Highlights in Renal Cell Carcinoma From the Seventeenth International Kidney Cancer Symposium
A Review of Selected Presentations From the Seventeenth International Kidney Cancer Symposium • November 2-3, 2018 • Miami, Florida
CheckMate 214 Retrospective Analyses of Nivolumab Plus Ipilimumab or Sunitinib in IMDC Intermediate/Poor-Risk Patients With Previously Untreated Advanced Renal Cell Carcinoma With Sarcomatoid Features
Despite advances in the targeted treatment of renal cell carcinoma (RCC), the sar-comatoid subtype continues to pre-sent challenges.1-3 Sarcomatoid dedifferentiation can occur in any RCC subtype or stage and is associated with resistance to established therapies. Most patients with sarcomatoid RCC have metastatic disease upon initial presentation, and the presence of sarcomatoid features independently pre-dicts poor survival. Checkpoint inhibition may provide a desirable alternative to currently available treat-ments for this RCC subtype. Sarcomatoid RCC tumors may express programmed death 1 (PD-1) and its ligand (PD-L1) at higher rates than clear cell RCC tumors that lack sarcomatoid elements.4 In a retrospective study, initial results based on inhibition of the immune checkpoint pathway showed promising efficacy in patients with metastatic RCC and sarcomatoid dedifferentiation.5
An exploratory analysis of the phase 3 CheckMate 214 study (Nivolumab Combined With Ipilimumab Versus Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma) retrospectively evaluated the efficacy and safety of nivolumab plus ipilimumab vs sunitinib in patients with RCC with or without sarcomatoid features.6 Included patients had treatment-naive, advanced or metastatic clear cell RCC, and intermediate- or poor-risk disease according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model. Patients had a Karnofsky performance score of at least 70%, and tumor tissue available for PD-L1 testing.
After stratification by IMDC prognostic score and region, patients were randomly assigned into the 2 treatment arms. Patients in arm A received nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for 4 cycles, followed by nivolumab (3 mg/kg) every 2 weeks. Patients in arm B received sunitinib (50 mg) once daily for 4 weeks on, 2 weeks off. Patients were treated until they developed disease progression or unacceptable toxicity.
The study randomly assigned 60 patients with sarcomatoid tumors to nivolumab plus ipilimumab (1 of whom was not treated) and 52 to sunitinib. The analysis also included 847 RCC patients with or without sarcomatoid features who were treated in CheckMate 214. In this comparator population, the study randomly assigned 425 patients to nivolumab plus ipilimumab and 422 to sunitinib.7 Across the 4 arms, patients had a median age of 58 to 62 years, and 70% to 75% were male. A poor IMDC prognostic score was reported in 21% to 29%. The most common metastatic sites were the lung (69%-81%), lymph node (45%-51%), and bone (19%-23%). Among patients with available tissue, tumor PD-L1 expression of at least 1% was observed in 50% of those with sarcomatoid RCC vs 27.5% of those in the comparator population.
Among patients with sarcoma-toid RCC, the confirmed objective res-ponse rate (ORR) was 56.7% (95% CI, 43.2%-69.4%) with nivolumab plus ipilimumab vs 19.2% (95% CI, 9.6%-32.5%) with sunitinib (P<.0001).In the comparator population of all patients randomly assigned to treat-ment, the ORR was 41.9% (95% CI, 37.1%-46.7%) vs 29.4% (95% CI, 25.1%-34.0%), respectively. The rate of com-plete response (CR) was 18.3% with nivolumab plus ipilimumab vs 0% with sunitinib. The median progression-free survival (PFS) was 8.4 months (95% CI, 5.2-24.0 months) in patients treated with nivolumab plus ipilimumab vs 4.9 months (95% CI, 4.0-7.0 months) in those who received sunitinib (hazard ratio [HR], 0.61; 95% CI, 0.38-0.97; P=.0329; Figure 1), based on investigator analysis. Median overall survival (OS) was 31.2 months (95% CI, 23.0 months to not reached) with nivolumab plus ipilimumab vs 13.6 months (95% CI, 7.7-20.9 months) with sunitinib (HR, 0.55; 95% CI, 0.33-0.90; P=.0155). OS was superior with nivolumab plus ipilimumab vs sunitinib regardless of the patient’s level of PD-L1 expression. Among patients with less than 1% PD-L1 expression, the median OS was 23.7 months with nivolumab plus ipilimumab vs 13.8 months with sunitinib. Among patients with an expression level of 1% or higher, median OS was not reached vs 13.8 months, respectively (Figure 2). No new safety signals were raised for either treatment.
