Poor-risk Renal Cell Carcinoma Research Articles

First-line dual immune checkpoint inhibitor therapies versus combination therapies comprising immune checkpoint inhibitors and tyrosine kinase inhibitors for advanced renal cell carcinoma: a comparative analysis of the effectiveness using real-world data.

There are few comparative studies on dual immune checkpoint inhibitors (ICIs) (i.e., IO-IO) and combination therapies comprising ICIs plus tyrosine kinase inhibitors (TKIs) (i.e., IO-TKI) for advanced renal cell carcinoma (RCC), especially in real-world settings. We retrospectively evaluated data of 175 patients with IMDC intermediate-risk or poor-risk RCC; as first-line therapy, 103 received IO-IO, and 72 received IO-TKI. An inverse probability of treatment weighting (IPTW) analysis was conducted to balance patients' backgrounds in the IO-IO and IO-TKI groups. Based on the IPTW analysis, progression-free survival (PFS) was longer in the IO-TKI group than in the IO-IO group (median: 15.6 vs. 8.3months; p = 0.0386). In contrast, overall survival was not different between groups (median: 46.7 vs. 49.0months; p = 0.465). Although the IPTW-adjusted objective response rate was not significantly different (51.2% vs. 43.9%; p = 0.359), the progressive disease rate as the best overall response was lower in the IO-TKI group than in the IO-IO group (3.3% vs. 27.4%; p < 0.0001). Regarding the safety profile, the treatment interruption rate was higher in the IO-TKI group than in the IO-IO group (70.3% vs. 49.2%; p = 0.005). In contrast, the IO-IO group had a higher corticosteroid administration rate (43.3% vs. 20.3%; p = 0.001). IO-TKI therapy exhibited superior effectiveness over IO-IO therapy in terms of PFS improvement and immediate disease progression prevention and was associated with a higher risk of treatment interruption and a lower risk of needing corticosteroids.

Trials in progress: TAM kinase inhibitor PF-07265807 and sasanlimab plus axitinib in patients with advanced or metastatic renal cell carcinoma—A phase 1, open-label, pharmacokinetic, safety and tolerability study.

TPS743 Background: Tumor-associated macrophage kinases (TAMK) are expressed on tumor cells during malignant transformation. Inhibition of AXL and MERTK, members of the TAMK family, may lower the immune activation threshold and promote antitumor immunity. PF-07265807 (ARRY-067) is a small-molecule inhibitor of MERTK and AXL showing antitumor activity in preclinical models as monotherapy or combined with anti-programmed cell death protein 1 (anti-PD-1) antibodies (ab). Sasanlimab is an anti-PD-1 ab with acceptable safety profile being tested (300 mg SC Q4W, Phase 3) in non-muscle invasive bladder cancer. Axitinib is a VEGF inhibitor approved (single agent and combined with anti-PD-1 inhibitors) for advanced renal cell carcinoma (RCC). This first-in-human Phase 1, open-label, multi-center study (NCT04458259) will evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of PF-07265807 in patients (pts) with advanced or metastatic solid tumors as a single agent and in combination with sasanlimab with or without axitinib. We describe here the dose escalation (Part 3) and dose expansion (Part 4) for the triplet combination of PF-07265807 + sasanlimab + axitinib. Methods: Eligible participants for the triplet cohorts are adult pts with confirmed unresectable advanced or metastatic clear cell RCC, with estimated creatinine clearance ≥30 mL/min and urinary protein &lt;2+ or ≥2+ but 24-h urine protein:creatinine ratio &lt;2 g/24 h. Pts for Part 4 need to have intermediate and poor risk RCC and no prior systemic therapy for metastatic disease. Other key eligibility criteria: measurable disease by RECIST 1.1 or non-measurable disease, ECOG PS 0–2, adequate bone marrow and liver function, and resolved acute effects of prior therapy. Each cycle is 21 days. Part 3 will determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of PF-07265807 in triplet therapy using a Bayesian logistic regression model and the escalation with overdose control principle. After the MTD/RP2D is identified, Part 4 will further evaluate the safety and preliminary efficacy of PF-07265807 combined with sasanlimab and axitinib. Treatment with study drug will continue until disease progression, consent withdrawal, or unacceptable toxicity, whichever occurs first. Primary endpoints of Part 3 are incidence of dose-limiting toxicities, adverse events (AE), and laboratory (lab) abnormalities. For Part 4, the primary endpoints are objective response rate and complete response rate; secondary endpoints include disease control rate; time-to-event endpoints; AEs; lab abnormalities; concentrations of PF-07265807 and its metabolite, sasanlimab, and axitinib; and incidence and titer of anti-sasanlimab anti-drug antibodies response. The study started in late 2020 and is recruiting. Clinical trial information: NCT04458259 .

Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced clear cell renal cell (HCRN GU16-260-Cohort A): Final report.

288 Background: Nivolumab (nivo) is FDA approved for patients (pts) with VEGFR TKI-resistant RCC and the nivo + ipilimumab (nivo/ipi) combination is FDA approved for treatment naïve pts with IMDC intermediate and poor risk renal cell carcinoma (RCC). Little information was available on the efficacy and toxicity of nivo monotherapy in treatment naïve RCC or the efficacy of nivo/ipi salvage in pts with tumors resistant to initial nivo monotherapy. Methods: Eligible pts with treatment naïve RCC received nivo 240mg IV q2 wk x 6 doses followed by 360mg IV q3 wk x 4 doses followed by 480 mg q4 wk until progressive disease (PD), toxicity, or completion of 96 wks of treatment (Part A). Pts with PD prior to, or stable disease (SD) at 48 wks (pSD) were potentially eligible to receive salvage nivo (3mg/kg)/ipi (1 mg/kg) q3 wk x 4 doses followed by q4 wk nivo maintenance for up to 48 wks (Part B). All pts were required to submit tissue from a metastatic lesion obtained within 12 months (mos) prior to study entry and prior to Part B for correlative studies. Results: 123 pts with clear cell(cc) RCC were enrolled between 5/2017 and 12/2019 at 12 participating HCRN sites. Data lock was 04/07/2021. Median Follow-up 26.9 mos. Median age 65 (32-86) years; 72% male. IMDC risk: favorable (Fav) 35 (28%), intermediate (I) 76 (62%) and poor (P) 12 (10%). 22 (18%) had a component of sarcomatoid histology (SARC). RECIST defined ORR was: 34.1% (25.8-43.2%) (CR 6.5%, PR 27.6%), SD 47 (35.8%). ORR by irRECIST was 39%. ORR by IMDC was: Fav 20/35 (57.1%) (39-74%), (I/P) 22/88 (25%) and for SARC 36.4%. ORR by PD-L1 status was 21/78 (27%), 8/16 (50%) and 6/8 (75%) for pts with tumor PD-L1 of 0, 1-20 or &gt; 20%, respectively (trend test p-value 0.002). 5/7 (71.4%) Fav pts with PD-L1 &gt; 1 responded. Median DOR was 27.6 (13.7, NA) mos with 26/42 responders including 17/20 (85%) with Fav Risk remaining progression free. Median PFS was 8.2 (5.5, 10.9) mos; (30.3 for IMDC Fav and 5.4 for I/P). 91 pts remain alive with 24 mos OS rate of 78%. 65 patients (59 PD, 6 pSD) were potentially eligible for salvage nivo/ipi (Part B), but 25 did not enroll due to symptomatic PD (6), grade 3-4 toxicity on nivo (17), or other (2) and 5 were not treated due to inability to confirm residual disease on a biopsy. ORR for Part B by RECIST was 11.4% (4/35) and by irRECIST 17.2%. Grade 3-5 treatment-related AEs (TrAE) (not including asymptomatic amylase/lipase) were seen in 20.3% in Part A and 14.2% in Part B with 1 death in each cohort. Conclusions: Nivo monotherapy is active in treatment naïve ccRCC across all IMDC groups. Although efficacy appears less than combination nivo/ipi in I/P pts, Fav pts had a notably high ORR and DOR. Efficacy appeared to correlate with tumor PD-L1 status, although at least half the responders had a tumor PD-L1 of 0. Salvage treatment with nivo/ipi after nivo was frequently not feasible and of limited benefit. Clinical trial information: NCT03117309.

