ABSTRACT
This report highlights key research from the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, with a focus on clear cell renal cell carcinoma (ccRCC) and non-clear cell RCC (nccRCC) across clinical trials and translational studies. Essential updates in the metastatic ccRCC clinical space encompass results from the CONTACT-03 study, which evaluated an immunotherapy containing regimen for patients who progressed on an initial immunotherapy containing regimen, alongside updated results from the KEYNOTE-426 and CLEAR trials. In the metastatic nccRCC domain, we review clinical trials of combination immunotherapies and tyrosine kinase inhibitors (TKIs). Additionally, we highlight exciting earlyphase studies exploring novel targets in RCC and engineered T-cell methodologies. Finally, we summarize notable efforts in translational research, emphasizing biomarker investigations to determine predictors of immunotherapy response, the application of molecular classifiers in RCC, and the relationship between the microbiome and RCC. There were many important RCC related abstracts presented at this year’s ASCO conference, attesting to the continued momentum of research in the field. All conference materials, including abstracts and presentations, can be accessed online through the conference website.
INTRODUCTION
The 2023 ASCO GU Conference brought together leading experts in the field to share the latest developments and insights into the diagnosis, treatment, and management of GU cancers. In this article, we will take a closer look at some of the exciting and promising findings from the 2023 ASCO GU pertaining to RCC.
METASTATIC ccRCC, PHASE III STUDIES
The oral abstract sessions for kidney cancer this year led to particularly insightful discussion. The frontline treatment landscape for metastatic ccRCC is currently dominated by immune-checkpoint inhibitor doublets (ICI) and combination vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKI) with ICI1. We were presented with the updated analysis of two key trials of VEGF-TKI/ICI combination therapies, KEYNOTE-426 (Abstract #LBA4501) and CLEAR (Abstract #4502)2,3. The former assessed axitinib and pembrolizumab (axi/pem) versus sunitinib, while the latter compared lenvatinib and pembrolizumab (len/pem) versus sunitinib. Both trials were performed in treatment naïve metastatic ccRCC.With over four years of follow-up data, the updated reports demonstrated consistent results with initial studies, showing significant improvements in objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) relative to sunitinib. A key area of discussion was centered on the sustainability of responses and how these compared with the responses observed in the CHECKMATE-214 study, which evaluated the ipilimumab/nivolumab (ipi/nivo) combination in the same patient population4. Among patients who responded in aforementioned studies, the median duration of response was 43.7 months for the len/pem arm and 23.6 months in the axi/pem arm. However, less than 30% of responders in both studies maintained response at 48 months, and the response curves do not yet appear to have plateaued. In a subsequent discussion, Dr. David Braun from Yale University contended that ipi/nivo, with which over 50% of responses are durable over 60 months, should be the preferred choice for most metastatic RCC patients without oligometastatic disease. He suggested that exceptions to this would be patients with impending organ failure or those in need of a rapid response.
Another pivotal finding was the outcome of the CONTACT-03 study, presented by Dr. Choueiri (Abstract #LBA4500). This study assessed the efficacy of atezolizumab plus cabozantinib versus cabozantinib alone, following progression in a regimen containing immunotherapy in metastatic ccRCC. The researchers found no significant differences in ORR, PFS, or OS between the two groups. However, the atezolizumab plus cabozantinib combination led to a notable increase in grade III/IV adverse events. Full results of the study have been published in The Lancet5.
This consequential study offers prospective evidence indicating that rechallenge with immunotherapy immediately post progression does not yield improved outcomes, but rather increases toxicity levels. Questions remain regarding the role of immunotherapy salvage in later lines, and the role of CTLA-4 targeted therapies in the salvage setting.
NOVEL THERAPEUTICS IN CCRCC
There were several early-stage trials and preclinical studies investigating novel therapies in ccRCC. Dr. Pili presented results from a combined Phase I/II study evaluating Etinostat (NCT03024437), an HDAC inhibitor with potential to modulate immunosuppressive tumor microenvironments. This was administered in combination with atezolizumab and bevacizumab in metastatic RCC (Abstract #4526). The dose escalation phase found Etinostat to be well tolerated, and in group A of the phase II study (evaluating the treatment in an immunotherapy naïve cohort, n = 15), the most common grade 3-4 adverse events were hypophosphatemia (25%), diarrhea (16.7%), thrombocytopenia (8.3%), and neutropenia (8.3%). In this cohort, the ORR was 60% (9 out of 14 patients evaluable patients), showcasing notable efficacy.