References
1. Mian BM, Bhadkamkar N, Slaton JW, et al. Prognostic factors and survival of patients with sarcomatoid renal cell carcinoma. J Urol. 2002;167(1):65-70.
2. Shuch B, Bratslavsky G, Linehan WM, Srinivasan R. Sarcomatoid renal cell carcinoma: a comprehensive review of the biology and current treatment strategies. Oncologist. 2012;17(1):46-54.
3. Shuch B, Bratslavsky G, Shih J, et al. Impact of pathological tumour characteristics in patients with sarcomatoid renal cell carcinoma. BJU Int. 2012;109(11):1600-1606.
4. Joseph RW, Millis SZ, Carballido EM, et al. PD-1 and PD-L1 expression in renal cell carcinoma with sarcomatoid differentiation. Cancer Immunol Res. 2015;3(12):1303-1307.
5. Ross JA, McCormick BZ, Gao J, et al. Outcomes of patients (pts) with metastatic renal cell carcinoma (mRCC) and sarcomatoid dedifferentiation (sRCC) after treatment with immune checkpoint inhibitors (ICI): a single-institution retrospective study [ASCO abstract 4583]. J Clin Oncol. 2018;36(15 suppl).
6. McDermott DF, Motzer RJ, Rini BI, et al. CheckMate 214 retrospective analyses of nivolumab plus ipilimumab or sunitinib in IMDC intermediate/poor-risk patients with previously untreated advanced renal cell carcinoma with sarcomatoid features. Abstract presented at: the Seventeenth International Kidney Cancer Symposium; November 2-3, 2018; Miami, Florida.
7. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290.
Phase Ib Study (COSMIC-021) of Cabozantinib in Combination With Atezolizumab: Results of the Dose-Escalation Stage in Patients With Treatment-Naive Advanced Renal Cell Carcinoma
Cabozantinib is a tyrosine kinase inhibitor (TKI) that may act synergistically with immune checkpoint inhibitors.1,2 The open-label phase 1b COSMIC-021 trial (Study of Cabozantinib in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors) evaluated cabozantinib plus atezolizumab, a PD-L1 antibody, in patients with solid tumors.3 The dose-escalation stage of the study used a 3 + 3 design. Enrolled patients had advanced or metastatic RCC or urothelial carcinoma. Patients with RCC were treatment-naive, and those with urothelial carcinoma had progressed on prior systemic platinum-based therapy. Patients had measurable disease and an Eastern Cooperative Oncology Group per-formance status of 0 or 1. All dose levels included atezolizumab (1200 mg, every 3 weeks). Cabozantinib was administered once daily at 20 mg (dose level –1), 40 mg (dose level 1), or 60 mg (dose level 2). Dose-limiting toxicities were evaluated during the first 21 days of treatment. Tumor assessment, using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, occurred every 6 weeks for the first 12 months and every 12 weeks thereafter.4 The primary objective was to determine the maximum tolerated dose and the recommended dose of cabozantinib in combination with atezolizumab for the expansion phase of the study.
