(UroToday.com) The 2025 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Annual Symposium held in San Francisco, CA between February 13–15, 2025 was host to a case-based session discussing treatment options for renal cell cancer following failure of immunotherapy.
Drs. Leslie Ballas and Kathryn Gessner, moderating the session, began with a case presentation of a 63-year-old male who presents with gross hematuria, 3-month duration of cough, and fatigue. On contrast-enhanced axial imaging, he is found to have a 10.9×10.7cm heterogeneously enhancing left renal mass abutting the adrenal gland, with no renal vein thrombosis, and bilateral pulmonary nodules with the largest at the left lung base measuring 5.5 × 4.8cm.
He undergoes a biopsy, which returns as poorly differentiated carcinoma with rhabdoid and sarcomatoid differentiation. IHC stains are noted to be positive for PAX-8, vimentin, and CAIX. Underlying clear cell component was felt to be the highest likelihood.
What is the optimal 1st line treatment approach? Dr. Matthew Campbell argued that given the presence of the sarcomatoid component, this patient is likely to benefit the most from an IO-IO combination, ipilimumab + nivolumab, based on subgroup analyses from the CheckMate 214 trial showing objective response rates (ORR) of up to 60% in these patients, with complete responses (CR) of up to 20%.1,2 Dr. Maria Bourlon concurred noting as well that patients with such histology are typically enriched for PD-1 biomarkers, which are associated with enhanced responses to IO-IO combinations.
In performing the biopsy, Dr. Viraj Master noted that every effort should be made to biopsy the enhancing component of the mass, in order to minimize the chance of sampling necrotic tissue and maximize the biopsy diagnostic yield. 14- or 16-guage needles should be used, where feasible.
The patient was started on ipilimumab + nivolumab and an improvements in the metastatic pulmonary lesion and primary renal lesion were observed.
However, at one-year post-systemic therapy, the patient was noted to have a new enhancing lesion in the left kidney:
At this point, the audience was queried regarding next best step, with the majority (76%) recommending repeat biopsy + nephrectomy.
The patient underwent a nephrectomy with pathology demonstrating evidence of residual viable renal cell carcinoma (0.9 x 0.8 cm), grade 4, with immunotherapy changes. Post-operative CT demonstrated post-surgical changes, with no evidence of metastatic disease.
What about next steps? The audience responded with resumption of nivolumab as the preferred choice (55.4%), followed by surveillance (28.6%).
Dr. Bourlon argued in favor of restarting nivolumab. She argued that this patient did not have evidence of disease progression of the metastatic sites, and, as such, did not develop failure of systemic therapy in this setting. Accordingly, switching to cabozantinib is not warranted in this setting. With regards to ‘adjuvant’ pembrolizumab or sunitinib, she argued that this patient has already been treated with systemic therapy and, thus, does not meet the eligibility criteria of KEYNOTE-564 or S-TRAC. Given that the disease recurrence was in the nephrectomy bed, with no other sites of metastases, maintenance nivolumab is indicated in this setting. She cautioned against the risk of undertreatment with surveillance of these patients.
Ultimately, this patient opted for surveillance and is reportedly free of disease recurrence at four years post-nephrectomy.
Next, Dr. Matthew Campbell discussed mechanisms of immunotherapy resistance in renal cell carcinoma. He noted that there are three types of immunotherapy resistance in renal cell cancer:3
- Primary: Primary disease progression as best response
- Adaptive: The immune system recognizes cancer, but cancer is able to evolve to survive
- This can overlap with other categories
- Acquired: The cancer initially responds to immunotherapy, but the patient eventually experiences relapse/progression
The Society for Immunotherapy of Cancer (SITC) further defined consensus definitions for resistance to combinations of immune checkpoint inhibitors, as defined in the table below. Notably, resistance definitions in the adjuvant setting were also agreed upon, which is particularly relevant for renal cell carcinoma patients at increased risk of recurrence following nephrectomy.