Dr. Beckerman reported results of a Phase II study that evaluated batiraxcept - an antibody targeting the AXL receptor, a protein implicated in RCC metastasis (NCT04300140). The antibody was studied as a standalone therapy, in combination with nivolumab and cabozantinib in the first-line setting, and paired with cabozantinib in previously treated patients (Abstract #4534). Batiraxcept was tolerable as a monotherapy, although the response rates were low with only 1 out of 10 patients demonstrating stable disease. However, in the prior therapy group, Batiraxcept with cabozantinib yielded a ORR of approximately 44% (11/25). Phase III trials examining this agent are planned.
Lastly, Dr. Roussy disclosed results of arm B5 from the Phase I/II KEYMAKER Trial (NCT04165798), which explored the use of belzutifan and lenvatinib post progression on immunotherapy and VEGF therapies in metastatic ccRCC. The combination proved well-tolerated with the most common adverse events being hypertension and anemia, which occurred at any grade in 43% of patients. The ORR in this cohort was 50% (12/24). This finding is promising, especially given the extensive prior exposure to immunotherapy and VEGF-TKI among this patient cohort.
Innovative work in the preclinical setting was also reported at the conference. Dr. Barisic presented a poster titled “T cell receptor-engineered T cells targeting a human endogenous retrovirus in kidney cancer” (Abstract #4542). The team developed a T-cell receptor-engineered T-cell that targets the human endogenous retrovirus, HERV-E, in an HLA-A11-restricted manner. In a murine model, these engineered HERV-E T-cells significantly slowed the progression of established human ccRCC tumor grafts, leading to a considerable increase in the survival of the animals compared to those that either received non-transduced T cells or no T cells (median survival 50 days vs. 20 and 20 days, respectively; p less than 0.001).
The exciting findings from this preclinical study are being carried forward into a Phase I clinical trial (NCT03354390), the preliminary results of which were presented by Dr. Nadal (Abstract #2549). Patients with HLA-A*11 positive, advanced, treatment-refractory ccRCC were included in this study. Out of the 14 patients enrolled, there were no dose-limiting toxicities or treatment-related deaths. However, 57% of patients developed Grade 3-4 neutropenic fever, and 7% developed Grade 3-4 capillary leak syndrome. Encouragingly, therapeutic responses were observed, with 7% (1/14) of patients demonstrating a partial response and 29% (4/14) maintaining stable disease for at least 8 weeks.
METASTATIC NON-ccRCC
Non-(n)ccRCC, comprising approximately 25% of new RCC diagnoses, represents a diverse collection of molecularly distinct tumors that necessitate focused study6. There were several prospective studies in the nccRCC space reported, including trials investigating combination Nivolumab/Cabozantinib (nivo/cabo) (Abstract #4537) and len/pem (Abstract #4518) in the first-line setting across nccRCC subtypes. In the Phase II KEYNOTE-B561 study, len/pem were assessed as the first-line treatment for metastatic non-clear cell RCC (NCT04704219). This study involved a cohort of 158 patients with various histologies: papillary (n = 93), chromophobe (n = 29), unclassified (n = 21), translocation (n = 6), and others (n = 9). The toxicity profile aligned with expectations for this combination. The combined ORR was 49% (77/148) and the disease control rate was 82% (121/148). In all patients, median PFS and OS were 17.9 months (95% CI, 13.5-NR) and NR (95% CI, NR-NR) Dr. Lee also presented results from a Phase II study evaluating nivo/cabo in nccRCC (NCT03635892), with a distinctive feature (relative to KEYNOTE-B561) being that the study permitted up to one previous line of therapy. Like KEYNOTE-B561, the toxicity profile was as expected for an ICI/TKI combination. The ORR for this group was 54% (14/26) in the first-line setting and 36% (5/14)in the second-line setting. In all patients, median PFS and OS were 13 months (95% CI: 7, 16), and 28 months (95% CI: 23, 43), respectively.
