib in patients with advanced renal cell carcinoma.

Dr. Jeanny Aragon-Ching: Yes, I would be happy to. So, just as a reminder, the combination of lenvatinib and pembrolizumab was initially approved by the FDA in August 2021 for first-line treatment of adult patients with advanced renal cell carcinoma. So, this was based on significant benefits that were seen in progression-free survival, which was a primary endpoint, but also showed improvement in the overall response rates compared with sunitinib in first-line advanced renal cell carcinoma.

So this abstract reports on longer-term follow-up now at a median of 49.8 months, and PFS favored the combination lenvatinib and pembrolizumab compared to sunitinib across all MSKCC risk groups, and PFS benefit versus lenvatinib and pembro compared to sunitinib was maintained with a hazard ratio of 0.47. And even overall survival was also maintained with the combination with a hazard ratio of 0.79, and the overall survival favored the combination across all risk groups. If we look at the CR rate, it was 18.3% for the combination compared to 4.8% with sunitinib, unless patients in the combination arm received subsequent anticancer therapies, and that's intuitive. And the PFS2 was also longer with the combination at 43 months compared to 26 months. Now, it is important to note that grade III or more treatment-related adverse events did occur in about 74% of the patients in the combination of lenvatinib and pembro, compared to 60.3% in patients with sunitinib.

Dr. Neeraj Agarwal: Jeanny, this is good news. So the main message from the abstract is that sustained results from this combination of lenvatinib plus pembrolizumab are being seen even after a longer follow-up of more than four years.

Dr. Jeanny Aragon-Ching: Yes, I agree. So now, moving on, Neeraj, to a different setting in the RCC space, let's look at Abstract 4519, which is titled "Efficacy of First-line Immunotherapy-based Regimens in Patients with Sarcomatoid and/or Rhabdoid Metastatic Non-Clear Cell RCC: Results from the IMDC," which will be discussed by Dr. Chris Labaki. So, Neeraj, based on this abstract, can you tell us a little bit more about the impact of these adverse pathologic risk features in non-clear cell RCC?

Dr. Neeraj Agarwal: Of course. So, using real-world patient data, the IMDC investigators compared the outcomes of patients with metastatic non-clear cell RCC who were treated with immunotherapy-based combination regimens versus those who were treated with VEGF-TKIs alone. They also assessed the impact of sarcomatoid and rhabdoid features on response to IO-based combinations versus VEGF-TKIs. Of 103 patients with metastatic non-clear cell RCC who had rhabdoid or sarcomatoid features, 32% of patients were treated with immunotherapy-based combinations.

After adjusting for confounding factors, the authors show that those treated with a combination of two immune checkpoint inhibitors or an immune checkpoint inhibitor with a VEGF-TKI combination had significantly improved overall survival, which was not reached in the immunotherapy combination group versus seven months within the VEGF-TKI group. Time to treatment failure and objective responses were also prolonged, significantly higher, and better in the immunotherapy groups compared with patients who were treated with VEGF-TKIs alone. Interestingly, if you look at those 430 patients with metastatic non-clear cell RCC who did not have sarcomatoid or rhabdoid features, they didn't seem to benefit with immunotherapy-based combinations.

Dr. Jeanny Aragon-Ching: This is an exciting update, Neeraj. What are the key takeaways from this abstract?

Dr. Neeraj Agarwal: So the main takeaway is if you see a patient with advanced non-clear cell RCC who has sarcomatoid and rhabdoid features, there appears to be a rather substantial and selective benefit with IO-based combinations. And in this context, I would like to highlight the ongoing SWOG 2200 trial also known as PAPMET2 trial, which is comparing the combination of cabozantinib plus atezolizumab. So immuno-therapy-based combinations versus cabozantinib alone in advanced papillary renal cell carcinoma setting. So this trial is being led by Dr. Benjamin Maughan and Dr. Monty Pal. And I like to encourage our listeners to consider referring their patients for involvement in this federally funded trial so that we can validate the data from this retrospective study in a prospective way.

So, Jeanny, let's now move on to another important disease type which is urothelial carcinoma. There is a very recent accelerated FDA approval of the drug combination of enfortumab vedotin and pembrolizumab for cisplatin-ineligible metastatic urothelial carcinoma patients. This is Abstract 4505, which is being presented by Dr. Shilpa Gupta and colleagues. Can you please tell us more about this update?