What are PD-1 mechanisms of resistance? Possible mechanisms include:
- Lack of B7-H1 (missing target)
- T cell exclusion
- Immunosuppressive immune cells
- Immune inhibitory receptors and T cell dysfunction
- Secreted immunosuppressive factors
- Antigen loss though immunoediting
- Defects in antigen presentation
- Loss of interferon signaling pathways
Possible mechanisms of resistance to anti-CTLA-4 agents, include:
- Loss of IFN-γ pathway genes in tumor cells
- Loss of MHC Class I antigen presentation
- Upregulation of PD-L1 on tumor cells and immune cells, including macrophages
- Upregulation of VISTA, an inhibitory immune checkpoint, that was shown to increase after ipilimumab therapy in prostate cancer patients4
Another possible mechanism of resistance is tertiary lymphoid structures generating and propagating anti-tumor antibody-producing plasma cells in renal cell cancer.5
Dr. Campbell noted that single-cell RNA-seq has uncovered co-evolving immune populations with RCC progression. T-cell exhaustion increases with advancing disease stage. Additionally, myeloid cells become increasingly more ‘pro-tumorigenic’ whereby M2-like genes are enriched in metastatic macrophages. Furthermore, there are interactions between the exhausted CD8 cells and M2-like tumor-associated macrophages, which leads to worse prognoses and resistance to immunotherapy.
Another emerging mechanism of resistance is through TGFβ, which mediates clear cell RCC resistance to IO + IO + TKI therapy.
Another possible underlying etiology of resistance is the gut microbiome, with the Dana Farber group demonstrating that metastatic RCC patients receiving antibiotics during systemic therapy having worse survival outcomes.6
There is ongoing work evaluating whether modulation of the gut microbiome using live bacterial supplementation can enhance response to ipilimumab + nivolumab in metastatic RCC.
Next, Dr. Lallas presented the 2nd case of a 38-year-old female who presented with a 6 month history of fatigue, weight loss, and mild dyspnea. She was found to have a renal mass invading the renal vein, multiple pulmonary nodules, and mediastinal lymphadenopathy.
She was started on cabozantinib + nivolumab and achieved a partial response.
16 months after completion of cabozantinib + nivolumab, with a maintained partial response in the primary and metastatic lesions, she was found to have a novel left scapular lesion, as imaged below:
Dr. Lallas queried the audience- what treatment would you offer next?
The majority of the audience (>90%) voted in favor of SABR. Dr. Master commented that surgical metastasectomy is likely to be highly morbid and challenging for tumors in this location. For patients with pulmonary lesions or other sites of bone metastases, such as fibular metastases, surgical extirpation is quick, associated with minimal morbidity, and often relieves metastasis-related musculoskeletal pain.
What is oligoprogression? Dr. Bourlon commented that this typically refers to a disease state, where the primary site of disease is controlled with systemic therapy, but there are a limited number of metastases (≤5) that have progressed. This excludes progressing intracranial lesions and situations where sites of progression involve ≥30% of all metastases.
It has been well-established that intratumoral heterogeneity exists, whereby some clones may respond to immunotherapy, whereas others are resistant leading to the development of oligoprogressive disease.
This patient proceeded to receive SBRT to the scapular lesion. Dr. Raquibul Hannan noted that this is considered consolidative SBRT, as opposed to palliative, given the absence of symptoms. This has important implications for the dose of radiotherapy administered. Evidence to support consolidative SBRT in this setting was demonstrated in a study by Dr. Hannan’s group published in 2021 of 51 metastatic RCC patients with oligoprogression who received SBRT to 71 disease sites. At a median follow-up of 19 months, the median PFS was extended by 8.6 months with SBRT.7 In patients on IO, the median PFS was longer at 28 months, suggesting an immunomodulatory or enhancing effect for SBRT in this setting.
Similar results were demonstrated by Cheung et al in a multicenter phase II trial of a tyrosine kinase inhibitor (pazopanib) + SAbR in 37 patients with 57 oligoprogressive tumors. The 1-year local control rate was 93%. The median PFS was 9.3 months, and the median time to change of systemic therapy was 12.6 months. No grade 3-5 adverse events were reported.9
In a phase II trial of patients receiving either TKI or IO, Dr. Hannan and colleagues showed within the context of a phase II trial of 20 patients with 37 sites of oligoprogressive disease that SAbR was able to extend PFS by 11.1 months.9 Importantly, a trend for improved PFS was observed for patients on IO therapy (p=0.04).
Moving back to the case presentation, this patient was noted to have an excellent local response to SBRT. IS there a role for a radical nephrectomy in this patient? Dr. Master argued that yes, there is, given the large size of the primary renal lesion, minimal metastatic burden which has responded to systemic therapy, and the success of SBRT for the oligoprogressive lesion.
He argued that cytoreductive nephrectomy in this setting is safe and may facilitate prolonged treatment-free intervals. In 2023, Shapiro et al. published the results of a multi-institutional collaboration of 75 consecutive patients who underwent a cytoreductive nephrectomy between 2017 and 2022 and had minimal extrarenal disease. Notably, 39% had an IVC tumor thrombus. There were no 90-day mortalities, and there was a 3% rate of Clavien Grade >3 complications. Notably, 74/75 patients had viable tumor at nephrectomy. Importantly, 48% of patients remained off systemic therapy at 36 months follow-up.10
At 1-year post-SBRT, the patient had evidence of systemic disease progression with new pulmonary nodules, mediastinal lymphadenopathy, and increased size of the primary tumor.
What is the 2nd line therapy recommended in this setting? Dr. Bourlon presented a treatment algorithm following failure of cabozantinib + nivolumab. Ideally, patients should be enrolled in clinical trials, where available. Otherwise, belzutifan, as demonstrated in the LITESPARK-005 trial, offers a PFS advantage in this setting (18 months: 24% versus 8.3% for everolimus, p=0.002).11 Alternative TKIs may be offered in this setting with ORRs of 20–30%.
Next, Dr. Gessner moved on to present the 3rd case of a 75 year old male with an excellent performance status (ECOG 0) who presented with hematuria and was found to have synchronous small volume metastatic RCC to the lungs, the largest measuring 2.8 cm, and an ~12 cm right tumor with a level 3 IVC thrombus, involving the hepatic veins.
He was started on pembrolizumab + axitinib, but 9 months later developed hematuria requiring multiple catheterizations and transfusions. The kidney tumor did not decrease in size (11 → 12 cm), but the lung metastases decreased from 2.8 cm to 9 mm.
What treatment should this patient be offered next?
One important pre-operative surgical consideration in these cases is the possibility of developing a desmoplastic-like, inflammatory reaction to the systemic immunotherapy that may make plane dissection challenging in some cases.
How can we better select patients who may benefit from upfront cytoreductive nephrectomy? The SCREEN Score was developed using surgical cohorts from 5 institutions and included 914 patients with a median tumor size of 9 cm and who were followed for a median of 43 months. The SCREEN model incorporates radiographic findings, patient symptoms, and laboratory values, as illustrated below:
Compared to the well-established IMDC risk score, the SCREEN score performed well in segregating cohorts for cytoreductive nephrectomy. In this surgical cohort, the IMDC risk classification system did well segregating favorable from intermediate/poor risk patients (median survival: 120 versus 26-27 months) but performed poorly in distinguishing survival outcomes in intermediate versus poor risk disease patients (26 versus 27 months). Conversely, using the SCREEN criteria, there was a clear segregation of survival outcomes by the risk category, with median survivals of 64, 28, and 10 months in the SCREEN favorable, intermediate, and poor risk patients, respectively.12 Dr. Master argued that this score could be used to select cytoreductive nephrectomy candidates, whereby those with favorable scores could be considered for a cytoreductive nephrectomy, whereas those with a poor risk score should proceed to systemic therapy, because their median overall survival was 10 months. The SCREEN score outperformed IMDC for survival prognostication with an AUC of 0.76 versus 0.55 for IMDC.
In cases where cytoreductive nephrectomy is not technically feasible, is cytoreductive SBRT a reasonable alternative in this setting?
For such challenging cases with viscera in close proximity, Dr. Hannan and colleagues have implemented a novel adaptive, hypofractionated regimen, where high doses are administered at prolonged intervals (i.e., one session every 4-8 weeks). This allows the tumor to shrink over time, which enhances the ability to eventually administer high doses to the peripheral aspect of the tumor.
There are currently two notable ongoing phase II trials evaluating cytoreductive SAbR in the setting of immunotherapy:
- CYTOSHRINK (NCT04090710) by CCTG
- Phase 2 randomized trial
- Accrual goal 78; 2:1 randomization
- Ipilimumab/Nivolumab
- SAMURAI (GU012, NCT05327686) by NRG
- Phase 2 randomized trial
- Accrual goal 240; 2:1 randomization
- Ipi/Nivo, Nivo/Cabo; Pembro/Axi, Axi/avelumab
The patient was started on ipilimumab + nivolumab and achieved a mixed response with mostly stable disease. However, after 6 cycles, he presented with a bilateral facial droop, facial numbness, and mild confusion. He was found to be hyponatremic with a Na of 118. His AM cortisol was low. He was diagnosed with secondary adrenal insufficiency due to hypophysis from the checkpoint inhibitor. Should ipilimumab + nivolumab be discontinued in this case?