Dr. McGregor shared findings from the CaNI study, a Phase II trial investigating a triplet combination of Cabozantinib, Ipilimumab, and Nivolumab (Cabo/Ipi/Nivo) in patients with metastatic nccRCC (Abstract #4520, NCT04413123). Prior systemic therapy was allowed in this cohort. In all patients, median PFS was 8.9 (95% CI, 4.2-12.7) months. Notably, most patients (n = 33, 84%) required dose reduction of cabozantinib, and only 45% received all four doses of ipi/nivo. This likely explains the lower-than-expected ORR (18%), though final results are still pending.
In all three studies, chromophobe RCC (chRCC) exhibited worse outcomes with immunotherapy/TKI therapies than other histological subtypes. A possible explanation for this disparity in outcomes was presented by Dr. Labaki, who performed immunoprofiling of chRCC through single-cell RNA sequencing and TCGA analysis, comparing it with other RCC subtypes. His analysis indicated that chRCC has a lower density of tumor infiltrating lymphocytes compared to other histological subtypes, and the infiltrating T-cells found in chRCC lack expression of immune checkpoints, suggesting a non-exhausted phenotype. Furthermore, these T-cells did not seem to display evidence of antitumor specificity, indicating that they might be "bystander" T-cells (Abstract #4558).
Another key presentation, also by Dr. Labaki, were the outcomes of immunotherapy as the first-line treatment in nccRCC with sarcomatoid or rhabdoid (S/R) features (Abstract #4519). In this retrospective analysis performed using International Metastatic RCC Database Consortium (IMDC) data, nccRCC patients with S/R features who received immunotherapy had a notably improved OS (median 19.3-NR in immunotherapy containing arms vs 3.9-13.0 in VEGF-TT arms, p < 0.0001). This provides compelling evidence supporting sarcomatoid features as a predictive biomarker for immunotherapy response in RCC, across histological subtypes.
TRANSLATIONAL RESEARCH HIGHLIGHTS
Many abstracts at the conference explored kidney cancer biology. We have chosen to highlight advances in immunotherapy biomarkers, molecular classifications, and microbiome-based research.
BIOMARKERS TO IMMUNOTHERAPY
Biomarkers which can predict ICI response are needed in RCC. Below, we highlight key abstracts investigating this important field. Dr. Motzer shared a subgroup analysis of the CHECKMATE 914 (Part A) trial, which examined the use of ipi/nivo as adjuvant therapy in patients with locally advanced ccRCC (Abstract #4506)7. Although the study failed to demonstrate a difference in disease-free survival (DFS) in the overall cohort, the subgroup analysis benefit for patients with grade 4 disease (n = 171) who were treated with ipi/nivo (n = 80, median DFS NR 95% CI: [35.9 – NE]) versus placebo (n = 91, DFS 41.4 months [23.8-NE]). Patients with sarcomatoid features (n = 40) appeared to derive even greater benefit, with a median DFS that was NR vs 21.0 months (5.2-NE) in the ipi/nivo (n = 19) vs placebo (n = 21) arms, respectively. Though limited by low numbers, these findings suggest a potential role for sarcomatoid de-differentiation as a biomarker in the adjuvant setting, particularly given the role of sarcomatoid features as a predictive biomarker to ipi/nivo in the metastatic setting8.
Dr. Ahrmar examined tissue samples from the HCRN GU16-260 study9, which investigated nivolumab monotherapy in metastatic RCC (Abstract #4549). The investigators performed multiparametric immunofluorescence on samples from 81 advanced RCC patients who received nivolumab as a first-line treatment. Their findings corroborated previous studies10, revealing that higher levels of CD8+ PD1+ TIM-3 and LAG-3 negative tumor infiltrating lymphocytes were associated with a better response to immunotherapy.
Dr. Braun presented additional biomarker analysis of the HCRN GU16-260 study9. Here, the investigators report on whole exome sequencing (WES) and single cell RNA sequencing (scRNAseq) on a subset of patients with primary refractory disease and compared to responders. They identified amplification of chromosome 11q13 in 6/18 primary refractory patients, compared to no 11q13 amplification in the responsive group. scRNAseq in primary refractory disease revealed an enrichment for a SLAMF7+ population of cytotoxic T cells. These findings reveal two new putative biomarkers (and mechanisms) for immunotherapy resistance in ccRCC which warrant further investigation.