A Multi-institutional, Retrospective Analysis of Patients with Metastatic Renal Cell Carcinoma to Bone Treated with Combination Ipilimumab and Nivolumab.

Bone metastases (BM) in renal cell carcinoma (RCC) patients are associated with poor outcomes. There are limited published data on outcomes in these patients with immunotherapy agents. We present a multi-institutional, retrospective analysis of metastatic RCC patients with BM treated with ipilimumab and nivolumab (I + N). Patient, tumor, and treatment-related variables were retrospectively collected from electronic medical records of patients with a histologically confirmed diagnosis of RCC and at least one radiographically confirmed BM prior to initiation of I + N. Best objective response was assessed by clinical chart review, imaging reports, and treating physician evaluation; progression-free survival (PFS) and overall survival (OS) were recorded as of 31 December 2020. Descriptive statistics were used to summarize patient characteristics and BM-related variables. Kaplan-Meier method and Mantel-Haenszel log-rank test were used to compare survival among groups. Cox regression univariable and multivariable models were used to correlate patient- and treatment-related variables to outcomes. Eighty patients with RCC and BM treated with I + N were identified. Patients were predominantly male and Caucasian presenting primarily with IMDC intermediate or poor-risk clear-cell RCC. Best response to I + N was progressive disease (46%), stable disease (28%), partial response (21%), and not evaluable (5%). Median PFS was 6.1 months (95% CI 3.8-8.9 months) with the majority of patients (65%) discontinuing I + N due to disease progression. Median OS was 25.6 months (95% CI 14.9-NA) with median follow-up of 25.2 months. A multivariable regression model for PFS showed several variables to be significantly associated with worse PFS including female gender [p = 0.02; hazard ratio (HR) 2.16; 95% CI 1.14-4.12], metastases to other sites (p = 0.006; HR 2.12; 95% CI 1.24-3.62) and presence of BM to ribs (p = 0.0007; HR 2.61; 95% CI 1.50-4.52). A multivariable Cox model of OS showed no prior radiation therapy to BM (p = 0.02; HR 2.17; 95% CI 1.13-4.17) and presence of liver metastases (p = 0.0006; HR 3.19; 95% CI 1.65-6.19) to be significantly associated with worse OS. RCC patients with ≥ 1 BM who received I + N therapy had a relatively low response rate, PFS, and OS. Strategies to improve outcomes in this subset of patients are needed.

Are immune checkpoint combination therapies for intermediate and poor risk renal cell carcinoma better than immune checkpoint inhibitors combined with kinase inhibitors?

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA (D F McDermott); and Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA (M B Atkins) [email protected]

Pembrolizumab plus axitinib and nivolumab plus ipilimumab as first-line treatments of advanced intermediate- or poor-risk renal-cell carcinoma: a number needed to treat analysis from the Brazilian private perspective

Background Considering clinical benefits of new combination therapies for metastatic renal-cell carcinoma (mRCC), this study aims to calculate the number needed to treat (NTT) and the cost of preventing an event (COPE) for pembrolizumab plus axitinib (P + A), and nivolumab plus ipilimumab (N + I) as first-line treatments, from the Brazilian private perspective. Methods Overall survival (OS) and progression-free survival (PFS) data for intermediate- and poor-risk groups were obtained from KEYNOTE-426 and CHECKMATE-214 trials for P + A and N + I, respectively, versus sunitinib as mRCC first-line treatment. Results Considering a 12-month time horizon, 6 patients should be treated with P + A to prevent one death with sunitinib use, resulting in a COPE of 3,893,903 BRL. Using N + I, NNT for 12-month OS rate was 13 compared to sunitinib, with a COPE of 6,357,965 BRL. Regarding PFS data, NNT was also 6 when comparing P + A versus sunitinib, with an estimated COPE of 3,893,903 BRL. Estimated NNT was 20 comparing N + I and sunitinib, resulting in a COPE of 10,172,744 BRL. Cost differences between two treatment options, reached more than 6 million BRL for PFS, and 2 million BRL for OS. Conclusion At the 12-month landmark, P + A suggests better economic scenario versus N + I as first-line mRCC treatment option for intermediate- and poor-risk groups, through an indirect comparison using sunitinib as a common comparator.