Dr. Bourlon highlighted guidance from the ASCO and ESMO recommendations relating to immune-related hypophysitis. Recommendations are based on grade of hypophysitis (Grades 1–4) and generally favor withholding ICIs until the condition has stabilized and appropriate hormone replacement has been initiated.
With regards to other immune-related adverse events, one of the important questions is: should a re-challenge be attempted? For conditions such as myocarditis, pneumonitis, and CNS toxicity, the general consensus appears to be no. However, for other conditions such as skin toxicity, endocrinopathies, colitis, and arthritis/arthralgia, a re-challenge is reasonable once conditions have been addressed/resolved.
For this patient, ipilimumab + nivolumab was discontinued. He remained on surveillance for 6 months, but later developed progression of a large painful 8th right rib metastasis.
Dr. Hannan argued in favor of a palliative (given pain) and consolidative approach (given this is the only site of disease progression) for this patient. What is the evidence for palliative radiotherapy for RCC? In an unpublished series from the UTSW group, 240 symptomatic RCC patients received radiotherapy to 581 sites for pain (93%), neurologic (4%), and respiratory (4.1%) symptoms. An overall improvement in symptoms was observed for 87% of patients. The median time to symptom resolution was 1.7 months. There was no significant difference between SAbR and conventional radiotherapy for symptom resolution.
Given this data, this patient was treated with SAbR/PULSAR 42 Gy in 3 treatments delivered over 3 months.
Moderated by:
- Kathryn Gessner, MD, PhD, UNC School of Medicine, Raleigh, NC
- Leslie K. Ballas, MD, Cedars-Sinai Medial Center, Los Angeles, CA
- Raquibul Hannan, MD, PhD, UT Southwestern Medical Center, Dallas, TX
- Viraj Master, Emory University School of Medicine, Atlanta, GA
- Maria T. Bourlon, MD, MSc, FASCO, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
- Matthew T. Campbell, MD, MS, The University of Texas MD Anderson Cancer Center, Houston, TX
Written by: Rashid K. Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025.
References:- Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018; 378(14):1277-1290.
- Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: Extended follow-up of efficacy and safety results from a randomized, controlled, phase 3 trial. Lancet Oncol 2019; 20(10):1370-1385.
- Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017; 168(4):707-723. 10.1016/j.cell.
- Gao J, Ward JF, Pettaway CA, et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med. 2017; 23(5):551-555.
- Meylan M, Petitprez F, Becht E, et al. Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer. Immunity. 2022; 55(3):527-541.e5.
- Lalani AK, Xie W, Lin X, et al. Effect of antibiotic use on outcomes with systemic therapies in metastatic renal cell carcinoma. Eur Urol Oncol. 2020; 3(3):372-381.
- Schoenhals JE, Mohamad O, Christie A, et al. Stereotactic ablative radiation therapy for oligoprogressive renal cell carcinoma. Adv Radiat Oncol. 2021; 6(5):100692.
- Cheung P, Patel S, North SA, et al. Stereotactic Radiotherapy for Oligoprogression in Metastatic Renal Cell Cancer Patients Receiving Tyrosine Kinase Inhibitor Therapy: A Phase 2 Prospective Multicenter Study. Eur Urol. 2021l 80(6):693-700.
- Hannan R, Christensen M, Hammers H, et al. Phase II Trial of Stereotactic Ablative Radiation for Oligoprogressive Metastatic Kidney Cancer. Eur Urol Oncol. 2022; 5(2):216-24.
- Shapiro DD, Karam JA, Zemp L, et al. Cytoreductive Nephrectomy Following Immune Checkpoint Inhibitor Therapy Is Safe and Facilitates Treatment-free Intervals. Eur Urol Open Sci. 2023; 50:43-46.
- Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma. N Engl J Med. 2024; 391:710-721.
- Abel EJ, Master VA, Speiss PE, et al. The Selection for Cytoreductive Nephrectomy (SCREEN) Score: Improving Surgical Risk Stratification by Integrating Common Radiographic Features. Eur Urol Oncol. 2024; 7(2):266-74.