Renal Cell Cancer Pts Research Articles

Real-world outcomes of patients (pts) with malignant solid tumors treated with immune checkpoint inhibitors (ICI) in relation to smoking status: The SAKK 80/19 SMOKER study.

6619 Background: ICIs are the standard of care for the treatment of different advanced solid organ tumors. Especially in advanced non-small-cell lung cancer, never-smokers were shown to have an inferior outcome when compared to ex-smokers/smokers, suggesting that the smoking status could be a predictive marker for survival benefits under ICI treatment. Methods: Pts within the Swiss Alpine Tumor Immunology Registry (AlpineTIR) treated with an ICI were differentiated by their smoking status (ex-smokers/smokers versus never-smokers). Overall survival (OS) and progression-free survival (PFS) from the start of the first ICI treatment were analyzed by smoking status. Further, subgroup analyses for OS and PFS were done for the most common disease entities. Results: A total of 702 pts were included, from which 455 pts (65%) were ex-smokers/smokers, 213 pts (30%) were never smokers, and 34 pts (5%) had an unknown smoking status. The median follow-up time from the administration of the first ICI to the statistical analysis was 2.7 years (95% CI: 2.3 to 3.2 years). The most frequent tumors were lung cancer (50%), melanoma (13%), renal cell cancer (7%), bladder cancer (6%), and others (24%). Across all indications, the median OS was 1.7 years (95% CI: 1.4 to 2.6 years) for never-smokers (n = 213) and 1.5 years (95% CI: 1.2 to 1.8 years) for smokers (n = 455) (HR: 1.10, 95% CI: 0.89 - 1.37). The median PFS was 6.3 months (95% CI: 4.4 to 8.3 months) for non-smokers and 6.2 months (95% CI: 5.2 to 7.0 months) for smokers (HR: 1.05, 95% CI: 0.87 - 1.27). In lung cancer pts, the median OS was 1.4 years (95% CI: 0.8 to 2.8 years) for never-smokers (n = 43) and 1.4 years (95% CI: 1.2 to 1.7 years) for smokers (n = 302) (HR: 1.02, 95% CI: 0.68 - 1.51). In melanoma pts, the median OS was 3.4 years (95% CI: 1.8 to not reached (NR) years) for never-smokers (n = 54) and 1.7 years (95% CI: 0.8 to NR years) for smokers (n = 34) (HR: 1.35, 95% CI: 0.72 - 2.53). In renal cell cancer pts, the median OS was 1.5 years (95% CI: 1.0 to 3.6 years) for never-smokers (n = 28) and 3.5 years (95% CI: 0.6 to NR years) for smokers (n= 17) (HR: 0.74, 95% CI: 0.31 - 1.78). In bladder cancer pts, the median OS was 1.8 years (95% CI: 0.6 to NR years) for never-smokers (n = 17) and 1.4 years (95% CI: 0.5 to NR years) for smokers (n = 26) (HR: 0.88, 95% CI: 0.39 - 1.99). Conclusions: No survival difference between smokers and non-smokers with metastatic solid organ tumors treated with ICIs could be detected. Interestingly, even in the subgroup of lung cancer pts, no difference was seen. Based on these data, the smoking status should not guide ICI treatment decisions.

INMUNOSUN-SOGUG trial: A prospective phase II study to assess the efficacy and safety of sunitinib as second-line (2L) treatment in patients (pts) with metastatic renal cell cancer (RCC) who received immunotherapy-based combination upfront.

5060 Background: Immunotherapy (IO)-based combinations have replaced tyrosine kinase inhibitors (TKI) as standard upfront treatment of metastatic RCC pts. Selection of 2L treatment after progression to novel combinations in 1st-line (1L) is mostly based on retrospective series or subgroups analysis of randomized trials. We aim to evaluate the activity and safety of sunitinib in advanced RCC after progression on an IO-based 1L approach. Methods: This is a prospective, non-randomized, open-label and multicenter phase II study. Pts with ECOG 0-2 and locally advanced or metastatic RCC after treatment in 1L with a prior PD-1 and/or PD-L1 and/or CTLA-4 inhibitor were included. Sunitinib was administered at 50 mg/day on a 4/2 schedule until disease progression. Primary endpoint was overall response rate (ORR) by RECIST v 1.1 criteria. Results: Twenty pts were enrolled in the study. Median age was 66 yo, 70% had intermediate prognosis by Heng's scale, and 88% ECOG 1. 45% of pts received atezolizumab, 30% pembrolizumab, 20% nivolumab and 15% ipilimumab-based regimens as 1L. ORR to 1L treatment was 45%. Median time from end of 1L to sunitinib onset date was 1.1 months (0.3-22.1). Two (10%) pts had partial response with sunitinib and 11 (55%) stable disease for a total disease control rate of 65%. With a median follow-up of 8.8 months, median PFS was 6.8 months (0.0-13.9) and median OS 13.6 months (10.5-16.6). Median duration of treatment was 4 months (0.9-16-2). Most common treatment-related adverse events, all grades, were asthenia (55%), dysgeusia (35%), diarrhea (30%), hypertension (30%), mucosal inflammation (25%), palmar-plantar erythrodysesthesia (25%), anemia (20%), neutropenia (20%) and nausea (15%); grade 3 were asthenia (15%), hypertension (10%) and neutropenia (10%). Conclusions: To our knowledge, the INMUNOSUN trial is the first study to evaluate prospectively the activity of a single agent TKI in a pure 2L setting of metastatic RCC pts treated with an IO-based approach upfront. ORR and PFS with sunitinib seem lower than expected when used as a 1L. Consistency in toxicity profile was observed. Clinical trial information: NCT03066427 .

CD68+ tumor-associated myeloid cells as the target of adenosine-induced gene products and predictor of response to adenosine blockade with ciforadenant (cifo) in renal cell cancer (RCC).