PDG5 Updated Lifetime Survival Estimates for Nivolumab+ipilimumab in Previously Untreated Advanced/Metastatic Intermediate- or Poor-Risk Renal Cell Carcinoma (1L aRCC)

PDG5 Updated Lifetime Survival Estimates for Nivolumab+ipilimumab in Previously Untreated Advanced/Metastatic Intermediate- or Poor-Risk Renal Cell Carcinoma (1L aRCC)

Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced renal cell carcinoma (RCC) (HCRN GU16-260).

5006 Background: Nivolumab (nivo) is FDA approved for pts with VEGFR TKI-resistant RCC and the nivo + ipilimumab (nivo/ipi) combination is FDA approved for treatment naïve pts with IMDC intermediate and poor risk RCC. Little information is available on the efficacy and toxicity of nivo monotherapy in treatment naïve RCC or the efficacy of nivo/ipi salvage therapy in pts with tumors resistant to initial nivo monotherapy. Methods: Eligible pts with treatment naïve RCC received nivo 240mg IV q2 wk x 6 doses followed by 360mg IV q3 wk x 4 doses followed by 480 mg q4 wk until progressive disease (PD), toxicity, or completion of 96 wks of treatment (Part A). Pts with PD prior to or stable disease (SD) at 48 wks (pSD) were potentially eligible to receive salvage nivo (3mg/kg) /ipi (1 mg/kg) q3 wk x 4 doses followed by q4 wk nivo maintenance for up to 48 wks (Part B). All pts were required to submit tissue from a metastatic lesion obtained within 12 months (mo) prior to study entry and prior to Part B. Pathology specimens will be analyzed by immunohistochemistry, quantitative immunofluorescence, WES and RNAseq with results linked to clinical outcome. Results: 123 pts with clear cell(cc) RCC were enrolled between 5/2017 and 12/2019 at 12 participating HCRN sites. Median age 65 (range 32-86 years); 72% male. IMDC favorable 30 (25%), intermediate 79 (65%) and poor risk 12 (10%). 22 (18%) had a component of sarcomatoid histology (SARC). 117 pts are currently evaluable for response. RECIST defined ORR was: 34 (29.3%)[CR 5 (4.3%), PR 29 (24.8%)], SD 47 (40.2%), PD 36 (30.7%). ORR by irRECIST was 35%. ORR by IMDC was: favorable 12/29 (41.4%), intermediate/poor 22/87 (25.3%) and for SARC 6/22 (27.3%). Median DOR is 13.8 (10.9, NA) mo. Median PFS is 7.4 (5.5, 10.9) mo. 110 pts remain alive. 60 pts (54 PD, 6 pSD) to date were potentially eligible for salvage nivo/ipi (Part B), but 28 did not enroll due to symptomatic PD (17), grade 3-4 toxicity on nivo (8), other (3). 27 of 32 Part B pts are currently evaluable for efficacy and 30 for toxicity. Best response to nivo/ipi was PR (11%), SD (30%), PD (59%). ORR by irRECIST was 19%. Grade 3-5 Treatment-related AEs (TrAE) were seen in 35/123 (28)% on nivo with 1 death due to respiratory failure. Grade 3-4 TrAE were seen in 10/30 (33%) on nivo/ipi with 0 deaths. Correlative studies are pending. Conclusions: Nivo monotherapy is active in treatment naïve ccRCC across all IMDC groups. Toxicity is consistent with prior nivo studies. Salvage treatment with nivo/ipi after nivo monotherapy was feasible in 53% of pts with PD/pSD, with 11% responding. Clinical trial information: NCT03117309 .

A phase II pilot study of the efficacy and safety of nivolumab and ipilimumab in T1aN0M0 renal cell carcinoma patients ineligible for surgical treatment.