Dr. Jeanny Aragon-Ching: Yeah, absolutely. So, as you mentioned, Neeraj, the FDA just granted accelerated approval in April 2023 for this combination of enfortumab vedotin or EV, which is and ADC, antibody drug conjugate against nectin-4 and the PD-1 inhibitor pembroluzimab. So it's a combination for patients with locally advanced or metastatic urothelial carcinoma who are considered cisplatin ineligible. So this is nearly a four-year follow-up.

So as a reminder, this was a phase 1b/2 trial that included 45 patients and it had a primary endpoint of safety and tolerability although the key secondary endpoints included confirmed overall responses, duration of response, progression-free survival, and the resist criteria was investigated via investigator and BICRs which is in a blinded independent central review. Even overall survival was a key secondary endpoint.

So, the bottom line was the confirmed overall response by BICR was 73.3%, the disease control rate was about 84%, and the CR rate was 15.6% with a PFS of close to 13 months, and a 12-month overall survival rate of 83%. However, it is important to cite that there were treatment-related adverse events including skin reactions in 66%, neuropathy occurred in 62%, and ocular disorders in 40%. And there was a little bit of pneumonitis in close to 9%, colitis, and hypothyroidism, so there are side effects to watch out for.

Dr. Neeraj Agarwal: So, Jeanny this is great. What is the key takeaway from this trial?

Dr. Jeanny Aragon-Ching: So I think the most important thing is we now have a new combination of EV and pembro which shows very promising responses and survival in part which led to the FDA accelerated approval in the cisplatin-ineligible population of patients. However, we must note that the phase 3 trial of EV302 will ultimately establish which approach is really beneficial for all of our cisplatin-ineligible patients, either a carboplatin-based chemotherapy regimen or a non-platinum-based regimen such as EV and pembro.

Dr. Neeraj Agarwal: Thanks Jeanny, would you like to discuss any other study in the bladder cancer space?

Dr. Jeanny Aragon-Ching: Absolutely. I think Abstract 4508 from Dr. Seth Lerner and colleagues will be very relevant to our colleagues. This abstract is SWOG S1011, which is a phase 3 surgical trial to evaluate the benefit of a standard versus an extended lymphadenectomy performed at the time of radical cystectomy for muscle-invasive bladder cancer.

Dr. Neeraj Agarwal: Yes. So this trial, as you said, is an important trial which randomized in a one-on-one fashion 618 patients with muscle-invasive bladder cancer undergoing radical cystectomy, and these patients were randomized to either standard lymph node dissection or an extended lymph node dissection. And standard lymph node dissection included, as we know, external and internal iliac and operative lymph node. The extended lymph node dissection included lymph nodes up to aortic bifurcation which included common iliac, presciatic, and presacral lymph nodes. At a median follow-up of approximately 6 years, there was no disease-free survival or overall survival benefit in patients undergoing an extended lymph node dissection compared to standard lymph node dissection. And extended lymph node dissection was also associated with greater morbidity and preoperative mortality.

Dr. Jeanny Aragon-Ching: Very interesting data, Neeraj. So these results, I think, will be very useful for a lot of our surgical colleagues in both academia and the community who may still be inclined to perform extended lymphadenectomy during cystectomy. This study shows that it's actually not necessary.

Dr. Neeraj Agarwal: Absolutely. So now let's move on to another disease type, which is very important - prostate cancer. There are several practice-informing abstracts that are worthwhile discussing. The first of these involves Abstract 5002, which looks at the impact of the PSA nadir as a prognostic factor after radiation therapy for localized prostate cancer, which will be presented by Dr. Praful Ravi and colleagues. Jeannie, can you please tell us more about this abstract?

Dr. Jeanny Aragon-Ching: Yeah, definitely. So this abstract, as you mentioned, Neeraj, is a prognostic impact of PSA nadir of more than or equal to 0.1 nanogram per ml within six months after completion of radiotherapy for localized prostate cancer - an individual patient data analysis of randomized trials from the ICECaP Collaborative. Basically, it refers to an attempt to evaluate early surrogate measures to predict for long term outcomes such as prostate cancer-specific survival, metastases-free survival, and overall survival. So they looked at a big registry from the ICECaP collaboration that included 10,415 patients across 16 randomized controlled trials. And those men underwent treatment for intermediate risk and high risk prostate cancer treated with either radiation therapy alone in about a quarter of patients, or they got RT with short-term ADT in about 58% of patients, and 17% of them got RT with long-term ADT.