5025 Background: Adenosine in the tumor microenvironment (TME) is immunosuppressive and may play a role in resistance to immunotherapy. We described an adenosine induced gene expression signature (AS, Fong, Cancer Disc 2020) that correlates with response to therapy with cifo, an adenosine A2A receptor antagonist, as monotherapy or in combination with atezolizumab in refractory RCC. These genes express chemokines that signal through CCR2 and CXCR2 to recruit myeloid cells including immunosuppressive tumor associated-M2 macrophages, which are thought to mediate resistance to anti-PD(L)1 treatment. We now identify tumor infiltrating CD68+ myeloid cells as the effector cell for adenosine mediated immunosuppression. Methods: 82 RCC pts have been treated in an ongoing Phase 1/1b trial evaluating cifo (100mg po bid) monotherapy or combination with atezolizumab (840mg IV q 2 weeks). Tumor biopsies, obtained at screening and on therapy, are available for analysis in 32 pts to date. RNA expression was measured in tumors using Nanostring. Immunohistochemistry (IHC) for CD68 was performed on biopsies with CD68+ tumors defined as > 4% tumor area containing CD68+ cells. Results: Pt characteristics are median age 63; median prior therapies 3, with 72% failing prior anti-PD(L)1. Gene expression of M2 markers consisting of CD68 (p = 0.0008) and CD163 (p = 0.03) was higher in baseline samples from AS+ compared to AS- pts. By IHC, 10 pts had CD68+ cells infiltrating the tumor; 9 of 10 AS+. Tumor regression was observed in 6 of 10 CD68+ pts (N = 3 monotherapy and 3 combination) including 4 partial responses (PR, RECIST). No PRs and 2 minor responses were seen in 22 pts who were CD68- (p < 0.005). Median time to progression was not reached for CD68+ vs 2 mo for CD68-. Paired biopsies showed a significant reduction in infiltrating CD68+ cells (p = 0.03) with treatment including 2 of 2 evaluable PRs. Conclusions: Adenosine immunosuppression is mediated by M2 macrophages, which can be reversed by cifo. Enumerating tumor infiltrating CD68+ cells may be a valuable biomarker for identifying pts that will respond to adenosine blockade. Clinical trial information: NCT02655822 .

Selective modulation of immune transcripts in extracellular vesicles from plasma of renal cell carcinoma patients receiving nivolumab.

719 Background: Patients (pts) displaying a full-fledged immune response show high levels of circulating extracellular vesicles (EVs) containing immune transcripts that might be transferred to neighboring cells to amplify immune responses, as in autoimmunity and transplantation. We hypothesized EV immune transcripts could reflect immune activation in cancer pts receiving immunotherapy with immune checkpoint inhibitors (ICI). These RNA-containing EVs may surrogate immune functionality and represent a plasma transcriptional signature of adaptive immunity that can be readily detected by liquid biopsy. Methods: Blood samples from metastatic renal cell cancer pts,treated with ICI nivolumab (n=8) or tyrosine kinase inhibitor cabozantinib (n=9) were collected at baseline, week 4 and 12. EV-RNA was isolated from plasma with membrane affinity spin columns and evaluated for CD274(PD-L1), IFNG, PDCD1 (PD-1), CD3 and GZMB (granzyme B) transcripts by qRT-PCR. Results: All pts showed a statistically significant increase of CD3, IFNG, GZMB, PD-1 and PD-L1 immune transcripts in plasma EVs, evidenced at 4 and 12 weeks of therapy. Treatment subgroup analysis revealed an upregulation of CD3, IFNG, GZMB and PD-1 transcripts only in plasma EVs of patients receiving nivolumab that was more evident in those showing clinical benefit (4/8), while PD-L1 increased significantly during cabozantinib treatment. Upon comparing transcripts with soluble proteins, PD-L1 displayed similar kinetics, while PD-1 increased only as transcript but not as protein, given its potential sequestration by the anti-PD-1 antibody. This effect was detectable only in nivolumab but not in cabozantinib treated pts. Conclusions: Monitoring immune transcripts carried by plasma EVs holds promise as potential tool to assess the entity of the ongoing immune activation during immunotherapy. Plasma EVs may be exploited as indicators of immune response and help to predict clinical efficacy at early on-treatment time points. This approach based on plasma EVs might represent a starting point for the development of a novel strategy to study immune responses in clinical setting.

Clinical validation of single nucleotide polymorphisms (SNPs) as predictive biomarkers in localized and metastatic renal cell cancer (RCC).

588 Background: SNPs predictive of survival outcomes in patients (pts) with localized and metastatic RCC have been identified previously by us [Garrigós C et al, 2017]. Fifteen SNPs in 9 genes involved in angiogenesis and metabolism of antiangiogenics were recognized as predictive/prognostic in a cohort of 102 pts. The aim of the present study is to validate these associations in an independent cohort of RCC pts Methods: Genotyping was performed in DNA isolated from paraffin-embedded tumor samples from 87 pts with localized and metastatic RCC. DNA was extracted by a commercial kit (QiAGEN) and amplified with a specific primers pool for each SNP as determined by the manufacturer (Lifetech). The 15 SNPs were individually genotyped by Real time quantitative PCR with specific primers and Taqman probes (Lifetech). The presence of the selected SNPs was correlated with clinical features such as disease free survival (DFS), progression free survival (PFS) and overall survival (OS). SPSS v24 was used for statistical analysis. Results: In the localized pts (n = 66), Fuhrman grades 3-4 and stage T3-T4 significantly associated with DFS (p = 0.025 and p = 0.004, respectively). The presence of allele C of rs307826 (FLT4 gene) correlated with a greater chance of relapse (p = 0.025) and also with a shorter DFS (21 vs 35 months, p = 0.007). For the metastatic pts (n = 21), allele C of rs307826 (FLT4 gene) and allele A of rs9800958 (PRKAR1B) were linked with a shorter PFS [(8 vs 18 months, p = 0.036) and (8 vs 17 months, p = 0.043) respectively]. In the localized cohort, allele T of rs2227543 (IL8 gene) was associated with longer OS (14 vs 3 months, p = 0.039) while allele G of rs10013228 (KDR gene) linked with worse OS (4 vs 17 months, p = 0.063). Conclusions: This analysis comes to confirm our previous observations that certain genotypes could be used as prognostic/predictive factors in RCC. This is particularly important in an era where multiple treatment options are available for this disease.

Everolimus (EVE) exposure as a predictor of toxicity (Tox) in renal cell cancer (RCC) patients (Pts) in the adjuvant setting: Results of a pharmacokinetic analysis for SWOG S0931 (EVEREST), a phase III study (NCT01120249).