TPS769 Background: Surgery remains the standard curative-intent therapy for localized renal cell carcinoma (RCC). Thus, systemic therapy for RCC should only be considered in patients who have contraindications to surgery. The phase 3 CheckMate 214 trial showed that a combination of nivolumab and ipilimumab has a significant impact on tumor burden in intermediate- and poor-risk metastatic RCC patients with a complete response rate of 11%. Median time to objective response was 2.8 months. Among all complete responders to nivolumab plus ipilimumab in the intention-to-treat population, 5% achieved a complete response at the first scan. We hypothesize that this combination could eliminate the primary tumor in T1aN0M0 patients ineligible for surgical treatment. Methods: This is a prospective, multicenter, non-randomized phase 2 pilot study. Patients with biopsy-proven clear-cell RCC of ≤4 cm (cT1a), no evidence of any metastases, and unable to have surgery or other nephron-sparing interventions (ablation) for any reason (functional single kidney with a central, high-complexity RCC, high risk of nephrectomy and dialysis, patients with complex coagulation disorders, etc.) or with preference to have no surgery or intervention for any reason will receive combination of ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, and nivolumab (240 mg intravenously) every 2 weeks during 16 weeks. The primary endpoint is complete response rate. Simon's two-stage design (Simon, 1989) is used. The null hypothesis that the true complete response rate is 11% will be tested against a one-sided alternative. This design yields a type I error rate of 0.05 and power of 0.9 when the true complete response rate is 60% (alternative hypothesis). In the first stage, 3 patients will be accrued. If there are no complete responses in these 3 patients, the study will be stopped. Otherwise, 5 additional patients will be accrued for a total of 8. The null hypothesis will be rejected if 3 or more responses are observed in 8 patients. Clinical trial information: NCT04134182.

A Cost-Effectiveness Analysis of Nivolumab and Ipilimumab Versus Sunitinib in First-Line Intermediate- to Poor-Risk Advanced Renal Cell Carcinoma.

The treatment paradigm of advanced renal cell carcinoma (RCC) has changed rapidly in recent years. In first-line treatment of intermediate- to poor-risk patients, the CheckMate 214 study demonstrated a significant survival advantage for nivolumab and ipilimumab versus sunitinib. The high cost of combined immune-modulating agents warrants an understanding of the combination's value by considering both efficacy and cost. The objective of this study was to estimate the cost-effectiveness of nivolumab and ipilimumab compared with sunitinib for first-line treatment of intermediate- to poor-risk advanced RCC from the U.S. payer perspective. A Markov model was developed to compare the costs and effectiveness of nivolumab and ipilimumab with those of sunitinib in the first-line treatment of intermediate- to poor-risk advanced RCC. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Drug costs were based on Medicare reimbursement rates in 2017. We extrapolated survival beyond the trial closure using Weibull distribution. Model robustness was addressed in univariable and probabilistic sensitivity analyses. The total mean cost per-patient of nivolumab and ipilimumab versus sunitinib was $292,308 and $169,287, respectfully. Nivolumab and ipilimumab generated a gain of 0.978 QALYs over sunitinib. The incremental cost-effectiveness ratio (ICER) for nivolumab and ipilimumab was $125,739/QALY versus sunitinib. Our analysis established that the base case ICER in the model for nivolumab and ipilimumab versus sunitinib is below what some would consider the upper limit of the theoretical willingness-to-pay threshold in the U.S. ($150,000/QALY) and is thus estimated to be cost-effective. This article assessed the cost-effectiveness of nivolumab and ipilimumab versus sunitinib for treatment of patients with intermediate- to poor-risk metastatic kidney cancer, from the U.S. payer perspective. It would cost $125,739 to gain 1 quality-adjusted life-year with nivolumab and ipilimumab versus sunitinib in these patients.

Role of immunotherapy in kidney cancer.

To summarize current knowledge on promising immunotherapeutic agents and to provide a brief outline of current use of immunotherapeutic agents in patients with locally advanced or metastatic renal cell carcinoma (RCC). Immunotherapy with mAbs directed against programed death cell protein 1, programed death-ligand 1 (PD-L1) and cytotoxic T-Lymphocyte Antigen 4 has become new first-line standard of care for moderate and poor-risk metastatic RCC patients. Similarly, the combination immune-oncology treatment and vascular endothelial growth factor (VEGF) mAbs also showed promising results in first-line therapy despite relative data immaturity. Finally, immune-oncology monotherapy (nivolumab) already represents second or third-line standard of care after tyrosine kinase inhibitor failure. Combination immune-oncology therapy represents the standard of care for management of intermediate-to-poor risk clear cell metastatic RCC. In addition, combination of immune-oncology and anti-VEGF antibody represents a treatment option across all risk levels in patient with elevated PD-L1 expression. Finally, nivolumab is one of two ideal treatment options in second-line clear cell metastatic RCC patients.

Retrospective review of cytotoxic chemotherapy and anti-angiogenic combinations in renal cell carcinoma: A single institution experience.

523 Background: Despite many therapeutic advances, Renal Cell Carcinoma (RCC) still is a leading cause of cancer morbidity and mortality. A recent phase 2 study has examined the combination of Sunitinib and Gemcitabine in a poor risk RCC trial population (Michaelson et al., Cancer 2015). There is limited data on such combinations in a non-clinical trial population. This retrospective study examines our institutional experience in treating predominantly high risk RCC patients with a combination of gemcitabine and an anti-angiogenic agent. Methods: IRB approval was obtained in order to review pathological and clinical data of RCC patients. A retrospective cohort was identified of RCC patients treated with Gemcitabine as well as an anti-angiogenic agent (Sunitinib or Pazopanib) between January 2011 and December 2015 at the Winship Cancer Institute at Emory University. Patient data was reviewed for clinical and pathological characteristics, treatments, prognostic factors, and tolerance. Kaplan Meier analysis was used to assess treatment associated time-to-disease progression (TTP) and overall survival (OS). Results: 12 patients received Gemcitabine and either Sunitinib (n=11) or Pazopanib (n=1). Clear cell (n=5) and non-clear cell varieties including papillary (n=5), chromophobe (n=1), and collecting duct (n=1) RCC were represented. The median line of therapy was 2 (range 0-5 prior therapies). 50% of patients were poor risk, 33% were intermediate risk, and 17% of patients had good risk disease by Heng Criteria. The overall median TTP was 2.9 months (range 0.82-16.5 months) and overall median OS was 8.3 months (range 2.3-16.5 months). This regimen was well tolerated with the most common adverse effects being fatigue in 50% (6/12) of patients, fever in 33% (4/12) of patients, and nausea in 33% (4/12) of patients. Conclusions: Our experience suggests that this combination is effective in advanced and heavily pretreated RCC patients, including poor risk RCC patients outside of a clinical trial format. Additional prospective data using similar combinations, may provide improved outcomes of RCC patients, especially with non-clear cell RCC patients.

Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK.Cancer. 2015 Oct 1;121(19):3435-43. [Epub 2015 Jun 8]. doi: 10.1002/cncr.29503.

BackgroundSarcomatoid renal cell carcinoma (RCC) is associated with an aggressive biology and a poor prognosis. Poor-risk RCC is defined by clinical prognostic factors and demonstrates similarly aggressive behavior. No standard treatment exists for patients with sarcomatoid RCC, and treatment options for patients with poor-risk disease are of limited benefit. The objective of this study was to investigate the efficacy of antiangiogenic therapy in combination with cytotoxic chemotherapy in clinically aggressive RCC. MethodsThis was a phase 2, single-arm trial of sunitinib and gemcitabine in patients with sarcomatoid or poor-risk RCC. The primary end point was the objective response rate (ORR). Secondary end points included the time to progression (TTP), overall survival (OS), safety, and biomarker correlatives. ResultsOverall, 39 patients had sarcomatoid RCC, and 33 had poor-risk RCC. The ORR was 26% for patients with sarcomatoid RCC and 24% for patients with poor-risk RCC. The median TTP and OS for patients with sarcomatoid RCC were 5 and 10 months, respectively. For patients with poor-risk disease, the median TTP and OS were 5.5 and 15 months, respectively. Patients whose tumors had>10% sarcomatoid histology had a higher clinical benefit rate (ORR plus stable disease) than those with≤10% sarcomatoid histology (P = 0.04). The most common grade 3 or higher treatment-related adverse events included neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7). ConclusionsThese results suggest that antiangiogenic therapy and cytotoxic chemotherapy are an active and well-tolerated combination for patients with aggressive RCC. The combination may be more efficacious than either therapy alone and is currently under further investigation.

Poor Risk Advanced Renal Cell Carcinoma: Outcomes from a Registry in a Tertiary Cancer Center.

Background:Poor-risk advanced Renal cell carcinoma (RCC) are an under-evaluated and difficult to treat subset of patients with poor prognosis. While Temsirolimus is the approved first line therapy for this category, Tyrosine kinase inhibitors (TKIs) are also commonly uses as initial treatment. We present an analysis of poor-risk advanced RCC treated in our institute.Materials and Methods:Patients diagnosed as poor-risk (as per Heng criteria) advanced RCC from June 2008 to December 2015 were analysed for baseline demographics, treatment received, toxicity (primarily Grade 3 and Grade 4), response rates (RR) and survival.Results:60 patients (43 males, 17 females) with a median age of 53 years were included for final analysis. Median ECOG PS was 1, clear cell was the predominant histology (63.3%), and 46.7% of patients had greater than 2 sites of metastases. Sorafenib, Sunitinib, Temsirolimus and Pazopanib were used to treat 43.3%, 36.7%, 8.3% and 6.7% of patients respectively, while 3 patients were offered upfront best supportive care. Common adverse events included skin rash (31.5%), HFS (Grade 2 and 3 – 30.8%), mucositis (26.3%), hypertension (24.5%), and dyslipidaemias (22.8%). 41 patients were available for response – overall response rate observed was 15%, while clinical benefit rate was 50%. Median progression free survival was 5.78 months (4.67-6.89) and median overall survival (OS) was 10.05 months (7.31-12.79).Conclusion:A majority of poor-risk metastatic RCC patients in our study were treated with TKIs and the survival outcomes appear to suggest that this strategy is a feasible alternative to Temsirolimus in the Indian setting.

Serum Lactate Dehydrogenase Predicts for Overall Survival Benefit in Patients With Metastatic Renal Cell Carcinoma Treated With Inhibition of Mammalian Target of Rapamycin

Lactate dehydrogenase (LDH) is an enzyme involved in anaerobic glycolysis and regulated by the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR)-containing complex 1 (PI3K/Akt/TORC1) pathway as well as tumor hypoxia/necrosis. High serum LDH levels are associated with poor prognosis in patients with cancer, including renal cell carcinoma (RCC). We tested whether serum LDH is prognostic and has predictive value in patients with metastatic RCC receiving an mTOR inhibitor. We evaluated pretreatment and post-treatment serum LDH in 404 poor-risk patients with RCC treated with the TORC1 inhibitor temsirolimus or interferon alfa in an international phase III randomized trial. The proportional hazards model was used to test for the prognostic and predictive association of LDH in predicting overall survival (OS). Mean baseline serum normalized LDH was 1.23 times the upper limit of normal (ULN; range, 0.05 to 28.5 × ULN). The multivariable hazard ratio for death was 2.81 (95% CI, 2.01 to 3.94; P < .001) for patients with LDH more than 1 × ULN versus patients with LDH ≤ 1 × ULN. The LDH-treatment interaction term was statistically significant for OS (P = .016). Among 140 patients with LDH above the ULN, OS was significantly improved with temsirolimus (6.9 v 4.2 months; P < .002). Among 264 patients with normal LDH, OS was not significantly improved with temsirolimus as compared with interferon therapy (11.7 v 10.4 months; P = .514). Serum LDH is a prognostic and a predictive biomarker for the survival benefit conferred by TORC1 inhibition in poor-risk RCC. Further investigation of the predictive role of LDH as a measure of benefit with PI3K/TORC1 pathway inhibition in other RCC risk groups and other tumor types is warranted.

Serum lactate dehydrogenase (LDH) as a biomarker for survival with mTOR inhibition in patients with metastatic renal cell carcinoma (RCC).

4631 Background: No predictive biomarkers currently exist in GU cancers. LDH is an enzyme detectable in serum that is often elevated in multiple cancers including RCC, has prognostic importance and is regulated by the PI3 kinase/Akt/mTOR pathway and tumor hypoxia/necrosis. We sought to evaluate pretreatment LDH as a predictive biomarker in patients with metastatic RCC. Methods: We evaluated pretreatment and post-treatment serum LDH in 404 poor-risk RCC subjects treated with the mTOR inhibitor temsirolimus or interferon alpha (IFN) in an international phase III randomized trial. Kaplan-Meier estimator and the proportional hazards model were used to examine the association of LDH with overall survival. Results: Mean baseline serum normalized LDH was 1.23 times the upper limit of normal (range 0.05 to 28.5x ULN). Among 140 subjects with elevated LDH, survival was significantly improved with temsirolimus (6.9 vs. 4.2 months, log- rank p<0.002). Among 264 subjects with normal LDH, survival was not improved with temsirolimus as compared to interferon therapy (11.7 vs. 10.4 months, log-rank p=0.514). There was a statistically significant interaction effect noted between normalized LDH and treatment group (p=0.031). The hazard ratio (HR) for death was 1.98 (95% confidence interval (CI) 1.6-2.5, p<0.0001) for patients with LDH>1x ULN compared to patients whose LDH ≤ 1x ULN. Adjusting for known prognostic factors, the HR for death was 2.01 for patients with LDH>1 ULN vs. ≤1 ULN (95% CI=1.6-2.6, p<0.0001). Post- treatment LDH at 2 months increased 1.7% vs. 27% in the IFN and temsirolimus arms, respectively. A decline in LDH with therapy was prognostic of OS (p<0.0001) but this association was weak (HR=1.00). Conclusions: Serum LDH is a potential pretreatment predictive biomarker for the survival benefit conferred by mTOR inhibition in patients with poor risk RCC. Further investigation of the predictive role of LDH as a measure of benefit with mTOR inhibition in other RCC risk groups and other tumor types is warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer-Wyeth, Wyeth Pfizer Pfizer, Wyeth

A phase I dose-finding study of sunitinib (SU) in combination with gemcitabine (G) in patients (pts) with advanced solid tumors

14522 Background: Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor that shows significant antitumor activity in renal cell carcinoma (RCC) and other cancers. This study assessed the maximum tolerated dose (MTD), safety and pharmacokinetic (PK) profile of SU in combination with G in advanced solid tumor pts. Methods: Pts received escalating oral doses of SU (25–50 mg/day) on a 6-week (wk) cycle (4 wks on, 2 wks off treatment; 4/2 schedule) with G (750–1250 mg/m2) IV over 30 min on Days 1, 8, 22, and 29. Subsequently, patients received SU on a 3-wk cycle (2 wks on, 1 wk off; 2/1 schedule) with G on Days 1 and 8. Safety was evaluated using adverse event (AE) reports and laboratory analyses. Objective responses were assessed by RECIST; PK data were analyzed at each dose level. Results: 34 pts (most common tumor types: RCC, n=19; pancreatic, n=11) received SU+G, including 8 pts on Schedule 4/2 and 26 pts on Schedule 2/1. Schedule 4/2 was not pursued beyond the initial dose level. On schedule 2/1, MTD has not yet been reached, and enrollment continues at the highest dose level (SU 50 mg/day + G 1250 mg/m2). On Schedule 2/1, grade (Gr) 4 non-hematologic AEs included myocardial infarction (n=1) and pulmonary embolism (n=1), neither considered related to study treatment. Gr 4 laboratory abnormalities included thrombocytopenia (n=1) and neutropenia (n=6), with no instances of febrile neutropenia. Evidence of antitumor efficacy has been observed on both schedules, in pts with pancreatic or renal cancer. Among 9 pts with poor-risk or sarcomatoid RCC, 5 pts exhibited partial responses and 3 had stable disease, across different dose levels. At all dose levels analyzed to date, the Cmax and AUC of the drugs and their metabolites following combination therapy were similar to those following single-agent SU or G dosing; these data indicate that there are no clinically significant drug-drug interactions during co-administration. Conclusions: Combination therapy with SU and G in pts with advanced solid tumors is well tolerated, does not result in significant drug-drug interactions, and is associated with notable antitumor activity. The efficacy and safety of this combination will be studied further in disease-specific clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Bayer, Genentech, Pfizer, Wyeth Pfizer Pfizer, Wyeth Pfizer