Analysis of Genomic Alterations in Metastases Could Help Inform Treatment in RCC

Rana R. McKay, MD

There is a distinct pattern of metastasis associated with prognostic significance in renal cell carcinoma (RCC), and identifying underlying genetic components of those metastases could help inform personalized treatment strategies for this patient population, according to Rana R. McKay, MD.

Various genes of intertest have been identified in various metastases of the lung, liver, bone, and more, and McKay said understanding the common mutations related to these sites can provide valuable insight into treatment.

“The sights of metastases have different genomic underpinnings compared with the kidney, and that could impact outcomes,” said McKay, a medical oncologist and associate professor of medicine at Moores Cancer Center, University of California San Diego Health.

In an interview with OncLive^® during the 2022 Genitourinary Cancers Symposium, McKay discussed findings from a real-world study on genomic alterations of metastases in RCC,¹ the rationale of the phase 3 COSMIC-313 trial (NCT03937219) in patients with previously untreated advanced or metastatic RCC, plus findings from the phase 1/2 COMRADE trial (NCT03317392) in patients with metastatic castration-resistant prostate cancer (mCRPC).²

OncLive^®: Could you provide an overview of the real-world data set that you presented at the symposium, which analyzed genomic alterations and transcriptional signatures across the spectrum of metastatic sites in patients with RCC?

McKay: We know from several large databases that site of metastasis is prognostic in RCC. We and others have demonstrated that bone and liver metastases are associated with worse prognosis, and pancreas metastases are associated with better prognosis. We are lacking with regard to underlying data as to why that is. Why does site of metastasis matter?

We sought to utilize a commercial database through [Caris Life Sciences] of RCC tumors from primary and distant metastases to comprehensively characterize the molecular features across sites of metastases. Our analysis was 3-pronged in nature. We looked at mutations and polymorphisms using initially a 592-gene panel and whole exome sequencing. We did whole transcriptome sequencing and PD-L1 expression on over 650 distinct samples.

We identified that there are mutations and, [in] the distribution of mutations of selected genes across different metastatic sites, there are common mutations that exist in kidney cancer, whether they are in the primary [tumor] or in the metastasis. Those are VHL mutations, PBRM1, SETD2, and KDM5C.

We also realized that there are differences when you look at the various sites compared with the kidney, and we did observe that PBRM1 alterations were more frequent in the lung, bone, [and] endocrine glands relative to the kidney. SETD2 seemed to be more prevalent in lung and gastrointestinal [GI] metastases. P53, for example, was more prevalent in the bone and central nervous system [CNS], and P10 was more prevalent in liver and CNS [metastases].

The other thing that we did was look at the [phase 3 IMmotion151 trial (NCT02420821) led by Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, examining] gene clusters across the different sites of metastasis. We did see differences in the molecular subgroup classifications between primary and metastatic sites. As we look at the breakdown more granularly, lung, bone, liver, skin, and GI metastases seem to have divergent molecular subtypes relative to the kidney, lung, and bone, [which] were enriched for the angiogenic stromal signature, whereas liver [tissue] seemed to be more enriched for the complement/Ω-oxidation signature.

That is important because these signatures have been associated with differential outcomes to treatments. For example, the angiogenic stromal signature seems to be associated with a more robust response to tyrosine kinase inhibitor [TKI]-based therapies, whereas a T-effector proliferative signature seems to be associated with a more robust response to immunotherapy. The complement/Ω-oxidation signature, for example, is 1 of those signatures that has been shown to be associated with poor outcomes in general.

As we think about the application of this data, understanding the molecular underpinnings for organotropism is going to help us personalize strategies for patients with kidney cancer in the future.

What are the next steps toward the application of these data?

What is lacking from this data set right now is clinical outcomes. We do not have the overlay of, ‘How did these patients do in this dataset? How did those patients with bone metastases that had X signature do with immunotherapy? How did they do with targeted therapy?’ Applying the clinical outcomes will help us understand how to optimize therapy selection for patients based on sites of metastases for any given patient.

What should be emphasized about the results of this study?

Although there are some similarities between the kidney and distant metastatic sites when we are looking at various genes of interest, there are key differences with the predominance of select genes in different metastatic sites relative to the kidney. There are differences between the gene signatures in different metastatic sites relative to the kidney and the tumor microenvironment, which could play a role with regard to treatment outcomes.

You also presented a poster at the symposium on the phase 1/2 COMRADE trial, which examined olaparib (Lynparza) and radium-223 dichloride (Xofigo) in mCRPC. Could you provide an overview of this study?

This was a trial that was looking to assess the potential synergy of radium-223, which is an alpha-emitting radiopharmaceutical that induces DNA damage with olaparib, which is a PARP inhibitor that prevents repair of single-strand DNA breaks within the tumor. The trial was designed as a phase 1/2 study. Phase 1 [was designed] to test the safety of the combination and the recommended phase 2 dose [RP2D] for olaparib, when olaparib is given in combination with radium-223. Phase 2 was designed to test the efficacy [of the combination].

Phase 1 has been completed, and [in] the data presented at the symposium, we identified that olaparib when combined with radium-223 was safe, and that the RP2D was 200 mg twice daily. In our data set, we presented the correlative data for all 12 patients who had enrolled onto the phase 1 portion of the trial. Patients underwent genomic testing to define their homologous recombination repair [HRR] gene status. Of 9 patients who had enough tissue to be profiled, 2 were found to have pathogenic HRR gene alterations. One was in BRCA2, and 1 was in CDK12. The patient who had the BRCA2 alteration had a progression-free survival [PFS] of 11.8 months compared with 3.1 months for the patient with the CDK12 alteration.

[We also looked] at RAD51 staining in archival tumor specimens. These are still early [data], but there was an individual with a CTNNB1 alteration that was negative for RAD51, which is a functional readout of HRR, suggesting that there is a homologous recombination deficiency, and that individual had a PFS of 10.2 months.

The summary here is that olaparib and radium-223 can be safely combined. We have identified the RP2D for the 2 drugs in combination, and there are biomarkers that are currently being developed to try to understand responses to therapy and enriching for responses.

What are the next steps for this combination?

Phase 2 is accruing patients. We have about 60 patients who have enrolled onto the phase 2 study. There will be an upcoming interim analysis to look at efficacy with radiographic PFS as a key primary end point for the trial. The results of the randomized phase 2 portion hopefully will be telling regarding next steps and moving this combination forward.

How could positive data from the phase 2 trial and future studies affect the treatment paradigm?

A lot of studies are looking at the combination of PARP inhibitors with various agents that have already demonstrated efficacy in prostate cancer. Data were presented with abiraterone acetate [Zytiga] combined with olaparib at this year’s meeting, and olaparib and other PARP inhibitors are being combined with other agents. There is a potential for synergy with olaparib and radium-223 in a safe manner that could be practice changing, but it is still very early.

In terms of ongoing trials, there’s the phase 3 COSMIC-313 trial, which is examining the combination of cabozantinib (Cabometyx) with nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with advanced RCC. What is unique about this study?

This is a modern-day study that is looking at evaluating the triplet of ipilimumab/nivolumab [with] cabozantinib, where the cabozantinib starts simultaneously with ipilimumab/nivolumab, compared with ipilimumab/nivolumab alone. This is 1 of the first trials being designed with a modern-day control arm of ipilimumab/nivolumab, as opposed to a single-agent TKI in the frontline setting.

The trial is enrolling patients with intermediate- and poor-risk clear cell RCC. The trial has completed accrual, and we are eagerly awaiting the results. The results of this study have the potential to be practice changing. Since 2018, we have moved into doublets in the frontline space, and with time, the field is now pushing into triplets for a select population of patients.

What has it been like to see research advanced at such a fast pace in RCC?

Over the past almost 2 decades, we have seen the life expectancy for patients with advanced kidney cancer lengthen and lengthen and lengthen and that is because of advances in the therapeutic paradigm, which is excellent to see. We still have work to do, but it has been exciting to be a part of that process.

Are there any specific areas within RCC that warrant additional research?

The big question is what to do in the adjuvant setting. We saw data at the symposium that were presented from the phase 3 KEYNOTE-564 study [NCT03142334] with updated 30-month follow-up of the efficacy of pembrolizumab [Keytruda] given in the adjuvant setting. There are a lot of questions to be had around the role of adjuvant immunotherapy. What is the right patient population? [Should we give a] single agent or can we combine [agents in the adjuvant setting]?

These are the next questions in the field. For patients that have received adjuvant immunotherapy, what is the best frontline option for them? Do the data of all the [immunotherapy] combinations in frontline studies still apply to somebody who is not naïve to checkpoint inhibitors and has progressed despite checkpoint inhibitors? As the treatments improve, new questions come up, and the landscape is shifting.

Are there any other clinical trials you want to highlight?

We presented the data about the differential outcomes for sites of metastases, and historically, patients with bone metastases have done poorly in kidney cancer. We have designed a study that is looking at cabozantinib with or without radium-223, which is a liquid radiopharmaceutical, to see if we can improve symptomatic skeletal-related events with the combination. The trial is called the phase 2 RadiCaL trial [NCT04071223]. It is open through the cooperative groups being led through Alliance. We are eager to promote the study and encourage involvement.

References

1. McKay RR, Barata PC, Elliott A, et al. Molecular alterations across sites of metastasis in patients with renal cell carcinoma (RCC). J Clin Oncol. 2022;40(suppl 6):287. doi:10.1200/JCO.2022.40.6_suppl.287
2. McKay RR, Xie W, Ajmera A, et al. Updated biomarker results from a phase 1/2 study of olaparib and radium-223 in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases (COMRADE). J Clin Oncol. 2022;40(suppl 6):119. doi:10.1200/JCO.2022.40.6_suppl.119