Dr. Rene discussed cytokine profiling performed on 60 patients with advanced nccRCC enrolled in a Phase II study investigating atezolizumab and bevacizumab (Abstract #4535, NCT02724878). They identified a cluster of inflammatory cytokines - MIP-1b, IL-1, MCP-1, IL-6, and IL-13 - whose circulating levels correlated strongly at baseline. Patients with higher circulating levels of these cytokines tended to have a worse IMDC score and decreased PFS (p = 0.028). This study has been published in Cancer Immunology Research11.
MOLECULAR CLASSIFICATION OF RCC
RCC is increasingly recognized as a disease with significant molecular heterogeneity. Accordingly, molecular-based classifiers, such as the IMmotion151 clusters, have been proposed to further subdivide and understand this disease12. We reported that genetic ancestry is associated with IMmotion151 subgroup classifications in a cohort of 253 patients with clear cell RCC (Abstract #4536). In particular, African ancestry is associated with an increased frequency of the "proliferative" cluster, which is characterized by VHL wild type disease, and low expression of a HIF2α gene signature. It is noteworthy that no specific cluster was exclusive to an ancestry group, and when considering IMmotion151 molecular clusters, genetic ancestry did not account for additional variation in gene expression. These findings emphasize the importance of stratifying patients based on tumor biology.
Dr. Reddy from Vindhya Data Science discussed this strategy further in her poster "Biomarker-driven prospective clinical trial in renal cell carcinoma: Developing machine learning models to allocate patients to treatment arms using RNA sequencing" (Abstract #4525). Through machine learning methods, the researchers were able to identify a model that can predict IMmotion151 cluster types in a manner that can be applied to individual samples in a prospective way. This ability to apply the model to single samples addresses a significant limitation of the original classifier. This strategy of stratifying patients based on IMmotion151 cluster type is now being applied in the OPTIC trial (NCT05361720), which aims to determine if patients should be allocated to TKI/IO or IO/IO treatment arms based on their cluster type. The results of this study will be watched closely as an example of how to integrate advancements in molecular classifications and machine learning with clinical practice.
MICROBIOME AND RCC
The microbiome's role in immunotherapy efficacy for Renal Cell Carcinoma (RCC) is a subject of ongoing investigation, as illustrated by several abstracts presented at this conference.
Dr. Costa Silva presented a correlative analysis of the NIVOREN phase II trial (NCT03013335), which examined the impact of nivolumab in patients with ccRCC who had shown progression on VEGF-TKI therapy (Abstract #4548). The researchers focused on serum soluble mucosal addressin cell adhesion molecule-1 (ssMAdCAM-1), a molecule expressed in the gastrointestinal (GI) tract that helps retain immunosuppressive enterotropic T-cells. The researchers hypothesized that high levels of ssMAdCAM-1, associated with ileal MADCAM-1 transcripts, could be linked to immunotherapy effectiveness. They found that low ssMAdCAM-1 levels were associated with antibiotic use and a low clinical benefit rate (37% versus 63%, p=0.0004). Additionally, low ssMAdCAM-1 predicted OS in a cohort of lung and bladder patients undergoing ICI therapy.
Dr. Dizman presented a correlative analysis of a phase I study examining CBM588 (NCT03829111)13, a live bacterial product that produces butyric acid, in combination with nivo/ipi versus nivo/ipi alone in treatment-naïve advanced ccRCC patients (Abstract #4556). Increased baseline levels of isobutyrate were observed in patients receiving CBM588, and further increases during treatment were associated with objective response. Moreover, the level of circulating acetic acid was correlated with CCL2 and CCL4, potentially providing a biological rationale for the combination therapy. Dr. Bari conducted an analysis comparing stool and plasma metabolomics in responders versus non-responders among 79 treatment-naïve RCC patients receiving immunotherapy-containing regimens (Abstract #4564). Microbial metabolites of Tryptophan were associated with ICB resistance and found at significantly higher levels in non-responders. Lastly, Dr. Mezza examined the intratumoral microbiome in 96 patients with metastatic RCC undergoing immunotherapy treatment (Abstract #4561). Increased bacterial diversity within tumors was linked with improved immunotherapy response, suggesting a potential role for the intratumoral microbiome in determining patient outcomes.