So, after a median follow-up of ten years, what they found was, if you had a PSA nadir that is over or equal to 0.1 nanogram per ml within six months after completion of radiation therapy, it was associated with worse prostate cancer-specific survival, metastases-free survival, and overall survival. For instance, the five-year metastases-free survival for those who achieved a PSA nadir of less than 0.1 was 91% compared to those who did not, which was 79%. Therefore, they concluded that if you achieve a bad PSA of 0.1 or above within six months after you completed radiation, you had worse outcomes.

Dr. Neeraj Agarwal: Jeanny, what is the key takeaway message from this study?

Dr. Jeanny Aragon-Ching: The key takeaway from this ICECaP analysis is that this information would be very important to augment a signal-seeking endpoint, especially for clinical trial development, so that we can develop further strategies to de-escalate for those who don't need systemic intensification or therapy intensification versus escalation for those who really do.

Dr. Neeraj Agarwal: So, my radiation oncology colleagues need to watch out for those patients who do not achieve a PSA of less than 0.1 nanogram per ml within the first six months of finishing radiation therapy. Very interesting data.

Dr. Jeanny Aragon-Ching: Yes, absolutely. So. Neeraj another important abstract for our fellow clinicians, switching gears a little bit now, is Abstract 5011, which is titled "Do Bone Scans Overstage Disease Compared to PSMA PET?" This was an international, multicenter retrospective study with blinded, independent readers. Can you tell us more about this abstract?

Dr. Neeraj Agarwal: Yes, a relatively small retrospective study, but still pertinent to our practice. So I'll summarize it. This study by Dr. Wolfgang Fendler and colleagues evaluated the ability of bone scans to detect osseous metastasis using PSMA PET scan as a reference standard. So in this multicenter retrospective study, 167 patients were included, of which 77 patients were at the initial staging of prostate cancer, 60 had biochemical recurrence after definitive therapy, and 30 patients had CRPC or castor-resistant disease.

These patients had been imaged with a bone scan and a PSMA PET scan within 100 days. And in all patients, the positive predictive value, negative predictive value and specificity for bone scan were evaluated at different time points. They had bone scan and PSMA PET scan and both were compared. And what they found was interesting. All these three values - positive predictive value, negative predictive value, and specificity for bone scan were 0.73, 0.82 and 0.82 in all patients, and in initial staging, it was even lower at 0.43 and 0.94 and 0.80.

So, without getting into too much detail regarding these numbers, I want to highlight the most important part of the study, that at the initial staging, 57% patients who had a positive bone scan had false positive bone scans. The interreader agreement for bone disease was actually moderate for bone scans and quite substantial for the PSMA PET scan.

Dr. Jeanny Aragon-Ching: So, Neeraj, what do you think is the key takeaway message here for our audience?

Dr. Neeraj Agarwal: The key takeaway message is that positive predictive value of bone scan was low in prostate cancer patients at initial staging, with the majority of positive bone scans being false positive. This suggests that a large proportion of patients which we consider to have low-volume metastatic disease by bone scan actually have localized disease. So in the newly diagnosed patients with prostate cancer, patients should ideally have a PSMA PET scan to rule out metastatic disease.

So, let's move on to another abstract I would like to discuss, which has important implications in treatment, especially now that lutetium 177 is approved, but frankly not available widely.

Dr. Jeanny Aragon-Ching: Yeah, that's actually very timely. So the abstract you're referring to is 5045, which is being presented by Dr. Yu Yang Sun and colleagues entitled "Effects of Lutetium PSMA 617 on Overall Survival in TheraP Versus VISION Randomized Trials: An Exploratory Analysis." So, Neeraj, can you tell us more about the relevance of this exploratory analysis?

Dr. Neeraj Agarwal: Definitely. In this abstract, Dr. Yang Sun and colleagues assess the effect of lutetium PSMA on overall survival in two different trials, TheraP and VISION trials. So, just for our listeners' recollection, the phase 2 TheraP trial compared lutetium PSMA and cabazitaxel in patients with mCRPC who had progression on docetaxel and had significant PSMA avidity on gallium PSMA pet scan, which was defined as a minimum uptake of SUV max of 20 at least one site of disease and SUV max of more than 10 at all sites of measurable disease.