4566 Background: S0931 is assessing recurrence-free survival in RCC pts randomized to receive EVE versus placebo for one year following nephrectomy. To date, there has been a higher than expected dropout rate due to bothersome tox. Previous reports have shown an association between EVE trough levels and both tox and disease response in RCC pts. Therefore, we have assessed EVE trough levels to evaluate the relationship between measured exposure and probability of tox. This analysis has been approved by the DSMC. Methods: Patients received 10 mg daily EVE or placebo for nine 6-week cycles. Pre-dose whole blood samples collected pre-cycle 2 and pre-cycle 3 were analyzed for EVE. Pts with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. When both trough levels were available, results were averaged. Pts were segregated into quartiles (Q) based on EVE levels and logistic regression was used to model the following adverse event outcomes using EVE trough as a predictor; any grade 3+ tox, grade 2+ triglycerides, grade 2+ hyperglycemia, grade 2+ oral mucositis, grade 2+ rash, and premature stopping of EVE. Hazard and odds ratios were adjusted for age, BMI and performance status. Results: This study reached its accrual goal and closed on 9/15/2016 with 1545 (775 EVE) randomized patients. A total of 386 pts are included in this preliminary analysis. Median EVE trough was 12.8 ng/mL (range 3.1, 75.6) per 10 mg dose. Event rates for tox were: any grade 3+ tox = 46%, grade 2+ triglycerides = 33%, grade 2+ hyperglycemia = 15%, grade 2+ oral mucositis = 34%, grade 2+ rash = 15%, and premature stopping of EVE = 40%. The risk of grade 2+ triglycerides was increased in Q2 and Q3 vs Q1 (OR = 2.95; p = 0.001 and OR = 3.48; p < 0.001). The risk of grade 2+ rash was increased in Q2 and Q4 vs Q1 (OR = 2.95; p = 0.02 and OR = 3.20; p = 0.01). There was also a trend towards an increased risk of any grade 3+ tox in Q3 vs Q1 (OR = 1.72; p = 0.07). Conclusions: This analysis has identified significant associations between EVE exposure and the probability of tox. EVE analysis is ongoing and the final results will be presented. Clinical trial information: NCT01120249.

Long-term (LT) disease-free survival (DFS) of melanoma (MM) and renal cell cancer (RCC) patients following high-dose interleukin-2 (HD IL2).

e21005 Background: HD IL2 treatment (Tx) produces durable complete responses (CRs) and surgical CRs. Patients (pts) achieving partial response (PR) and stable disease (SD) demonstrate improved survival compared with pts who progress. Methods: 7 HD IL2 Tx centers identified pts with survival > 5 years (yrs) after HD IL2. DFS was from end of IL2 to January 2017. Tx courses generally consisted of 2 1-week cycles of HD IL2, 600,000-720,000 U/kg IV every 8 hours. We collected data on pts Tx with HD IL2 alone, or HD IL2 plus local Tx (surgery or radiation (SRS) leading to CR) with survival > 5 yrs after HD IL2 Tx. Results: 72 pts are reported: 29 RCC (male 22, female 7) and 43 mm (male 26, female 17). Median age at Tx of RCC is 54 yrs (range, 47-67 yrs) and of mm is 50 yrs (range, 24-72 yrs). Sites of metastatic disease for 26 mm pts were lymph nodes (LN) -18, lungs-12, bone-6, liver-9, brain-3, other organs-10 and for 22 RCC pts were lung-17, LN-5, adrenal-4, bone-3, other organs-8. Number of IL2 courses received: 1-10 pts, 1.5-4 pts, 2-28 pts, 2.5-5 pts, 3-24 pts, 4-one pt. Among the 29 RCC pts, there are 24 CRs, 3 surgical CRs and 2 PRs with no further Tx. Among 43 mm pts, there are 34 CRs, 2 near CRs, and 7 Surgical/SRS CRs. DFS in these pts after HD IL2 Tx ranges from 5+ yrs to 30+ yrs, median 10.5+ yrs. 10 RCC and 16 mm are alive > 5 - < 10 yrs after IL2, and 19 RCC and 27 mm are alive > 10 yrs after IL2. LT toxicity among these 72 pts includes hypothyroidism-5 pts, arthralgias/arthritis-5 pts, vitiligo-3 pts, and 1 pt each: neuropathy, PVCs, and normal pressure hydrocephalus. Additional pts may be added as records become available. Conclusions: We document LT DFS ( > 5 yrs) after CR or PR from HD IL2 alone. Surgical or SRS conversion of PR to CR can produce durable CRs. LT DFS was observed in pts with visceral and bone metastases, not only those with LN or lung sites. Neither age, sex, nor number of courses of IL2 predicted LT DFS. Chronic toxicity due to IL2 is uncommon in LT survivors.

An exploratory study to investigate the immunomodulatory activity of radiation therapy in combination with pembrolizumab in patients with renal cell cancer.

e16058 Background: Preclinical data suggest there are synergistic effects of radiation therapy (RT) and check point inhibitors in anticancer immunity. The primary objective of this study was to explore the immunomodulatory activity of RT alone or in combination with Pembrolizumab (pembro) in solid tumors including renal cell cancer (RCC) patients (pts). Methods: RCC pts who progressed after at least one front-line therapy were eligible. Pts were treated with either RT (8Gy x 1 or 4Gy x 5) followed by (f/b)pembro or 1 dose pembro f/b RT f/b pembro. Pre- and post RT tumor biopsy was obtained to evaluate PD-L1 expression (assay by QualTeck). Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry. Treatment response was measured based on modified RECIST criteria. Results: Twelve RCC patients were enrolled including 2 with non-clear cell subtype. One pt was not evaluable since pt quickly deteriorated and was taken off study. As of January 13, 2017, 2 pts are still on active treatment. Two pts had partial response (18%) and were on study for at 54 and 63 weeks. One responder was treated with 8 Gy f/b pembro while 1 was treated with 1 dose pembro f/b RT f/b pembro. Five pts had stable disease of 18 to 45 weeks and 4 pts (36%, non-responders) had progression in 9 weeks. For adverse events, 1 pt developed grade 3 pneumonitis after 10 cycles of pembro (RT to adrenal mets). Grade 3 AEs include Fatigue, Nausea, Hyperglycemia, Lymphopenia, thrombocytopenia and AST elevation (post RT for liver mets). PDL1 expression and tumor infiltrating lymphocytes presence after RT showed various patterns. Preliminary flow cytometry showed persistent higher numbers of monocytes in non-responders comparing with responders. CD4+, CD8+ and NK cells and other markers are under analyzed and the results will be presented. Conclusions: The combination of RT (8Gy or 20Gy) with pembro is feasible and tolerated, and demonstrates clinical activity. The AE profile is similar to single agent pembro. Monocytes, T and NK cell kinetics are being examined. (ClinicalTrials.gov ID: NCT02318771) Clinical trial information: NCT02318771.