CONCLUDING REMARKS
This year’s ASCO Conference was notable for several important studies ranging from practice changing phase III studies to important translational work. Here-in we highlighted key abstracts, organized by study type (phase III, early clinical studies, and exploratory) and histological subtype (ccRCC and nccRCC). There are many more RCC related abstracts available through the ASCO conference materials, and we encourage our readers to explore these important studies.REFERENCES
1. Kashima, S. & Braun, D. A. The Changing Landscape of Immunotherapy for Advanced Renal Cancer. Urologic Clinics 50, 335–349 (2023). 2. Rini, B. I. et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. New England Journal of Medicine 380, 1116–1127 (2019). 3. Motzer, R. et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. New England Journal of Medicine 384, 1289–1300 (2021). 4. Albiges, L. et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open 5, e001079 (2020). 5. Pal, S. K. et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. The Lancet 0, (2023). 6. Zoumpourlis, P., Genovese, G., Tannir, N. M. & Msaouel, P. Systemic Therapies for the Management of Non–Clear Cell Renal Cell Carcinoma: What Works, What Doesn’t, and What the Future Holds. Clin Genitourin Cancer 19, 103–116 (2021). 7. Motzer, R. J. et al. Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial. The Lancet 401, 821–832 (2023). 8. Tannir, N. M. et al. Efficacy and safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. Clinical Cancer Research 27, 78–86 (2021). 9. Atkins, M. B. et al. Phase II Study of Nivolumab and Salvage Nivolumab/Ipilimumab in Treatment-Naive Patients with Advanced Clear Cell Renal Cell Carcinoma (HCRN GU16-260-Cohort A). Journal of Clinical Oncology 373, (2022). 10. Pignon, J. C. et al. Irrecist for the evaluation of candidate biomarkers of response to nivolumab in metastatic clear cell renal cell carcinoma: Analysis of a phase II prospective clinical trial. Clinical Cancer Research 25, 2174–2184 (2019). 11. Saliby, R. M. et al. Circulating and intratumoral immune determinants of response to atezolizumab plus bevacizumab in patients with variant histology or sarcomatoid renal cell carcinoma. Cancer Immunol Res (2023) doi:10.1158/2326-6066.CIR-22-0996. 12. Motzer, R. J. et al. Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade. Cancer Cell 38, 803-817.e4 (2020). 13. Dizman, N. et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nature Medicine 2022 28:4 28, 704–712 (2022).
The RCC highlights of this year's conference included the ZIRCON study which evaluated
radiolabeled 89Zr-DFO-girentuximab (a monoclonal
antibody targeting CA IX) for detection of clear cell
RCC in patients with indeterminate renal masses. This
phase III trial included patients with renal masses (≤7
cm, cT1) who were scheduled to undergo a nephrectomy
in 90 days and all patients received a single dose of
Radiolabeled 89Zr-DFO-girentuximab (37 MBq ± 10%;
10 mg girentuximab) on Day 0 and underwent PET/CT
imaging on Day 5 (± 2 days) prior to surgery. The study
met its co-primary end points exceeding the sensitivity
and specificity thresholds and confirmed a favorable
toxicity profile (Shuch, Pantuck et al. 2023). This study
lays the foundation and provides a convenient non-invasive platform for pre-treatment risk stratification
of clear cell RCC akin to PSMA in prostate cancer.
Dr. Choueiri presented an exploratory post
hoc subgroup analysis of KEYNOTE 564 across the
UISS (University of California Los Angeles Integrated
Staging System) risk groups and disease stage. The
Keynote 564 trial showed an improvement in disease
free survival in patients with clear cell RCC with a
high risk of recurrence leading to the FDA approval
of pembrolizumab in the adjuvant setting. The UISS
is a commonly used prognostic model that predicts
the 5-year survival rates following a nephrectomy.
In this trial, most patients in both the arms were
categorized in the UISS intermediate group (75%) with
5.9% of patients having M1NED disease. Up to 88% of
patients had AJCC Stage 3 disease. The results showed
that adjuvant pembrolizumab prolonged disease-free survival across subgroups by AJCC Stage, TNM
staging, Fuhrman grading and UISS risk compared to
placebo. The extent of benefit was most pronounced in
patients with M1NED disease (HR: 0.28, 95% CI: 0.11
– 0.73), AJCC stage 3 (HR: 0.68, 95% CI: 0.51 – 0.89)
and Stage 4 disease (HR: 0.42, 95% CI: 0.20 – 0.87).
This exploratory analysis further supports the use of
pembrolizumab in patients with a high risk of recurrence
in the adjuvant setting (Choueiri, Tomczak et al. 2023).
Dr. Powles presented an updated analysis of
the COSMIC 313 trial which was the first phase 3 trial
exploring the triplet combination of cabozantinib along
with ipilimumab and nivolumab versus ipilimumab
and nivolumab, a contemporary control arm in patients
with advanced RCC with intermediate or poor IMDC
risk. With an additional follow up of 5 months, the
progression free survival (PFS) benefit with the triplet
combination was maintained in the overall population
with a HR of 0.74 (95% CI 0.61-0.90) and HR of 0.68
(95% CI 0.54-0.86) in the intermediate risk population.
Similarly, the objective response rate was also higher
with the triplet combination in the intermediate
risk group compared to the poor risk group. There
were no major differences in the treatment exposure
between both the triplet arms that could explain the
enhanced efficacy in the intermediate risk group
(11.3 months in the intermediate risk population and
10.4 months in the poor risk population). The daily
dose of cabozantinib received was also similar in
both the groups. Adverse events leading to treatment
discontinuation was more common in the intermediate
risk population compared to the poor risk group. It is
important to note that patients in the poor risk group
had significantly fewer nephrectomies compared to the
intermediate risk group (40% and 50% in the triplet
arm and comparator poor risk group compared to 73%
and 69% in the triplet and comparator intermediate
risk group respectively) and this could be one of the
reasons behind the lower response rates in this patient
population. Another likely explanation is that the poor
risk group is biologically more immune driven than
angiogenesis driven compared to the favorable risk
population (Rini, Huseni et al. 2018, Tannir, Signoretti
et al. 2021). Overall survival follow up in ongoing
(Powles, Motzer et al. 2023) and will be important to
consider for regulatory approval of this combination
in intermediate and poor risk IMDC risk groups.
Treatment free survival is a meaningful clinical
end point that has not been traditionally evaluated
as a predefined end point in clinical trials. Dr. Atkins
presented the updated analysis of treatment free
survival of HCRN GU16-260-Cohort A (Atkins, Jegede
et al. 2023). In this study, 128 patients with advanced
clear cell RCC received treatment with nivolumab
and based on their response they received additional
treatment with nivolumab for up to 96 weeks if they
had a partial response or a complete response or salvage
ipilimumab was added if they had progressive disease or
stable disease at 48 weeks. Treatment free survival was
defined as the area between the Kaplan Meier curves for
time from registration to stopping protocol therapy and
time from registration to starting subsequent therapy or
death estimated at a mean of 36 months. The response
rate in the favorable risk group was 57.9% with the
overall response rates being 35.9% at 3 years, 65.6% of
patients with favorable risk were alive and treatment
free compared to 27.1% of patients with intermediate/
poor risk disease. The overall PFS was 14.6%. The 36
month mean treatment free survival was 36% in the
favorable risk group which included 4% of patients with
TRAE >3 and the treatment free survival was 22% in
the intermediate/poor risk group which included 3% of
patients with TRAE >3. Based on this study, salvage ipi/
nivo in is a viable option in patients who do not respond
to nivolumab monotherapy in the front line setting
and has a robust treatment free survival with limited
toxicity. The maximum benefit was obtained by the
favorable risk group like the DFS benefit in favorable
risk group in the Checkmate 214 trial supporting the use
of this regimen in favorable risk patients (45% vs 36%)
Dr. Albiges presented to interim results of
CaboPoint which is a phase II study of cabozantinib in
adults with advanced clear cell RCC with progressive
disease after front line checkpoint inhibitor therapy.
The study consisted of two cohorts: Cohort A including
patients with progressive disease after ipilimumab
and nivolumab and cohort B including patients with
progressive disease on immunotherapy and a VEGFR
TKI. Most patients had intermediate risk disease
with upfront metastatic disease and did not have a
nephrectomy. The ORR in cohort A was 31.7% (95%
CI, 20.3-45) and Cohort B was 25% (95% CI, 10.7-44.9).
Cabozantinib was effective as a second line treatment
option irrespective of the front-line regimen used, with
patients with intermediate risk disease having failed
ipilimumab and nivolumab seemed to benefit the most
with a RR of 40%. The duration of front line therapy
also had an impact with patients benefitting more if
they received cabozantinib in the primary refractory
setting having had progressive disease within 6 months
of front line therapy (Albiges, Powles et al. 2023).
The updated results of the BIONIKK trials were
also presented (Vano, Phan et al. 2023). This was a
randomized phase II trial that prospectively selected
patients to receive either nivolumab, nivolumabipilimumab or a VEGRF TKI based on the tumor
molecular group. They had previously reported high
efficacy of VEGFR TKI in CCRCC2 tumors (51%) and
high efficacy of nivolumab with ipilimumab in CCRC4
(50%) compared to CCRC1 (39%) tumors. After a
follow up of 46.5 months, the median overall survival
was not reached for ipilimumab /nivolumab and was
35 months for nivolumab (HR compared to nivo/ipi:
1.56, 95% CI: 0.99 to 2.46) and 45 months for VEGFR
TKI (HR compared to nivo/ipi: 1.29, 95% CI: 0.76 to
2.19). When the overall survival was characterized by
molecular group, superior survival was observed with
the ipilimumab/nivolumab combination compared
to nivolumab alone in CCRC1 (HR: 1.44) and CCRC4
(HR: 1.64) groups. There was no difference in survival
with treatment with either VEGFR TKI or ipilimumab/
nivolumab in the CCRC2 (HR: 1.15) group. About 80%
of patients went on to receive second line treatment
and most of them received a VEGFR TKI (79%).
After a median follow up of 34 months, there was a
higher response rate after ipilimumab and nivolumab
(33%) than after single agent nivolumab (11%) in the
CCRC4 group and the CCRC2 group has the highest
response rate of 62% post ipilimumab and nivolumab
and 57% post VEGRF TKI. The updated results
confirmed the feasibility of biomarker driven trials
in RCC and the efficacy of ipililumab/nivolumab in
CCRC4 and VEGFR TKI in CCRC2 molecular groups.
Dr. Siva reviewed the use of radiation in oligometastatic
kidney cancer. The ASCO guidelines include
radiotherapy for management of patients with low
volume metastatic disease (Rathmell, Rumble et al.
2022) . In a meta-analysis of 28 studies including 1600
patients with almost 4000 treated lesions, the local
control rate for both intra cranial and extracranial
lesions was 90%. Prospective trials of radiation
in oligometastatic RCC have shown that SABR
(stereotactic ablative radiation) can be effectively
delivered in lieu of systemic therapy. In a single center
study of 30 patients with low burden of disease (having
1 median number of metastases) with a median follow
up of 17.5 months, the one-year progression free
survival was 64%, the median progression free survival
was 23 months and importantly, at one year, 82% of
patients did not receive any systemic therapy (Tang,
Msaouel et al. 2021) . Radiation can also be used in
the oligoprogressive setting to prolong the efficacy of
systemic therapy.
In a
multicenter trial of 37 patients with oligoprogressive
disease, SABR to the oligoprogressive sites resulted
in a 93% one-year disease control rate and a
progression free survival of 9.3 months. SABR can
also be safely delivered with immunotherapy. In the
RAPPORT trial, patients received a combination
of six months of pembrolizumab with SABR taking
advantage of the synergy between radiotherapy and
immunotherapy inducing tumor antigen and cytokine
release by radiotherapy which can prime the tumor
microenvironment and likely transform a cold to
hot microenvironment. The median progression
free survival was 15 months, and the two-year local
control rate was 92% (Siva, Bressel et al. 2022) .
SABR therefore, provides a safe, non-invasive option
of prolonging the efficacy of systemic therapy and has
synergy with immunotherapy
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