The study enrolled 10 patients with clear cell RCC and 2 with non–clear cell RCC at 3 sites in the United States. The median follow-up was 33 weeks (range, 26-50 weeks). All patients were receiving active treatment at the data cutoff point. Six patients entered into the dose level 1 cohort and 6 into the dose level 2 cohort. The patients’ median age was 65.5 years (range, 49-77 years), and two-thirds were male. Both patients with non–clear cell RCC were enrolled in the lower dose cohort. IMDC risk status was favorable or intermediate in 11 patients. All patients had undergone prior nephrectomy. One patient enrolled in the lower dose cohort had received prior systemic therapy.
Based on investigator evaluation, the ORR was 50% (95% CI, 12%-88%) at dose level 1 and 83% (95% CI, 36%-100%) at dose level 2. One patient (8%) in the lower-dose cohort had a confirmed CR. A partial response (PR) was confirmed in 2 patients (33%) treated at dose level 1 and 5 patients (83%) at dose level 2. The remaining patients had stable disease, yielding a disease control rate of 100%. Among the 10 patients with clear cell RCC, the ORR was 80% and included 1 CR and 7 PRs. Among the 2 patients with non–clear cell RCC, 1 had progressive disease after approximately 30 weeks of study treatment and 1 had stable disease. The PD-L1 expression level was low for all 9 patients with available tumor tissue, and 6 of these patients had an objective response. The best sum of the target lesion change from baseline is shown in Figure 3. Time on treatment ranged from approximately 26 weeks to 50 weeks (Figure 4).
No dose-limiting toxicities, ser-ious adverse events (AEs), or AEs of grade 4 or 5 were observed in either cohort. AEs requiring a dose reduction of cabozantinib occurred in 50% of patients treated at dose level 1 and in 100% of patients treated at dose level 2. AEs leading to dose interruptions occurred in 50% vs 67%, respectively. The dose of atezolizumab was inter-rupted owing to an AE in 17% at dose level 1 vs 67% at dose level 2. In the entire study population of 12 patients, the most common grade 3 AEs were hypertension (42%), hypo-phosphatemia (17%), and dia-rrhea (17%). Grade 3 immune-related AEs included increased levels of ala-nine, aspartate, or gamma-glutamyl transferase, increased lipase, and muscular weakness, each of which was observed in 1 patient (8%).
In summary, the combination of cabozantinib plus atezolizumab was well-tolerated and yielded a response in 8 of 10 patients with clear cell RCC. The recommended dose for the expansion phase was 40 mg daily for cabozantinib, with atezolizumab given at 1200 mg every 3 weeks. The expansion phase will evaluate the combined treatment in 12 tumor types, including RCC, urothelial carcinoma, and castration-resistant prostate cancer.
References
1. Lalani AA, McGregor BA, Albiges L, et al. Systemic treatment of metastatic clear cell renal cell carcinoma in 2018: current paradigms, use of immunotherapy, and future directions [published online October 13, 2018]. Eur Urol. doi:10.1016/j.eururo.2018.10.010.
2. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298-2308.
3. Agarwal N, Vaishampayan UN, Green M, di Nucci F, Scheffold C, Pal S. Phase 1b study (COSMIC-021) of cabozantinib in combination with atezolizumab: results of the dose-escalation stage in patients with treatment-naive advanced renal cell carcinoma. Abstract presented at: the Seventeenth International Kidney Cancer Symposium; November 2-3, 2018; Miami, Florida.
4. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
Second-Line VEGFR TKI Outcomes After First-Line Immune Checkpoint Blockade in Metastatic Renal Cell Carcinoma
Several drugs are now available for the treatment of advanced or metastatic RCC. These targeted therapies have diverse mechanisms of action, inhibiting the tyrosine kinase moiety on cellular receptors, the mammalian target of rapamycin, and members of the immune checkpoint pathway. With a large number of targeted therapies now available, treatment sequencing must be optimized to increase the CR rate and durability of responses, and to address the development of resistance to treatment.1 A retrospective study evaluated the efficacy of second-line therapy with a TKI directed against the vascular endothelial growth factor receptor (VEGFR) after first-line therapy with an immune checkpoint inhibitor in patients with metastatic RCC.2 The study included patients treated at 2 cancer centers and was based on chart review. IMDC risk was calculated based on the initiation of second-line VEGFR TKI therapy, and outcomes were based on blinded review according to RECIST 1.1.3
The study enrolled 70 patients. At diagnosis of metastatic RCC, their median age was 59 years (range, 43.6-74.8 years), and 71% were male. Stage IV disease was reported in 61% of patients. All of the patients had clear cell histology, and 20% had sarcomatoid dedifferentiation. At the time that the second-line treatment was initiated, the patients’ IMDC risk score was favorable in 11%, intermediate in 69%, and poor in 20%. As first-line therapy, 17% of patients had received PD-1 monotherapy, 47% had received a PD-1 agent combined with CTLA-4 blockade, and 36% had received VEGF therapy combined with an inhibitor of PD-L1. The reasons for discontinuing first-line treatment included progressive disease in 83% and toxicity in 17%. The median duration of first-line treatment was 6.3 months (range, 0.48-27 months). The second-line treatment included axitinib (36%), cabozantinib (28%), pazopanib (27%), and sunitinib (9%).
Second-line treatment yielded an ORR of 41.2% and included 1 CR (1.5%; Figure 5). The disease control rate was 94.1%. The median PFS was 13.2 months (95% CI, 10.1 months to not reached), and 2-year PFS was 34.2%. The median OS was not reached (95% CI, 19.5 months to not reached), and 1-year OS was 79.6% (95% CI, 70.2%-90.3%).
The median duration of second-line therapy was 10.1 months (95% CI, 6.9-15.2 months). Thirty-three patients (47%) discontinued second-line treatment after developing progressive disease. Thirty-two patients (46%) required a dose reduction during second-line treatment. In 12 patients (27%), treatment with the VEGFR TKI was discontinued owing to AEs that included liver toxicity (7%), fatigue/anorexia (4%), aortic dissection (3%), palmar/plantar erythrodysesthesia (1%), and gastrointestinal bleeding (1%).
References
1. Fischer S, Gillessen S, Rothermundt C. Sequence of treatment in locally advanced and metastatic renal cell carcinoma. Transl Androl Urol. 2015;4(3):310-325.
2. Kotecha R, Shah A, Lemke E, et al. Second-line VEGFR TKI outcomes after first-line immune checkpoint blockade in metastatic renal cell carcinoma. Abstract presented at: the Seventeenth International Kidney Cancer Symposium; November 2-3, 2018; Miami, Florida.
3. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
Rationally Targeting the Bone With Radium Plus Cabozantinib
Bone metastases are frequently observed in patients with RCC and cause significant morbidity. In most patients, bone metastases lead to skeletal-related AEs, such as pain requiring radiation, pathologic fractures, spinal cord compression, and the need for surgery. Two large retrospective studies demonstrated an association between the presence of bone metastases and reduced survival.1,2 Among 2749 patients with metastatic RCC in a clinical trials database, the median OS was significantly reduced in those with bone metastases (13.2 vs 20.1 months; HR, 0.774; P<.0001).2 Both studies concluded that the presence of bone metastases was associated with reduced OS in all risk groups. In RCC patients, bone metastases result from dysregulation of markers of bone formation and resorption, affecting both osteoblasts and osteoclasts. Radium-223 dichloride is an alpha-emitting radiopharmaceutical that is a calcium mimetic.3 As such, it selectively binds to areas of increased bone cell turnover and is incorporated into the bone stroma.
Radium-223 is approved by the US Food and Drug Administration for the treatment of patients with castration-resistant prostate cancer and bone metastases.4 A pilot study evaluated radium-223 plus VEGFR-targeted therapy in patients with metastatic RCC of any histology and at least 1 bone metastasis that had not been treated with radiation.5,6 The study treated 15 treatment-naive patients with pazopanib and 15 previously treated patients with sorafenib. There was a safety run-in period for the first 6 patients in each cohort. Radium-223 (55 kBq/kg) was administered every 28 days for up to 6 infusions in both cohorts. Bone turnover markers were assessed at baseline, every 8 weeks, and off-treatment. The primary endpoint was the change in markers of bone turnover. In the entire study population, 77% of patients were male, and the median age was 62 years. Seventy percent of patients had clear cell histology, and 33% had liver metastases. A prior symptomatic skeletal event was reported in 83% of patients, 37% had received prior osteoclast-targeted therapy, and 84% had IMDC intermediate- or poor-risk disease.
The treatment combination was feasible and safe. Dose reductions were required in 1 patient in the pazopanib cohort and 4 patients in the sorafenib cohort. Patients received a median of 3 doses of radium-223. No dose-limiting toxicity was observed during the safety run-in. A treatment-related AE of grade 3/4 occurred in 44% of patients. Hematologic AEs were infrequent, with no grade 3/4 anemia, leukopenia, or thrombocytopenia in the pazopanib arm and 1 event (7%) of grade 3 anemia in the sorafenib arm.
All markers of bone formation and resorption showed dramatic declines at weeks 8 and 16 compared with baseline. N-terminal propeptide of type I procollagen showed the most dramatic change in expression level, from 45.5 µg/mL at baseline to a median maximum decline of –59.3 µg/mL. Other bone turnover markers, including C-terminal telopeptide, N-terminal telopeptide, bone-specific alkaline phosphatase, and osteocalcin showed maximum median declines of 29.2% to 50%.
The ORR was 23% with pazopanib plus radium-223 vs 9% with sorafenib plus radium-223. The median PFS was 8.2 months in the pazopanib cohort vs 3.6 months in the sorafenib cohort. Median OS was 16.6 months vs 14.2 months, respectively. Symptomatic skeletal events were observed in 47% of the pazopanib cohort vs 13% of the sorafenib cohort. By comparison, in the phase 3 COMPARZ trial (Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma), treatment with pazopanib in 557 patients with metastatic RCC yielded an ORR of 31%, a PFS of 8.4 months, and an OS of 28.4 months.7 In both the current study and the COMPARZ trial, the Functional Assessment of Cancer Therapy—Kidney Symptom Index-19 questionnaire showed slightly worse outcomes while patients were receiving treatment.
Cabozantinib may be the superior TKI to combine with radium-223 in this setting (Figure 6).8,9 In a subgroup analysis of the phase 3 METEOR trial (A Study of Cabozantinib [XL184] vs Everolimus in Subjects With Metastatic Renal Cell Carcinoma), cabozantinib yielded a median PFS of 7.4 months in RCC patients with bone metastases.9 The RADICAL trial will evaluate daily cabozantinib with or without radium-223 in patients with RCC of any histology and at least 2 untreated bone metastases. The trial will enroll patients who have received 2 or more prior lines of therapy and have current or prior symptoms related to bone metastases. Patients with impending spinal cord compression or pathologic fracture will be excluded. All patients will receive daily cabozantinib (40 mg to 60 mg). They will be randomly assigned to receive treatment with or without 6 cycles of radium-223 (55 kBq/kg every 28 days). The primary endpoint is symptomatic skeletal event–free survival. Enrollment of 132 patients is anticipated to provide an 84% power to detect a 42% reduction in the HR for symptomatic skeletal-related events.
References
1. McKay RR, Kroeger N, Xie W, et al. Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy. Eur Urol. 2014;65(3):577-584.
2. McKay RR, Lin X, Perkins JJ, Heng DY, Simantov R, Choueiri TK. Prognostic significance of bone metastases and bisphosphonate therapy in 77 patients with renal cell carcinoma. Eur Urol. 2014;66(3):502-509.
3. Parker C, Nilsson S, Heinrich D, et al; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.
4. Xofigo [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc; 2013.
5. McKay R. Rationally targeting the bone with radium plus cabozantinib. Paper presented at: the Seventeenth International Kidney Cancer Symposium; November 2-3, 2018; Miami, Florida.
6. McKay RR, Bossé D, Gray KP, et al. Radium-223 dichloride in combination with vascular endothelial growth factor–targeting therapy in advanced renal cell carcinoma with bone metastases. Clin Cancer Res. 2018;24(17):4081-4088.
7. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369(8):722-731.
8. Choueiri TK, Escudier B, Powles T, et al; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;
373(19):1814-1823.
9. Escudier B, Powles T, Motzer RJ, et al. Cabozantinib, a new standard of care for patients with advanced renal cell carcinoma and bone metastases? Subgroup analysis of the METEOR trial. J Clin Oncol. 2018;36(8):765-772.
Phase II Trial of Intermittent Nivolumab in Patients With Metastatic Renal Cell Carcinoma Who Have Received Prior Anti-Angiogenic Therapy (NCT03126331)
Nivolumab is an approved treatment for patients with metastatic RCC who have received prior antiangiogenic therapy. The optimal duration of therapy, however, has not been confirmed. Recent studies suggest that some cancer treatments may provide a benefit even after treatment discontinuation. In a retrospective analysis of patients with advanced RCC in the phase 3 CheckMate 214 trial, patients in the nivolumab plus ipilimumab arm who discontinued treatment had a significantly prolonged treatment-free interval compared with those who discontinued in the sorafenib arm (P<.0001).1 In a prospective phase 2 study of patients with treatment-naive, clear cell, metastatic RCC, treatment breaks from sunitinib did not appear to reduce clinical efficacy.2
A phase 2 trial evaluated inter-mittent nivolumab in patients with metastatic RCC who had received prior antiangiogenic therapy.3,4 Treatment consisted of nivolumab (240 mg every 2 weeks or 480 mg every 4 weeks) administered for 12 weeks. Patients with a tumor burden decrease of less than 10% continued with standard therapy. Patients with a 10% or higher decrease in tumor burden stopped treatment for 12 weeks. After the treatment interruption, patients with a tumor burden increase of 10% or more resumed therapy until disease progression or a reduction in tumor burden of at least 10%. Treatment was withheld in patients whose tumor burden did not increase by 10% or more. The study’s primary objective was to determine the feasibility of intermittent nivolumab in patients with metastatic RCC.
Enrolled patients had histologic confirmation of RCC of any histology and advanced or metastatic disease as defined by RECIST 1.1.5 Patients had received 3 or fewer prior treatments for advanced or metastatic RCC, and had a Karnofsky performance status of at least 70%. The trial accrued 14 patients from September 2017 through June 2018. The cohort was closed to further accrual after the approval of nivolumab plus ipilimumab as first-line treatment for metastatic RCC. Among the 14 enrolled patients, 93% were male, and the median age was 65 years (range, 57-72 years). Most patients (93%) had clear cell RCC histology, and 64% had an Eastern Cooperative Oncology Group performance status of 0. IMDC risk was favorable in 7%, intermediate in 86%, and poor in 7%. Metastatic sites included the lymph nodes (57%), bone (57%), lung (50%), and liver (21%). Eighty-six percent of patients had received 1 prior therapy, and sunitinib was the most recent therapy in 57% of patients.
After a median follow-up of 24.1 weeks (range, 4-57.4 weeks), the best responses were PR (29%), stable disease (43%), and progressive disease (29%; Table 1). Five patients (36%) were eligible for the intermittent phase. Four patients were eligible for the intermittent phase after 12 weeks, and 1 patient was eligible after 24 weeks of treatment with nivolumab. The median treatment-free interval was 24 weeks (range, 6-45 weeks; Figure 7). A new cohort will be enrolled to evaluate intermittent therapy and reinduction with ipilimumab plus nivolumab as first-line treatment in patients with metastatic RCC.
References
1. McDermott D, Rini BI, Motzer RJ, et al. Treatment-free interval (TFI) following discontinuation of first-line nivolumab plus ipilimumab (N+I) or sunitinib (S) in patients (pts) with advanced renal cell carcinoma [ESMO abstract 874P]. Ann Oncol. 2018;29(suppl 8).
2. Ornstein MC, Wood LS, Elson P, et al. A phase II study of intermittent sunitinib in previously untreated patients with metastatic renal cell carcinoma. J Clin Oncol. 2017;35(16):1764-1769.
3. Ornstein MC, Wood LS, Allman K, et al. Phase II trial of intermittent nivolumab in patients with metastatic renal cell carcinoma who have received prior anti-angiogenic therapy. Abstract presented at: the Seventeenth International Kidney Cancer Symposium; November 2-3, 2018; Miami, Florida.
4. ClinicalTrials.gov. Intermittent nivolumab in metastatic renal cell carcinoma patients. https://clinicaltrials.gov/ct2/show/NCT03126331. Identifier: NCT03126331. Accessed December 10, 2018.
5. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
A Secreted PD-L1 Splice Variant That Covalently Dimerizes and Mediates Immunosuppression
PD-L1 expression on RCC tumors is associated with a poor prognosis.1 In a phase 3 pivotal trial of patients with previously treated advanced RCC, PD-1 blockade with nivolumab yielded a median OS of 27.4 months in those with PD-L1 expression of less than 1% vs 21.8 months in those with expression of 1% or higher.2 Soluble PD-L1 has been identified as a potential prognostic biomarker that may be associated with outcomes for certain patients receiving treatment with checkpoint inhibitors.3 Compared with serum from healthy donors, serum from stage IV melanoma patients prior to treatment showed increased levels of soluble PD-L1.
secPD-L1 is a splice variant of soluble PD-L1 with a unique 3’ end. It also has 18 amino acids that are unique to this variant, including a cysteine residue that may allow it to dimerize. Dr Kathleen Mahoney presented results of in vitro studies that were performed to characterize secPD-L1.4 Overexpression of secPD-L1 in the 300-19 leukemia cell line yielded dimers and higher multimers in the size range of 65 kD to 130 kD. Treatment with ß-mercaptoethanol showed a protein of approximately 40 kD, which was similar in size to the extracellular domain of PD-L1. Site-directed muta-genesis was used to replace cysteine-239 with a serine residue, and this elim-inated the secPD-L1 multimers. An in vitro assay showed that secPD-L1 inhibited T-cell proliferation and production of γ-interferon in a dose-dependent manner. The unique 3’ end of secPD-L1 was used for quan-titative polymerase chain reaction and sequencing analyses. A positive correlation was observed between expression of full-length PD-L1 and secPD-L1 in cancer cell lines (Figure 8). A search of The Cancer Genome Atlas database showed that most tumors expressed both full-length PD-L1 and secPD-L1. In contrast, the majority of normal tissues expressed full-length PD-L1 but did not express secPD-L1. By gene set enrichment analysis, tumors that expressed secPD-L1 were found to express high levels of γ-interferon and S100A8. Expression of genes associated with myeloid-derived suppressor cells was also associated with expression of secPD-L1.
References
1. Erlmeier F, Weichert W, Schrader AJ, et al. Prognostic impact of PD-1 and its ligands in renal cell carcinoma. Med Oncol. 2017;34(6):99.
2. Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813.
3. Zhou J, Mahoney KM, Giobbie-Hurder A, et al. Soluble PD-L1 as a biomarker in malignant melanoma treated with checkpoint blockade. Cancer Immunol Res. 2017;5(6):480-492.
4. Mahoney K. A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression. Abstract presented at: the Seventeenth International Kidney Cancer Symposium; November 2-3, 2018; Miami, Florida.