An exploratory study to investigate the immunomodulatory activity of radiation therapy in combination with pembrolizumab in patients with renal cell cancer.

518 Background: Preclinical data suggest there are synergistic effects of radiation therapy (RT) and check point inhibitors in anticancer immunity. The primary objective of this study was to explore the immunomodulatory activity of RT alone or in combination with Pembrolizumab (pembro) in solid tumors including renal cell cancer (RCC) patients (pts). Methods: RCC pts who progressed after at least one front-line therapy were eligible. Pts were treated with either RT (8Gy x 1 or 4Gy x 5) followed by (f/b) pembro or 1 dose pembro f/b RT f/b pembro. Pre- and post RT tumor biopsy was obtained to evaluate PD-L1 expression (assay by QualTeck). Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry. Treatment response was measured based on modified RECIST criteria. Results: 12 RCC patients were enrolled including 2 with non-clear cell subtype. One pt was not evaluable since pt quickly deteriorated and was taken off study. As of September 30, 2016, 5 pts were still on study with 3 pts having partial response (27.2%, responders) and were on study for at least 9.8 months. 2 responders were treated with 8 Gy f/b pembro while 1 was treated with pembro f/b RT f/b pembro. Six pts (54.5%, non-responders) had PFS between 2 – 4 m and were off study. For adverse events, 1 pt developed grade 4 pneumonitis after 10 cycles of pembro (RT to adrenal mets). Grade 3 AEs include fatigue, nausea, hyperglycemia, lymphopenia, thrombocytopenia, and AST elevation (post RT for liver mets). PDL1 expression and tumor infiltrating lymphocytes presence after RT showed various patterns. Preliminary flow cytometry showed persistent higher numbers of monocytes in non-responders compared with responders. CD4+, CD8+, and NK cells and other markers are under-analyzed and the results will be presented. Conclusions: The combination of RT (8Gy or 20Gy) with pembro is feasible and tolerated, and demonstrates clinical activity. The AE profile is similar to single agent pembro. Monocytes, T, and NK cell kinetics are being examined. Clinical trial information: NCT02318771.

Abstract CT098: Anti-tumor activity of PEGylated human IL-10 (AM0010) in patients with advanced solid tumors

Abstract Purpose: IL-10 inhibits inflammation but stimulates cytotoxic CD8 T cells. In preclinical models, PEGylated IL-10 induces rejection of tumors and establishes CD8 T cell memory. PEG-IL-10 (AM0010) activates the anti-apoptotic STAT3 in tumor infiltrating activated CD8 T cells. This leads to the expansion of tumor reactive memory CD8 T cells both in the tumor and the blood. The primary objective of this phase 1 study is to establish tolerability and anti-tumor activity of AM0010 alone and in combination with chemotherapy and anti PD-1 immunotherapy. Here we report the results of AM0010 in the monotherapy dose escalation and one expansion cohort in renal cell cancer (RCC). Procedures: 33 patients (pts) with advanced cancers including melanoma, RCC, non-small cell lung, colorectal, ovarian, prostate and pancreatic cancer were enrolled in cohorts of 3-6 pts each, followed by disease specific expansion cohorts at the recommended phase 2 dose (RP2D). AM0010 was self-administrated daily subcutaneously for the duration of treatment and responses were monitored following immune related response criteria (irRC). Immune responses were monitored through analysis of serum cytokines, activation of blood derived T cells, immunosequencing for peripheral T cell clonality and immunohistochemistry for the infiltration of tumors by CD8 T cells. Results: 33 pts were enrolled in dose escalation cohorts with AM0010 monotherapy at doses from 1 to 40 μg/kg. MTD was not established. The RP2D (20μg/kg) was determined based on tolerability, single agent anti-tumor activity and immune activation. Patients were heavily pretreated with a median of 5 prior treatments. Most treatment related adverse events (TrAE) were low grade and included anemia, thrombocytopenia, rash, injection site reaction, fatigue, increased lipase, dyslipidemia and transaminitis. G3/4 non-hematopoietic TrAEs were observed in 11 of 51 pts. G3/4 anemia or thrombocytopenia TrAEs were observed in 13 pts. Most TrAEs were transient with only one patient discontinuing treatment due to a TrAE. Immune related TrAEs such as colitis, pneumonitis and endocrine disruption were not observed. AM0010 induced a dose dependent Th1 cytokine signature (IL-18, IFNγ, IL-7) and a reduction of TGFβ in the serum of pts. AM0010 increased PD-1 positive activated CD8 T cells in the blood and the tumor and decreased proliferation of FoxP3 Tregs in the blood. AM0010 lead to an oligoclonal expansion of T cell clones in the blood without affecting the overall number of lymphocytes. Many of the expanded T cell clones were not detectable before treatment. Partial responses (PR) were observed in pts with RCC and uveal melanoma. Four of 15 RCC pts treated at RP2D (27%) had an objective response. Prolonged stable disease of 6 or more months was observed in several indications including colon cancer. Conclusion: AM0010 is well-tolerated and leads to sustained and systemic immune stimulation. The pharmacodynamics and clinical activity observed support the further exploration of AM0010 in monotherapy and in combination regimens with checkpoint inhibitors and with cytotoxic chemotherapies. Trial registration: www.clinicaltrials.gov NCT02009449 Citation Format: Jeffrey R. Infante, Aung Naing, Kyriakos P. Papadopoulos, Karen A. Autio, Patrick A. Ott, Deborah J. Wong, Gerald S. Falchook, Manish Patel, Shubham Pant, Melinda Whiteside, John B. Mumm, Ivan H. Chan, Johanna C. Bendell, Todd M. Bauer, Filip Janku, Milind Javle, Rivka R. Colen, Nizar M. Tannir, Martin Oft. Anti-tumor activity of PEGylated human IL-10 (AM0010) in patients with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT098.

Abstract C49: Phase 1 study of CB-839, a first-in-class, orally administered small molecule inhibitor of glutaminase in patients with refractory solid tumors

Abstract Background: CB-839 is a first-in-class highly selective inhibitor of glutaminase (GLS), a key enzyme in the utilization of glutamine by many cancer cells. Inhibition of GLS blocks the ability of tumor cells to use glutamine as a source of energy and anabolic building blocks. CB-839 has broad activity, inducing cell death or growth arrest in triple negative breast cancer (TNBC), KRAS-mutant non-small cell lung cancer (NSCLC), clear cell renal cell cancer (RCC), and mesothelioma cell lines. GLS inhibition with CB-839 has also been shown to synergistically combine with several standard of care (SOC) chemotherapies and signal transduction inhibitors. Methods: CX-839-001 is an ongoing Phase 1 study of escalating doses of CB-839 given continuously in 21 day cycles in advanced and/or treatment-refractory solid tumor patients (pts) to evaluate safety and tolerability, and to identify the recommended Phase 2 dose (R2PD). It was initially given three times daily (TID) without food, but based on PK and safety data, the drug is now being given twice daily (BID) with meals. Pharmacokinetics (PK) is monitored on Days 1 and 15; pharmacodynamics is measured in platelets and in tumor biopsies. Pts are currently being enrolled at the RP2D, 600 mg BID, with the tumor types noted above as well as pts receiving CB-839 in combination with SOC agents, including paclitaxel in TNBC, docetaxel in KRAS-mutant NSCLC, erlotinib in EGFR-mutant NSCLC, and everolimus in RCC. Results: Safety data from 85 pts enrolled in the trial revealed a low rate of Gr3/4 AEs, with 9.4% (8/85) of pts experiencing a Gr3/4 AE related to CB-839. One DLT occurred on study, a drug-related Gr3 creatinine elevation in a patient with diabetic nephropathy at the 250 mg TID dose level. Reversible, asymptomatic Gr3 elevations in transaminases occurred mostly on the TID schedule in 6/32 pts (18.8%), with only one Gr3 event occurring among 53 pts (1.9%) receiving the BID regimen. Clear exposure-dependent inhibition of GLS in platelets was seen 4 hr after the first dose of CB-839, with >90% inhibition at PK trough for most pts at the RP2D. A total of 93 pts have been enrolled on the monotherapy cohorts of the trial as of 24 July 2015, including 32 pts on TID dosing (100-800 mg) and 61 pts on BID dosing (600-1000 mg). Radiographic stable disease (SD) was observed in 6 (19%) of 31 efficacy-evaluable pts receiving CB-839 on the TID schedule and 17 (40%) of 43 efficacy-evaluable pts on the BID schedule. Pts with SD have been on study for a median of >5 cycles (range 3-18); 15 (65%) of these pts remain on treatment. Seven of 11 (64%) evaluable RCC pts on the BID dose schedule showed SD, 5 of whom remain on study. A TNBC patient has maintained SD for more than one year and has had a 23% reduction in tumor burden. GLS expression was evaluated by IHC and found to be moderate to high in most patient tumor samples. Additional correlative studies will also be presented. Conclusions: CB-839 has been well tolerated when administered BID with food at and above doses that produced robust inhibition of GLS in platelets and in tumors. Evidence of prolonged SD in pts receiving single agent CB-839, together with strong preclinical data in combination with SOC agents including paclitaxel, everolimus and erlotinib, provides a clear rationale for continued evaluation of CB-839 in several tumor types, as a single agent and in combination with SOC therapies. Citation Format: Funda Meric-Bernstam, Angela DeMichele, Melinda L. Telli, Pamela Munster, Keith W. Orford, George D. Demitri, Gary K. Schwartz, Othon Iliopoulos, James W. Mier, Taofeek K. Owonikoko, Mark K. Bennett, Manish R. Patel, Jeffery R. Infante, James J. Harding. Phase 1 study of CB-839, a first-in-class, orally administered small molecule inhibitor of glutaminase in patients with refractory solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C49.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of patients with brain metastases (BM) from renal cell cancer (RCC).

e15546 Background: About 2–11% of all patients (pts) with RCC develop BM, leading to a poor prognosis and a median survival of <6 months after whole brain radiotherapy. The role of targeted therapy in the management of BM is controversial. This study was designed to evaluate EGFR TKIs in RCC pts with BM. Methods: eligible pts had confirmed RCC and BM (≥1 lesion of ≥10mm diameter) aged >18 years with ECOG performanse status (PS) of 0–2. From June 2009 to January 2013, 11 pts with RCC and BM were enrolled in this study. 10 pts (91%) had extracranial metastases. 6 pts received sunitinib (50mg/day, 4 weeks, every cycle), 4 pts received sorafenib (800 mg/day) and 1 patient received pazopanib (800 mg/day) until radiologically-verified progressive disease. The primary endpoints were objective response rate (ORR) - complete and partial response in the brain and in the extracranial lesions, progressive-free survival (PFS) and overall survival. Demographics were: median age - 59 years (range 44–74 years); male/female - 10/1; PS 1/2 - 7/4; previously treated/untreated - 10/1; number of BM: ≤3/>3 - 6/5. Previous treatment: nephrectomy – 10 pts (91%), cytokines – 6 pts (54,5%), targeted therapy (before BM) – 4 pts (36,4%). Local control of BM: previous neurosurgery – 2 pts (18,2%), radiosurgery – 4 pts (36,4%), previous neurosurgery + radiosurgery – 2 pts (18,2%). Results: ORR in the brain was 27,3% (3 partial responses). All partial responses in the brain achieved in patients who received targeted therapy and radiosurgery. Stable disease in the brain was 54,5% (6 pts). 1 patient with stable in the brain received targeted therapy and radiosurgery, 5 pts received targeted therapy. ORR in the extracranial lesions was 20% (2 partial responses). Stable disease in the extracranial lesions was 50% (5 pts). The median of PFS was 6 months. The median of overall survival was 10 months. Conclusions: surgery and radiotherapy, including radiosurgery, must be considered as optimal local treatment for pts with RCC and BM. Targeted drugs have demonstrated their ability to achive a clinical and X-ray verified objective effect (as stabilization in most cases) in treating of pts with disseminated RCC and BM.

Osteonecrosis of the jaw (ONJ) in patients with renal cancer treated with bisphosphonates (BPs) and sunitinib or other targeted therapy (TT) agents: A multicenter survey.

e15182 Background: ONJ has been very rarely reported in patients (pts) suffering from bone metastases of renal cell cancer (RCC) treated with BPs, such as pamidronate (P) and zoledronic acid (Z). Recently reports of ONJ cases among cancer pts receiving TT agents (sunitinib, bevacizumab, sorafenib, etc) w/o BPs have been published, including few cases among RCC pts. TT agents have been consequently suspected to be a possible risk factor for ONJ. On December 2010, EMA (European Medicine Agency) issued two safety warnings about ONJ risk after sunitinib or bevacizumab treatment; in the “dear doctor” alert letters, manufacturers reported the following data about ONJ cases registered among patients treated on clinical trials or on post-marketing setting (in all types of cancer): 27 ONJ cases among 101.400 pts after sunitinib and 55 ONJ cases among 800.00 pts after bevacizumab worldwide. Methods: We conducted a limited survey, asking three Medical Oncology units and four referral Oral Medicine and Surgery centres (involved in ONJ tertiary care), in different regions of Italy, to look for ONJ and RCC in their database. Nineteen cases of ONJ in RCC pts have been found. Available details of oncologic and dental history have been collected so far of 16 pts; of further 3 cases data reporting authorization is ongoing. Results: Pts characteristics of 16 evaluated pts: sex: 13/3 M/F; median age 63 years (range 45-72). BP treatment: 13 Z, 1 P, 1 Z+P, 1 Ibandronate. BP treatment duration at the ONJ onset: 12 months (range 1-36). Latest TT treatment at the ONJ diagnosis time: sunitinib (13 cases), sorafenib (1), bevacizumab (1), deforolimus (1). Previous treatments: sorafenib (3), IL2, capecitabine. Site of ONJ: 9 in mandible, 4 in maxilla, 2 in both (1 unspecified). Possible risk factors or precipitating events, such as teeth extraction, oral surgery, dental implants, have been reported on 8/16 cases. Conclusions: Incidence of ONJ in RCC pts is largely underestimated in literature. In selected Italian centers, an unexpected rate of ONJ among RCC pts has been observed. We planned a new survey, enlarged to medical oncology units and oral care centers in all Italian regions.

Association of genetic markers in angiogenesis- or exposure-related genes with overall survival in pazopanib (P) treated patients (Pts) with advanced renal cell carcinoma.

303 Background: Pazopanib, an oral tyrosine kinase inhibitor of VEGFR, PDGFR and c-Kit, has been approved for the treatment of advanced renal cell cancer (RCC). Interindividual variability in response and survival is observed among advanced RCC pts treated with P. Our previous analyses showed that germline variants in angiogenesis (IL8, HIF1A, VEGFA)- and exposure (NR1IR)-related genes may predict progression free survival and/or response rate to P monotherapy (ASCO 2010 abstract 4520). This study sought to test the hypothesis that differences in overall survival (OS) can be explained, at least in part, by germline genetic variants in angiogenesis- and/or exposure-related genes. Methods: Twenty-seven functional polymorphisms within 13 genes were evaluated in 241 P treated pts with advanced RCC from a phase III study (ESMO 2010 abstract LBA22) and a single arm Phase II study. Genetic association with OS was analyzed using the Cox proportional hazards model. Results: Six polymorphisms in IL8, FGFR2, VEGFA, FLT4, and NR1I2 showed nominally significant association with OS (p≤0.05). A median OS of 29.6 months was observed in pts carrying wild-type IL8 2767 AA genotype (n=68, 31%), compared to 14.8 months in those with the TT variant genotype (n=36, 16%) (HR (95%CI) = 2.3 (1.4, 3.9) for TT vs. AA, p=0.002]. The median OS for pts who were heterozygous for this IL8 polymorphism was 23.9 months (n=119, 53%). The FGFR2 IVS2 + 906C>T variant TT genotype was associated with inferior OS compared with the wild-type CC genotype (median OS, 21.4 vs. 28.0 months, HR (95%CI) = 2.0 (1.2, 3.2), p=0.009). Similarly, shorter OS was observed for the VEGFA −1154G>A variant AA genotype compared with the wild-type GG genotype [median OS, 16.7 vs. 25.3 months, HR (95%CI) = 2.2 (1.3, 3.6), p=0.004]. The variant genotypes of the NR1IR (−25385C>T) and FLT4 (1480A>G) polymorphisms were also associated with reduced OS (p<0.05). Conclusions: Germline variants in angiogenesis- and exposure-related genes may be associated with survival outcome for P monotherapy in pts with advanced RCC. These associations are considered exploratory and require confirmation in an independent dataset. [Table: see text]

Management and outcome of venous thromboembolic events (VTEs) during sunitinib treatment

14625 Background: Sunitinib (SU) is a multi target tyrosine kinase inhibitor approved by FDA and EMEA in Renal Cell Cancer (RCC) and Gastric intestinal stromal tumor (GIST). SU has not been reported to increase the rate of VTEs in RCC, GIST. VTEs’ management and outcome under SU treatment is unknown. We reviewed cases of VTEs in RCC, GIST and NSCLC pts treated with SU. Methods: RCC, GIST and NSCLC pts treated with SU in prospective clinical trials at Institut Gustave Roussy (IGR) were analyzed to assess the risk of VTEs rate and identify predisposing factors. SU was given at 50 mg/d 4 wks out of 6, as a 2nd or 3rd line in GIST, as maintenance therapy after 4 cycles of paclitaxel-carboplatin in NSCLC and in RCC pts after cytokine failure. Key exclusions criteria of these trials were: pts with history of thrombosis within 6 months, brain metastasis, PS WHO>1, or squamous cell lung cancer. Diagnoses of symptomatic pulmonary embolism (PE) confirmed by CT pulmonary angiography were centrally reviewed. Results: Between Aug.05 and Oct.06, 72 pts were included (21 GIST, 8 NSCLC, 43 RCC). Baseline characteristics were (RCC/GIST/NSCLC): female 23%/57%/50%, mean age 54/54/51yrs, PS 0: 84%/57%/38%, indwelling central venous catheters (ICVC) 0%/0%/100%, bone metastases: 11%/0%/75%, liver metastases: 76 %/28%/37%. None has history of previous cancer or surgery within 1 yr. Five pts (6.9%, 95%CI: 3.0–15.2%) developed symptomatic PE., 3 in NSCLC pts (37%), 1 in RCC (2%) and 1 in GIST (5%). PE occurred early aftersunitinib initiation (4 wks in 2 pts, 6 wks in 2 pts, 10 wks in 1 pt). In case of PE, SU was interrupted in NSCLC but continued in GIST and RCC pts. All 5 PE were treated with low molecular weight heparin (LMWH). In 1 pt (GIST), LMWH was discontinued after 4 months due to a grade 3 esophageal hemorrhage (peptic esophagitis) but SU was maintained for 3 additional months untill disease progression. In 1 pt (RCC), LMWH and SU were maintained for up to 24 months. Conclusions: The incidence of symptomatic PE among pts treated with SU was within the expected range for cancer patients receiving chemotherapy, but PE occurred early after SU initiation. Concomitant SU and LMWH treatment is feasible but might expose to severe hemorrhage. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Oncology Pfizer Oncology

The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access trial in North America: Safety and efficacy

5011 Background: A prior phase III trial (TARGETs) demonstrated that sorafenib (SOR) doubled median progression-free survival versus placebo in previously treated clear cell renal cell cancer (RCC) patients (pts). The ARCCS trial made SOR available to a broader range of RCC pts through an expanded access program. Methods: This open-label, nonrandomized trial enrolled pts with advanced RCC not eligible for, or without access to, other SOR clinical trials; ECOG PS 0–2 with waivers granted for pts with ECOG PS 3–4; age =15 yrs; and adequate prior treatment of brain metastases. Major exclusion criteria included treatment <4 wks prior, life expectancy <2 mos, uncontrolled hypertension, and severe renal impairment requiring dialysis. Objectives were to analyze the safety and efficacy (response by RECIST) of 400 mg bid SOR in a community-based setting. Enrollment ceased on 12/20/05 when SOR became commercially available in the US, and those with no prior therapy or non-clear cell RCC continued in an extension protocol. Enrollment completed in Canada in 8/06. Results: A total of 2488 pts were valid for safety: 69% male with median age 63 yrs and most (83%) had prior nephrectomy; histologies included 78% clear-cell, 7% papillary, 1% chromophobe, and <1% collecting duct and oncocytoma. Median time from diagnosis for all pts was 1.4 yrs (range <1–34). Of those pts receiving prior therapy (n=1249), treatments included interferon alfa (54%), interleukin 2 (43%), bevacizumab (23%), thalidomide (12%), and sunitinib (2%). Grade 3 and 4 adverse events occurring in > 2% pts were hand- foot skin reaction 7.2%, fatigue 5.3%, hypertension 4.4%, rash/desquamation 4%, dehydration and dyspnea 2.7%, and diarrhea 2.5%. Efficacy assessment, mainly PFS, was limited by the short median time (14 wks) on study due to many pts enrolling during the last 2 months of the study. Of 1,850 pts evaluable for response, 17.5% had unconfirmed PR. One (0.1%), 67 (3.6%), 1479 (79.9%) and 303 (16.4%) had CR, PR, SD, and PD, respectively. Conclusions: ARCCS pts were representative of the broader range of RCC pts in the community including those excluded from previous SOR trials. Toxicity and response rates were similar to those reported previously, supporting the generalizability of the phase III trial data. [Table: see text]

Adjuvant low-dose interleukin-2 (IL2) plus interferone-alpha (IFN) in operable renal cell cancer (RCC). A phase III, randomized, multicenter, independent trial of the Italian Oncology Group for Clinical Research (GOIRC)

LBA5028 Background: For pts with non-metastatic RCC, no standard adjuvant treatment exists. Immunotherapy (IT) using IFN and/or IL2 is effective in metastatic disease setting. Low and chronically repeated doses of IL2 plus IFN induce a persistent stimulation of the immune system with no relevant toxicity. Methods: From July1994 to March 2006, surgically treated RCC pts were randomized to the following arms: A) low-dose IT; B) control arm. IT consisted of a 4-week cycle of s.c. IL2 (5 days/wk, 1 million UI/sqm bid d 1,2 and 1 million UI/sqm × 1 d 3,4,5) + IFN (1,8 million UI/sqm d 3,5 of each week). Cycles were repeated every 4 months for the first 2 years and every 6 months for the remaining 3 years. Each patient received 12 cycles in 5 years. Inclusion criteria were as follows: histological diagnosis of RCC, age <75 yrs, radical or partial nephrectomy within the past 3 months, pT1 (diameter of T > 2,5 cm), T2, T3 a-b-c; pN0-pN3, M0; good cardiac and renal function and no autoimmune disease. Based on a planned sample size of 320 pts, the trial was designed to have a 80% power to detect a 15% improvement in 5-year survival. Results: A total of 310 pts were randomized: 157 on arm A, 153 on arm B. Pts characteristics were well balanced between the two arms. At a median follow-up of 52 months, 77 pts relapsed: 35 in arm A and 42 in arm B. In the first 5 years of observation, disease free survival (DFS) curves were similar in the two arms, but diverged thereafter. DFS at 5 and 10 years was 0.73 and 0.73 in arm A vs 0.73 and 0.60 in arm B with an estimated Hazard Ratio (HR) of 0.84 (95% CI: 0.54–1.33 p=0.47). Efficacy of IT was more evident in patients with good PS (HR 0.78; 0.47–1.30 p=0.35); age<60 yrs (HR 0.61; 0.31–1.19 p=0.15), and low tumor grade (HR 0.70; 0.38–1.27 p=0.24). As for overall survival, 59 deaths were observed with no differences between the two arms. Toxicity was mild and limited to WHO grade 1 or 2 in the majority of cases. Conclusions: Low-dose adjuvant IL2+IFN is feasible in RCC and seems to reduce the risk of recurrence after 5 years from diagnosis. Follow-up update is still ongoing. No significant financial relationships to disclose.

Phase I study of isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 given as three-times weekly oral dose in patients (pts) with advanced solid tumors

3007 Background: MGCD0103 is a novel isotype-selective inhibitor of human HDACs. Deacetylation of histones by HDACs is postulated to inactivate tumor suppressor genes leading to neoplastic transformation. Inhibition of these enzymes might restore normal growth control. Methods: A phase I trial of MGCD0103, given as a three-times weekly oral dose 2 out of every 3 weeks, has been performed in pts with advanced solid tumors. Main endpoints are safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) assessments of HDAC activity and histone acetylation status in buffy coat white cells. Results: Five dose levels have been evaluated (mg/m2): 12.5, 20, 27, 36, and 45. As of January, 2006, 28 pts have been enrolled with the following demographics: M:F = 18:10; median age (range) = 60 (29–75); ECOG 0:1:2 = 9:13:1 (n = 23); primary tumor sites: colorectal (8), renal (5), lung (4), others (11); prior chemotherapy, radiotherapy, immunotherapy were given to 22, 12 and 2 pts, respectively (n=23). A total of 62 cycles have been administered, with median = 2 and range=1–7 cycles. MGCD0103 has been well tolerated; most common AEs (23 pts): grade 1–3 fatigue (91% of pts), grade 1–2 nausea and vomiting (70 and 48%), anorexia (26%), constipation (39%). Disease stabilization > 2 cycles has been observed in 3 renal cell cancer pts (4, 6, and 7 cycles) and 1 colorectal cancer pt (4 cycles). Preliminary PK analyses demonstrated intra-pt PK variability, however co-administration of acidic carbonated beverage (protocol amendment) appears to reduce variability without altering average Cmax or AUC (0–24) comparing Day 1 with Day 14. There was little accumulation or decrease in concentrations with extended dosing, and t1/2 was dose-independent at 7.7–11.3 hr. (±0.6–1.6). PD data reveal dose-dependent maximal inhibition of HDAC activity in patients co-administered an acidic beverage. Conclusions: At doses evaluated MGCD0103 appears tolerated and exhibits favourable PK and PD. [Table: see text]

Summary of results in patients with metastatic renal cell cancer (RCC) from phase I studies of RAD001 (everolimus)

14599 Background: Activation of mammalian target of rapamycin (mTOR) is implicated in the pathogenesis of RCC. Hereditary RCC in tuberous sclerosis pts is associated with loss of function of TS complex genes and resultant activation of mTOR. In non-hereditary RCC, mutation of VHL reduces opposition to mTOR-dependant upregulation of HIF. HIF-1α stimulates growth-factor-mediated activities (VEGF, PDGF, TGFα) supporting tumor-growth and proliferation. RAD001, an orally bioavailable inhibitor of mTOR, could have a role in the treatment of pts with RCC. Methods: All pts with metastatic RCC treated in two phase 1 studies of RAD001 in advanced solid cancer were reviewed. Changes in tumor were assessed using RECIST. Results: There were 12 pts (8.2% of total study population) with histology of clear cell (10 pts), papillary (1 pt), sarcomatoid (1 pt). Dosing was either weekly (20 mg:1 pt, 50 mg:2 pts, 70 mg:4 pts) or daily (10 mg:5 pts). 8 pts were male, 4 female. Median age 60 yrs (range: 44–76). Baseline performance status (WHO) was 0 (2 pts) or 1 (10 pts). Metastatic sites included lung (9 pts), bone (7 pts), liver (2 pts). 10 pts had failed prior drug therapy including IL-2 (2 pts), bevacizumab & erlotinib (7 pts), others (5 pts). Most frequent suspected drug reactions (3 pts or more) were: fatigue, diarrhea, rash, anorexia, mucositis, nausea, abdominal distension, vomiting, headache. Gr.3 events in single pts comprised: hypertriglyceridemia, hyperglycemia, epistaxis with prolonged bleeding time. 6 pts were progression-free at 6 months, 4 pts beyond 12 months (max. 20 months ongoing). Partial response apparent in 1 pt (papillary) on D334 is ongoing at D502. Conclusions: Advanced RCC pts can benefit from RAD001 as indicated by prolonged stable disease in half the cohort. Tumor shrinkaqe may appear only after several months of treatment. Toxicity is mostly mild and similar to patients with other tumor types. Further studies of RAD001 in pts with RCC are planned. [Table: see text]

Carbonic Anhydrase IX (CAIX) expression predicts for renal cell cancer (RCC) patient response and survival to IL-2 therapy

4512 Background: RCC response to IL-2 Rx and patient (pt) survival have been correlated to histology including the presence of clear cell and alveolar and the absence of papillary and granular features (Upton et al Proc ASCO, 2003) and CAIX expression (Bui et al Clin Ca Res 2003;9:802). In an effort to confirm and expand these findings we undertook a nested case-control study within the Upton cohort. Methods: Paraffin-embedded tissue sections of RCC were immunostained with an Ab to CAIX and expression levels were correlated with pathology findings, clinical outcome and the Upton model relating them. The percentage of CAIX positive tumor cells was utilized to separate high (> 85%) vs low (≤ 85%) expressers. Results: Tissue specimens were obtained from 66 pts (51M, 15F). 27 of the selected pts (41%) had responded (10CR/17PR) to IL-2. 24 (36%), 31 (47%) and 11 (17%) were classified as good, intermediate, and poor prognosis according to the Upton model. 41 specimens (62%) had high CAIX expression. 21 of 27 (78%) responding pts had high CAIX expression compared to 20/39 (51%) non-responders (OR=3.3; p=0.04); a similar survival benefit was seen (p=0.04). Survival >5 yrs was seen only in high CAIX expressors. High CAIX staining was associated with better pathology prognosis, and when stratified by group, the ORs of CAIX expression were unequal across groups (p=0.08) . The stongest association was in the intermediate group where 9/9 responders has high CAIX expression vs.11/22 non-responders, suggesting a possible refinement of the Upton model. A resultant group with good pathology or intermediate pathology and high CAIX contained 26 of 27 (96%) responders compared to only 18/39 (46%) non-responders (OR=30; p<0.01). Survival benefit was also seen (p< 0.01). Conclusions: We conclude that CAIX expression is an important predictor of outcome in RCC pts receiving IL-2-based Rx and can enhance prognostic information obtained from pathology specimens. While this refinement to the pathology model requires validation, data suggest that IL-2 Rx might ultimately be reserved for pts with Upton model good pathology alone or intermediate pathology and high CAIX staining. No significant financial relationships to disclose.