In this trial, 20 of 101 patients in the cabazitaxel arm crossed over to lutetium PSMA, and 32 of 99 patients in the lutetium PSMA arm crossed over to cabazitaxel. In the VISION trial, patients with mCRPC who previously progressed on at least one ARPI and one taxane-based therapy and had a positive gallium PSMA scan, and here, positivity was not stringently pre-specified as it was done in the context of TheraP trial. So, positive gallium pet scans were randomly assigned in two to one fashion to receive either lutetium PSMA plus best supportive care or standard of care versus standard of care.

And I'd like to highlight that the standard of care comprised ARPIs and bone protecting agents and these patients were not allowed to have cytotoxic chemotherapy such as cabazitaxel in the standard of care arm. Now, overall survival was similar in the lutetium PSMA group regardless of whether they got lutetium PSMA in the VISION trial or TheraP trial. There was no difference in overall survival with lutetium in the lutetium arms of VISION and TheraP trial with a hazard ratio of 0.92. And there was no difference in the overall survival between the lutetium PSMA and the cabazitaxel group in the TheraP trial if you use counterfactual analysis, assuming crossover had not occurred. So, quite interesting in my view.

Dr. Jeanny Aragon-Ching: Yeah, thanks Neeraj for that wonderful synopsis and discussion. So, what is the key take home message then?

Dr. Neeraj Agarwal: The main message in this new exploratory analysis, which combined both the TheraP and VISION trials, is that lutetium PSMA and cabazitaxel seem to be associated with similar overall survival benefit in these highly selected patients with PSMA positivity. Additionally, the difference in the observed effect of lutetium PSMA and overall survival in the TheraP and VISION trials may be actually better explained by the use of different treatments in the respective control arms of these trials. And these results, in my view, are quite pertinent for those patients and providers who do not have access to lutetium-177 therapy.

Let's go to another abstract that is currently relevant to our practice, given many patients with advanced prostate cancer who have concurrent diabetes; I'm talking about Abstract 5066. Jeanny, can you please tell us more about this abstract?

Dr. Jeanny Aragon-Ching: Certainly, Neeraj. So this abstract will be presented by Dr. Amy Shaver and colleagues. So it's also very relevant, since many men who are diagnosed with prostate cancer frequently also have a concomitant diagnosis of type 2 diabetes mellitus. So, this was a SEER-Medicare population database analysis that looked at men who were treated with either abiraterone or enzalutamide and also had concomitant diagnosis of type 2 diabetes mellitus (DM). And they were identified using ICD-9 and ICD-10 codes and they were all tied in to acute care utilization. So they looked at CMS research data codes and ER hospitalization visits six months after treatment initiation was recorded. So all in all, they took a sample of 11,163 men, of whom close to 62% were treated with abiraterone and about 38% were treated with enzalutamide.

So, of these, about 27% of them had type 2 DM, of whom 59% received abiraterone and about 41% had enzalutamide. So, the bottom line is, compared to those without diabetes mellitus, those who had type 2 diabetes had worse acute care utilization, which was 43% higher than those who got abiraterone compared to enzalutamide, and also had higher overall mortality. Therefore, the bottom line is, having type 2 diabetes mellitus, unfortunately, portends worse outcomes in men with prostate cancer, so careful attention needs to be paid to those who are starting out already with such comorbidities. So Neeraj, any final thoughts you have regarding this abstract and overall before we wrap up on the podcast today?

Dr. Neeraj Agarwal: Absolutely. So it looks like, based on this very important pertinent Abstract 5066, which talks about the impact of diabetes on our patients, I think we need to be very watchful regarding the impact of diabetes on our patients who are being treated with abiraterone or enzalutamide, especially drugs which are known to make the metabolic syndrome and diabetes worse. I think close monitoring and close attention to control of diabetes is very important. So with that, I would urge the listeners to come and join us at the Annual Meeting, not only to celebrate these successes but also to help disseminate this cutting-edge data to practitioners and maximize the benefit to our patients across the globe.

And thank you to our listeners for joining us today. You will find links to the abstracts we discussed today on the transcript of this episode. Finally, if you value the insights that you hear on our ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast.

Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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Dr. Neeraj Agarwal

@neerajaiims

Dr. Jeanny Aragon-Ching

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Disclosures:

Dr. Neeraj Agarwal:

Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences

Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas

Dr. Jeanny Aragon-Ching:

Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono

Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,

Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics.