By Clinical Content Hub

David A. Braun, MD, PhD
Yale Cancer Center, New Haven, Connecticut

The 2022 American Society of Clinical Oncology (ASCO®) Annual Meeting featured a broad range of presentations on advanced renal cell carcinoma (aRCC) that explored both ongoing management challenges and advances in timely detection of disease, newer therapies, and prediction of treatment outcomes. Investigators discussed results of new and updated trials of systemic therapy and shared their approaches to phenotyping, genetic characterization, and assaying methods.

David Braun, MD, PhD, is an assistant professor of medicine in medical oncology, the Goodman and Gilman Yale Scholar, and a principal investigator in the Center of Molecular and Cellular Oncology at Yale Cancer Center in New Haven, Connecticut. He is the principal investigator in the Braun Lab at Yale School of Medicine. Dr Braun shares his perspective on the clinical impact and importance of selected aRCC studies presented at ASCO.

What were some examples of intriguing, practice-changing, and seminal data on aRCC presented at ASCO this year?

Several RCC studies presented could help decide the future of this field of medicine. One of these included long-awaited results of the EVEREST (SWOG S0931) trial ( Identifier: NCT01120249) of adjuvant everolimus vs placebo for the management of RCC.1 At a median follow-up of more than 6 years, there was a nonsignificant trend towards improved recurrence-free survival with everolimus but no overall survival (OS) benefit. Notably, it is possible that the recurrence-free survival benefit with everolimus occurred specifically among patients with very-high-risk disease (pT3a or higher and/or node-positive). While this study was interesting and important, it will not change the standard of care.
The CALYPSO trial ( Identifier: NCT02819596) is also worth mentioning.2 It was a screening phase 2 study of the programmed death-ligand 1 (PD-L1) inhibitor durvalumab combined with either the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor tremelimumab or with the targeted mesenchymal epithelial transition (MET) factor receptor inhibitor savolitinib for patients with advanced clear cell RCC. Some patients in the trial received savolitinib monotherapy. A confirmed response rate of at least 50% was considered worthy of further investigation. Unfortunately, no treatment arm met this prespecified activity level. This study underscores the importance of attempting to identify biologically-defined subpopulations of patients who may benefit from such treatment, particularly with targeted agents like savolitinib. It is encouraging that much of this molecular investigation is underway.
In terms of cancers other than RCC, I would like to share just a few good ones from the conference. Perhaps at the top of the list is the practice-changing DESTINY-Breast04 study ( Identifier: NCT03734029).3 This was an open-label phase 3 randomized trial of the human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate trastuzumab deruxtecan vs chemotherapy of the physician’s choice in patients with previously HER2-low metastatic breast cancer. The study defined HER2-low as a HER2 score of 1+ on immune histocompatibility complex testing or 2+ with negative in situ hybridization results. Treatment with trastuzumab deruxtecan substantially improved progression-free survival (PFS) and OS and will change the standard of care for these patients.
Another important study is the presentation on the anti-programmed death protein 1 (anti-PD-1) antibody dostarlimab in locally advanced, mismatch-repair deficient rectal cancer, which demonstrated a 100% complete response rate in all 12 patients.4 While the patient population studied is small, this is almost certainly reflective of the biology and immune responsiveness of this specific disease and not of the specific drug. It is still a striking result and a very important finding for these patients.

What studies evaluated assays applicable to the detection and monitoring of aRCC? Examples include use of circulating tumor DNA (ctDNA) levels for this purpose and other liquid biopsy methods.

The most striking results of ctDNA testing came not from RCC but from colon cancer. In the multicenter phase 2 DYNAMIC trial, patients with stage 2 colon cancer were randomly assigned to receive either standard adjuvant management or ctDNA-guided management for decision making regarding adjuvant chemotherapy.5 A personalized tumor-informed ctDNA assay was used after surgery for stage 2 colon cancer. Strikingly, ctDNA-guided management reduced the use of adjuvant chemotherapy by nearly half while maintaining the same recurrence-free survival. This study beautifully elucidates the power of ctDNA in general and besides early detection, it is potentially useful for guiding adjuvant therapy.
However, the story has always been more complicated for patients with RCC. This difference is due in part to intratumor heterogeneity, which is a hallmark of renal cancer. There are fewer “standard” or hotspot mutations in RCC, making detection using a standardized gene panel much more challenging.6 Even with new bespoke approaches that utilize a custom panel for a patient’s tumor — which is helpful in the adjuvant setting or potentially to track disease activity but is not useful for early detection — RCC remains a challenge because it sheds much less DNA than most other solid tumors. The most promising approach I have seen is the detection of cell-free methylated DNA, where hundreds of differentially methylated DNA regions can be detected in the blood and based on a pretrained classifier, could potentially be used for early detection of tumor DNA. Results of an early proof-of-concept study were very exciting and now further validation will be required to bring this forward for patients more broadly.7

Beyond simply detecting the presence or absence of tumor — either for early detection or following surgical resection — a recent work demonstrated using a similar approach to identify noninvasive neuroendocrine prostate cancer.8 Again using cell-free methylated DNA detection, these investigators were able to successfully identify neuroendocrine prostate cancer in a cohort of patients with castration-resistant disease. This study shows the broad potential to use this technology to identify different molecular subtypes, including phenotypes associated with therapeutic response or resistance.
Another innovative approach is to recover not only circulating DNA but also entire circulating tumor cells (CTCs). In one such study, a high number of detected CTCs was associated with worse overall survival in patients enrolled in a phase 2 immunotherapy trial in RCC.9
While there are certainly many challenges ahead, given these promising methods for detecting cell-free methylated DNA, personalized tumor mutations, and CTCs, I would expect the field of molecular-based RCC detection and monitoring to move forward substantially in the coming years.

Many novel therapies that can be safely combined with existing agents are finding their way into the clinic, but substantial work is still required to determine if any will improve the lives of patients with RCC.

There were several notable reports on combination immunotherapy plus treatment with a tyrosine kinase inhibitor (TKI) treatment for the management of aRCC. Can you outline some key findings and their implications for standards of care in terms of combination therapy for aRCC? What novel treatment strategies and clinical care advances do you see on the horizon?

One important RCC study presented was an exploratory analysis of CheckMate 9ER ( Identifier: NCT03141177), a phase 3 trial that demonstrated the superior benefit of first-line nivolumab plus cabozantinib vs monotherapy with sunitinib in patients with aRCC.10 Results showed that the depth of response (eg, more tumor shrinkage) was greater with nivolumab plus cabozantinib and was associated with improved PFS and OS compared with monotherapy with sunitinib. These findings are in line with other studies that have identified associations between deep responses and durable clinical benefit. The key to watch for in future updates is whether these deep responses are truly long-term and lead to cure in some patients or they simply prolonging the time to progression.
In a phase 1b/2 study, patients with previously-treated clear cell RCC who received batiraxcept in combination with cabozantinib tolerated the therapy well.11 This is a promising sign that this new agent can be safely combined with other therapy. There was also an early potential signal for efficacy, with the majority of patients having some tumor shrinkage. Overall, substantially more work will need to be done to establish the efficacy of this new agent.
The KEYNOTE-426 trial ( Identifier: NCT02853331) assessed progression after the first subsequent therapy and found that combination therapy with pembrolizumab plus axitinib was superior to sunitinib monotherapy in front-line treatment of metastatic clear cell RCC.12 This work demonstrated a PFS2 benefit for the combination therapy across all International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups, further supporting immuno-oncology therapy plus TKI therapy targeting vascular endothelial growth factor (VEGF) as an excellent first-line option for patients with aRCC.

Results from a phase 1b trial of the novel first-in-class nuclear exportin 1 inhibitor selinexor in combination with nivolumab with or without ipilimumab in patients with aRCC are also worth considering.13 There are preclinical data to support the idea that treatment with this combination may create a more favorable tumor microenvironment. Combination treatment including selinexor was well tolerated, demonstrating that this new agent can be used effectively with other agents. The response rates were modest, though it is difficult to get any true signal for efficacy with such small patient numbers.
There are 2 main messages emerge from these studies: First, immune-oncology therapy plus VEGF-targeting TKI therapies continue to demonstrate superior clinical benefits compared with sunitinib in first-line treatment for aRCC, further supporting their use as a standard-of-care option. Second, many novel therapies that can be safely combined with existing agents are finding their way into the clinic, but substantial work is still required to determine if any will significantly improve the lives of patients with RCC

Updates on LITESPARK-00114 ( Identifier: NCT02974738) and LITESPARK-00415 ( Identifier: NCT03401788) demonstrated continued clinical efficacy of belzutifan monotherapy for patients with pretreated von Hippel-Lindau (VHL) disease-related RCC. How can these results inform hypotheses about the genetics of VHL disease, and about hypoxia-inducible factor-2α (HIF-2α) as a drug target?

Results from LITESPARK-001 and LITESPARK-004 further reinforce the excitement in the field regarding this first-in-class therapy. It is a game changer for patients with VHL disease and early data are extremely promising in the management of sporadic clear cell RCC. Whereas VHL disease is often more homogeneous and driven by HIF-2α, sporadic clear cell RCC is more genetically heterogeneous; that is, while there is near universal inactivation of the VHL tumor suppressor, not all instances of sporadic clear cell RCC are dependent on HIF-2α signaling, particularly after multiple lines of therapy.16 It will therefore be critical to follow up on results of the phase 3 trial of belzutifan vs everolimus in previously treated sporadic clear cell RCC (LITESPARK-005; Identifier: NCT04195750). However, many in the field are understandably optimistic about this new agent, and if approved, it will quickly find its way into combination trials in earlier lines of therapy.

It is still difficult to identify suitable biomarkers to guide treatment decisions in aRCC. Several presentations at ASCO, for example, included evaluations of the usefulness of protein polybromo-1 (PBRM1) and long noncoding RNA signatures. Could you touch on any new insights, challenges, and opportunities that emerged from the meeting in terms of advancing biomarker-guided practice?

There is still a critical need to identify biomarkers for immunotherapy response in RCC. Unfortunately, there’s a lot of work to do in this area. Unlike most other solid tumors, high tumor mutation burden, neoantigen load, and CD8+ T-cell infiltration are not associated with improved response to PD-1 blockade in RCC.17 We and others previously identified truncating mutations in PBRM1 as being associated with response to PD-1 blockade, though the effect size in modest and potentially is context-dependent (eg, after prior VEGF-targeting TKI therapy).18 Data presented at the conference this year do not resolve these challenges any further. Nevertheless, it was interesting that one of the studies used a systematic review/meta-analysis approach19 of identifying an association between PBRM1 alterations and longer PFS in the second-line PD-1 blockade setting. Conversely, a study evaluating the MSK-IMPACT data found no association between PBRM1 loss-of-function mutations and response.20 These studies clearly show the challenges of biomarker discovery in RCC, the potential benefits of analyzing more homogeneous clinical cohorts, and the need to take into account the specific clinical context for an individual patient.
Moving forward, I believe the keys to success will be to increase the size of cohorts used for analysis, integrate multiple features such as tumor-intrinsic somatic alterations and the amount of specific infiltrating immune populations, and critically validate any findings in external cohorts.

Based on presentations at ASCO this year, tumor subtyping based on molecular features and gene expression appears to have the potential to inform disease outcome prediction in RCC. How can these efforts also further our understanding of how RCC originates and becomes potentially lethal?

In a fundamental investigation presented at ASCO, the molecular subtype of clear cell RCC was used successfully to define specific biologic subgroups that benefit from specific therapy (eg, combination therapy with atezolizumab plus bevacizumab vs monotherapy with sunitinib).21,22 However, further evaluation to verify the stability and validity of these molecularly-defined clusters and to determine whether they are predictive of clinical response across different types of therapy is needed to confirm the robustness of these findings.
Beyond “bulk” RNA-sequencing analysis, RCC clinical study results published during the past year have shown us how single-cell RNA-sequencing and spatial phenotyping approaches can provide enormous insight into the molecular changes that occur in patients with disease progression or recurrence.23-26 Ultimately, the goal will be to use these deep molecular characterizations to better understand how RCC develops, identify targets for prevention, and understand the mechanism behind disease progression and resistance to therapy. These detailed studies will provide a roadmap for future therapeutic interventions for our patients with this disease.

Key Takeaways

  • Advanced renal cell carcinoma remains markedly challenging to detect and characterize, and treatment outcomes are difficult to predict. This is due in part to the remarkable genetic heterogeneity of these tumors, paucity of DNA shedding, and lack of reliable biomarkers to guide treatment.
  • Cutting-edge research on methods of detecting RCC and monitoring treatment outcomes includes assays of ctDNA, cell-free methylated DNA, and entire circulating tumor cells.
  • Existing immuno-oncological and antiangiogenesis combination therapies continue to elicit better clinical response than monotherapy with sunitinib.
  • Novel combination therapies are showing promise. Additional research is needed to identify the patient subpopulations most likely to benefit from specific regimens.

This Q&A was edited for clarity and length


David A. Braun, MD, PhD, reported affiliations with AbbVie Inc; AVEO Pharmaceuticals, Inc; Bristol Myers Squibb Company.


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                                                                                                                                                Reviewed June 2022